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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Vitamin D and cognitive function: A Mendelian randomisation study</title><author><name sortKey="Maddock, Jane" sort="Maddock, Jane" uniqKey="Maddock J" first="Jane" last="Maddock">Jane Maddock</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000000122478951</institution-id><institution-id institution-id-type="GRID">grid.14105.31</institution-id><institution>MRC Lifelong Health and Ageing at UCL,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Zhou, Ang" sort="Zhou, Ang" uniqKey="Zhou A" first="Ang" last="Zhou">Ang Zhou</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8994 5086</institution-id><institution-id institution-id-type="GRID">grid.1026.5</institution-id><institution>Centre for Population Health Research, Sansom Institute, University of South Australia,</institution></institution-wrap>Adelaide, Australia</nlm:aff></affiliation></author><author><name sortKey="Cavadino, Alana" sort="Cavadino, Alana" uniqKey="Cavadino A" first="Alana" last="Cavadino">Alana Cavadino</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2171 1133</institution-id><institution-id institution-id-type="GRID">grid.4868.2</institution-id><institution>Wolfson Institute of Preventive Medicine, Queen Mary University of London,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Ku Ma, El Bieta" sort="Ku Ma, El Bieta" uniqKey="Ku Ma E" first="El Bieta" last="Ku Ma">El Bieta Ku Ma</name><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8024</institution-id><institution-id institution-id-type="GRID">grid.8391.3</institution-id><institution>University of Exeter Medical School,</institution></institution-wrap>Exeter, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Bao, Yanchun" sort="Bao, Yanchun" uniqKey="Bao Y" first="Yanchun" last="Bao">Yanchun Bao</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0942 6946</institution-id><institution-id institution-id-type="GRID">grid.8356.8</institution-id><institution>Institute for Social and Economic Research (ISER), University of Essex,</institution></institution-wrap>Colchester, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Smart, Melissa C" sort="Smart, Melissa C" uniqKey="Smart M" first="Melissa C." last="Smart">Melissa C. Smart</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0942 6946</institution-id><institution-id institution-id-type="GRID">grid.8356.8</institution-id><institution>Institute for Social and Economic Research (ISER), University of Essex,</institution></institution-wrap>Colchester, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Saum, Kai Uwe" sort="Saum, Kai Uwe" uniqKey="Saum K" first="Kai-Uwe" last="Saum">Kai-Uwe Saum</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0492 0584</institution-id><institution-id institution-id-type="GRID">grid.7497.d</institution-id><institution>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ),</institution></institution-wrap>Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Schottker, Ben" sort="Schottker, Ben" uniqKey="Schottker B" first="Ben" last="Schöttker">Ben Schöttker</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0492 0584</institution-id><institution-id institution-id-type="GRID">grid.7497.d</institution-id><institution>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ),</institution></institution-wrap>Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2190 4373</institution-id><institution-id institution-id-type="GRID">grid.7700.0</institution-id><institution>Network Aging Research (NAR), University of Heidelberg,</institution></institution-wrap>Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="Aff9">Institute of Health Care and Social Sciences, FOM University, Essen, Germany</nlm:aff></affiliation></author><author><name sortKey="Engmann, Jorgen" sort="Engmann, Jorgen" uniqKey="Engmann J" first="Jorgen" last="Engmann">Jorgen Engmann</name><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Department of Epidemiology and Public Health, University College London,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Kj Rgaard, Marie" sort="Kj Rgaard, Marie" uniqKey="Kj Rgaard M" first="Marie" last="Kj Rgaard">Marie Kj Rgaard</name><affiliation><nlm:aff id="Aff11"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4689 5540</institution-id><institution-id institution-id-type="GRID">grid.412244.5</institution-id><institution>Division of Internal Medicine, University Hospital of North Norway,</institution></institution-wrap>Tromsø, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="Aff12"><institution-wrap><institution-id institution-id-type="ISNI">0000000122595234</institution-id><institution-id institution-id-type="GRID">grid.10919.30</institution-id><institution>Endocrinology Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway,</institution></institution-wrap>Tromsø, Norway</nlm:aff></affiliation></author><author><name sortKey="Karhunen, Ville" sort="Karhunen, Ville" uniqKey="Karhunen V" first="Ville" last="Karhunen">Ville Karhunen</name><affiliation><nlm:aff id="Aff13"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Center for Life Course Health Research, University of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff14"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4685 4917</institution-id><institution-id institution-id-type="GRID">grid.412326.0</institution-id><institution>Oulu University Hospital,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Zhan, Yiqiang" sort="Zhan, Yiqiang" uniqKey="Zhan Y" first="Yiqiang" last="Zhan">Yiqiang Zhan</name><affiliation><nlm:aff id="Aff15"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1937 0626</institution-id><institution-id institution-id-type="GRID">grid.4714.6</institution-id><institution>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,</institution></institution-wrap>Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Lehtim Ki, Terho" sort="Lehtim Ki, Terho" uniqKey="Lehtim Ki T" first="Terho" last="Lehtim Ki">Terho Lehtim Ki</name><affiliation><nlm:aff id="Aff16"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2314 6254</institution-id><institution-id institution-id-type="GRID">grid.5509.9</institution-id><institution>Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere,</institution></institution-wrap>Tampere, Finland</nlm:aff></affiliation></author><author><name sortKey="Rovio, Suvi P" sort="Rovio, Suvi P" uniqKey="Rovio S" first="Suvi P." last="Rovio">Suvi P. Rovio</name><affiliation><nlm:aff id="Aff17"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2097 1371</institution-id><institution-id institution-id-type="GRID">grid.1374.1</institution-id><institution>Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku,</institution></institution-wrap>Turku, Finland</nlm:aff></affiliation></author><author><name sortKey="Byberg, Liisa" sort="Byberg, Liisa" uniqKey="Byberg L" first="Liisa" last="Byberg">Liisa Byberg</name><affiliation><nlm:aff id="Aff18"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Surgical Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="Lahti, Jari" sort="Lahti, Jari" uniqKey="Lahti J" first="Jari" last="Lahti">Jari Lahti</name><affiliation><nlm:aff id="Aff19"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0410 2071</institution-id><institution-id institution-id-type="GRID">grid.7737.4</institution-id><institution>Department of Psychology and Logopedics, University of Helsinki,</institution></institution-wrap>Helsinki, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff20"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0410 2071</institution-id><institution-id institution-id-type="GRID">grid.7737.4</institution-id><institution>Helsinki Collegium for Advanced Studies, University of Helsinki,</institution></institution-wrap>Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Marques Vidal, Pedro" sort="Marques Vidal, Pedro" uniqKey="Marques Vidal P" first="Pedro" last="Marques-Vidal">Pedro Marques-Vidal</name><affiliation><nlm:aff id="Aff21"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0423 4662</institution-id><institution-id institution-id-type="GRID">grid.8515.9</institution-id><institution>Department of Medicine, Internal Medicine, Lausanne University Hospital,</institution></institution-wrap>Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Sen, Abhijit" sort="Sen, Abhijit" uniqKey="Sen A" first="Abhijit" last="Sen">Abhijit Sen</name><affiliation><nlm:aff id="Aff22"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 1516 2393</institution-id><institution-id institution-id-type="GRID">grid.5947.f</institution-id><institution>Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU),</institution></institution-wrap>Trondheim, Norway</nlm:aff></affiliation></author><author><name sortKey="Perna, Laura" sort="Perna, Laura" uniqKey="Perna L" first="Laura" last="Perna">Laura Perna</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0492 0584</institution-id><institution-id institution-id-type="GRID">grid.7497.d</institution-id><institution>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ),</institution></institution-wrap>Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Schirmer, Henrik" sort="Schirmer, Henrik" uniqKey="Schirmer H" first="Henrik" last="Schirmer">Henrik Schirmer</name><affiliation><nlm:aff id="Aff23"><institution-wrap><institution-id institution-id-type="ISNI">0000000122595234</institution-id><institution-id institution-id-type="GRID">grid.10919.30</institution-id><institution>Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway,</institution></institution-wrap>Tromsø, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="Aff24"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9637 455X</institution-id><institution-id institution-id-type="GRID">grid.411279.8</institution-id><institution>Department of Cardiology, Akershus University Hospital,</institution></institution-wrap>Lørenskog, Norway</nlm:aff></affiliation></author><author><name sortKey="Singh Manoux, Archana" sort="Singh Manoux, Archana" uniqKey="Singh Manoux A" first="Archana" last="Singh-Manoux">Archana Singh-Manoux</name><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Department of Epidemiology and Public Health, University College London,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="Aff25"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0206 8146</institution-id><institution-id institution-id-type="GRID">grid.413133.7</institution-id><institution>INSERM, U1018, Centre for Research in Epidemiology and Population Health, Hôpital Paul Brousse,</institution></institution-wrap>Villejuif, France</nlm:aff></affiliation></author><author><name sortKey="Auvinen, Juha" sort="Auvinen, Juha" uniqKey="Auvinen J" first="Juha" last="Auvinen">Juha Auvinen</name><affiliation><nlm:aff id="Aff13"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Center for Life Course Health Research, University of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff14"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4685 4917</institution-id><institution-id institution-id-type="GRID">grid.412326.0</institution-id><institution>Oulu University Hospital,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Hutri K Honen, Nina" sort="Hutri K Honen, Nina" uniqKey="Hutri K Honen N" first="Nina" last="Hutri-K Hönen">Nina Hutri-K Hönen</name><affiliation><nlm:aff id="Aff26"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2314 6254</institution-id><institution-id institution-id-type="GRID">grid.5509.9</institution-id><institution>Department of Pediatrics, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere,</institution></institution-wrap>Tampere, Finland</nlm:aff></affiliation></author><author><name sortKey="K Honen, Mika" sort="K Honen, Mika" uniqKey="K Honen M" first="Mika" last="K Hönen">Mika K Hönen</name><affiliation><nlm:aff id="Aff27"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2314 6254</institution-id><institution-id institution-id-type="GRID">grid.5509.9</institution-id><institution>Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere,</institution></institution-wrap>Tampere, Finland</nlm:aff></affiliation></author><author><name sortKey="Kilander, Lena" sort="Kilander, Lena" uniqKey="Kilander L" first="Lena" last="Kilander">Lena Kilander</name><affiliation><nlm:aff id="Aff28"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Public Health and Caring Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="R Ikkonen, Katri" sort="R Ikkonen, Katri" uniqKey="R Ikkonen K" first="Katri" last="R Ikkönen">Katri R Ikkönen</name><affiliation><nlm:aff id="Aff19"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0410 2071</institution-id><institution-id institution-id-type="GRID">grid.7737.4</institution-id><institution>Department of Psychology and Logopedics, University of Helsinki,</institution></institution-wrap>Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Melhus, H Kan" sort="Melhus, H Kan" uniqKey="Melhus H" first="H Kan" last="Melhus">H Kan Melhus</name><affiliation><nlm:aff id="Aff29"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Medical Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="Ingelsson, Erik" sort="Ingelsson, Erik" uniqKey="Ingelsson E" first="Erik" last="Ingelsson">Erik Ingelsson</name><affiliation><nlm:aff id="Aff29"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Medical Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</nlm:aff></affiliation><affiliation><nlm:aff id="Aff30"><institution-wrap><institution-id institution-id-type="ISNI">0000000419368956</institution-id><institution-id institution-id-type="GRID">grid.168010.e</institution-id><institution>Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine,</institution></institution-wrap>Stanford, California, USA</nlm:aff></affiliation></author><author><name sortKey="Guessous, Idris" sort="Guessous, Idris" uniqKey="Guessous I" first="Idris" last="Guessous">Idris Guessous</name><affiliation><nlm:aff id="Aff31"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0721 9812</institution-id><institution-id institution-id-type="GRID">grid.150338.c</institution-id><institution>Unit of Population Epidemiology, Division of Primary Care Medicine, Department of Community Medicine, Primary Care and Emergency Medicine, Geneva University Hospitals,</institution></institution-wrap>Geneva, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff32"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 6502</institution-id><institution-id institution-id-type="GRID">grid.189967.8</institution-id><institution>Department of Epidemiology, Rollins School of Public Health, Emory University,</institution></institution-wrap>Atlanta, Georgia, USA</nlm:aff></affiliation><affiliation><nlm:aff id="Aff33"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2165 4204</institution-id><institution-id institution-id-type="GRID">grid.9851.5</institution-id><institution>Department of Ambulatory Care and Community Medicine, University of Lausanne,</institution></institution-wrap>Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Petrovic, Katja E" sort="Petrovic, Katja E" uniqKey="Petrovic K" first="Katja E" last="Petrovic">Katja E. Petrovic</name><affiliation><nlm:aff id="Aff34"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8988 2476</institution-id><institution-id institution-id-type="GRID">grid.11598.34</institution-id><institution>Division of General Neurology, Department of Neurology, General Hospital and Medical University of Graz,</institution></institution-wrap>Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Schmidt, Helena" sort="Schmidt, Helena" uniqKey="Schmidt H" first="Helena" last="Schmidt">Helena Schmidt</name><affiliation><nlm:aff id="Aff35"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8988 2476</institution-id><institution-id institution-id-type="GRID">grid.11598.34</institution-id><institution>Research Unit for Genetic Epidemiology, Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz,</institution></institution-wrap>Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Schmidt, Reinhold" sort="Schmidt, Reinhold" uniqKey="Schmidt R" first="Reinhold" last="Schmidt">Reinhold Schmidt</name><affiliation><nlm:aff id="Aff36"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8988 2476</institution-id><institution-id institution-id-type="GRID">grid.11598.34</institution-id><institution>Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz,</institution></institution-wrap>Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Vollenweider, Peter" sort="Vollenweider, Peter" uniqKey="Vollenweider P" first="Peter" last="Vollenweider">Peter Vollenweider</name><affiliation><nlm:aff id="Aff21"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0423 4662</institution-id><institution-id institution-id-type="GRID">grid.8515.9</institution-id><institution>Department of Medicine, Internal Medicine, Lausanne University Hospital,</institution></institution-wrap>Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Lind, Lars" sort="Lind, Lars" uniqKey="Lind L" first="Lars" last="Lind">Lars Lind</name><affiliation><nlm:aff id="Aff29"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Medical Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="Eriksson, Johan G" sort="Eriksson, Johan G" uniqKey="Eriksson J" first="Johan G." last="Eriksson">Johan G. Eriksson</name><affiliation><nlm:aff id="Aff37"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0410 2071</institution-id><institution-id institution-id-type="GRID">grid.7737.4</institution-id><institution>Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, University of Helsinki,</institution></institution-wrap>Helsinki, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff38"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0409 6302</institution-id><institution-id institution-id-type="GRID">grid.428673.c</institution-id><institution>Folkhälsan Research Center,</institution></institution-wrap>Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Michaelsson, Karl" sort="Michaelsson, Karl" uniqKey="Michaelsson K" first="Karl" last="Michaëlsson">Karl Michaëlsson</name><affiliation><nlm:aff id="Aff18"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Surgical Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="Raitakari, Olli T" sort="Raitakari, Olli T" uniqKey="Raitakari O" first="Olli T." last="Raitakari">Olli T. Raitakari</name><affiliation><nlm:aff id="Aff17"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2097 1371</institution-id><institution-id institution-id-type="GRID">grid.1374.1</institution-id><institution>Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku,</institution></institution-wrap>Turku, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff39"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 215X</institution-id><institution-id institution-id-type="GRID">grid.410552.7</institution-id><institution>Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital,</institution></institution-wrap>Turku, Finland</nlm:aff></affiliation></author><author><name sortKey="H Gg, Sara" sort="H Gg, Sara" uniqKey="H Gg S" first="Sara" last="H Gg">Sara H Gg</name><affiliation><nlm:aff id="Aff15"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1937 0626</institution-id><institution-id institution-id-type="GRID">grid.4714.6</institution-id><institution>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,</institution></institution-wrap>Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Pedersen, Nancy L" sort="Pedersen, Nancy L" uniqKey="Pedersen N" first="Nancy L." last="Pedersen">Nancy L. Pedersen</name><affiliation><nlm:aff id="Aff15"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1937 0626</institution-id><institution-id institution-id-type="GRID">grid.4714.6</institution-id><institution>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,</institution></institution-wrap>Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Herzig, Karl Heinz" sort="Herzig, Karl Heinz" uniqKey="Herzig K" first="Karl-Heinz" last="Herzig">Karl-Heinz Herzig</name><affiliation><nlm:aff id="Aff40"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Research Unit of Biomedicine, University of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff41"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Biocenter Oulu, University of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff42"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4685 4917</institution-id><institution-id institution-id-type="GRID">grid.412326.0</institution-id><institution>Medical Research Center (MRC) and Oulu University Hospital,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff43"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2205 0971</institution-id><institution-id institution-id-type="GRID">grid.22254.33</institution-id><institution>Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences,</institution></institution-wrap>Poznan, Poland</nlm:aff></affiliation></author><author><name sortKey="J Rvelin, Marjo Riitta" sort="J Rvelin, Marjo Riitta" uniqKey="J Rvelin M" first="Marjo-Riitta" last="J Rvelin">Marjo-Riitta J Rvelin</name><affiliation><nlm:aff id="Aff13"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Center for Life Course Health Research, University of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff44"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2113 8111</institution-id><institution-id institution-id-type="GRID">grid.7445.2</institution-id><institution>Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London,</institution></institution-wrap>London, UK</nlm:aff></affiliation></author><author><name sortKey="Veijola, Juha" sort="Veijola, Juha" uniqKey="Veijola J" first="Juha" last="Veijola">Juha Veijola</name><affiliation><nlm:aff id="Aff42"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4685 4917</institution-id><institution-id institution-id-type="GRID">grid.412326.0</institution-id><institution>Medical Research Center (MRC) and Oulu University Hospital,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff45"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Research Unit of Clinical Neuroscience, Department of Psychiatry, University of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff46"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4685 4917</institution-id><institution-id institution-id-type="GRID">grid.412326.0</institution-id><institution>Department of Psychiatry, University Hospital of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Kivimaki, Mika" sort="Kivimaki, Mika" uniqKey="Kivimaki M" first="Mika" last="Kivimaki">Mika Kivimaki</name><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Department of Epidemiology and Public Health, University College London,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="Aff47"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0410 2071</institution-id><institution-id institution-id-type="GRID">grid.7737.4</institution-id><institution>Clinicum, University of Helsinki,</institution></institution-wrap>Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Jorde, Rolf" sort="Jorde, Rolf" uniqKey="Jorde R" first="Rolf" last="Jorde">Rolf Jorde</name><affiliation><nlm:aff id="Aff11"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4689 5540</institution-id><institution-id institution-id-type="GRID">grid.412244.5</institution-id><institution>Division of Internal Medicine, University Hospital of North Norway,</institution></institution-wrap>Tromsø, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="Aff12"><institution-wrap><institution-id institution-id-type="ISNI">0000000122595234</institution-id><institution-id institution-id-type="GRID">grid.10919.30</institution-id><institution>Endocrinology Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway,</institution></institution-wrap>Tromsø, Norway</nlm:aff></affiliation></author><author><name sortKey="Brenner, Hermann" sort="Brenner, Hermann" uniqKey="Brenner H" first="Hermann" last="Brenner">Hermann Brenner</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0492 0584</institution-id><institution-id institution-id-type="GRID">grid.7497.d</institution-id><institution>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ),</institution></institution-wrap>Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2190 4373</institution-id><institution-id institution-id-type="GRID">grid.7700.0</institution-id><institution>Network Aging Research (NAR), University of Heidelberg,</institution></institution-wrap>Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Kumari, Meena" sort="Kumari, Meena" uniqKey="Kumari M" first="Meena" last="Kumari">Meena Kumari</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0942 6946</institution-id><institution-id institution-id-type="GRID">grid.8356.8</institution-id><institution>Institute for Social and Economic Research (ISER), University of Essex,</institution></institution-wrap>Colchester, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Department of Epidemiology and Public Health, University College London,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Power, Chris" sort="Power, Chris" uniqKey="Power C" first="Chris" last="Power">Chris Power</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Llewellyn, David J" sort="Llewellyn, David J" uniqKey="Llewellyn D" first="David J." last="Llewellyn">David J. Llewellyn</name><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8024</institution-id><institution-id institution-id-type="GRID">grid.8391.3</institution-id><institution>University of Exeter Medical School,</institution></institution-wrap>Exeter, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Hypponen, Elina" sort="Hypponen, Elina" uniqKey="Hypponen E" first="Elina" last="Hyppönen">Elina Hyppönen</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8994 5086</institution-id><institution-id institution-id-type="GRID">grid.1026.5</institution-id><institution>Centre for Population Health Research, Sansom Institute, University of South Australia,</institution></institution-wrap>Adelaide, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="Aff48"><institution-wrap><institution-id institution-id-type="GRID">grid.430453.5</institution-id><institution>South Australian Health and Medical Research Institute,</institution></institution-wrap>Adelaide, Australia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">29038561</idno><idno type="pmc">5643555</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643555</idno><idno type="RBID">PMC:5643555</idno><idno type="doi">10.1038/s41598-017-13189-3</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000E42</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000E42</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Vitamin D and cognitive function: A Mendelian randomisation study</title><author><name sortKey="Maddock, Jane" sort="Maddock, Jane" uniqKey="Maddock J" first="Jane" last="Maddock">Jane Maddock</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000000122478951</institution-id><institution-id institution-id-type="GRID">grid.14105.31</institution-id><institution>MRC Lifelong Health and Ageing at UCL,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Zhou, Ang" sort="Zhou, Ang" uniqKey="Zhou A" first="Ang" last="Zhou">Ang Zhou</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8994 5086</institution-id><institution-id institution-id-type="GRID">grid.1026.5</institution-id><institution>Centre for Population Health Research, Sansom Institute, University of South Australia,</institution></institution-wrap>Adelaide, Australia</nlm:aff></affiliation></author><author><name sortKey="Cavadino, Alana" sort="Cavadino, Alana" uniqKey="Cavadino A" first="Alana" last="Cavadino">Alana Cavadino</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2171 1133</institution-id><institution-id institution-id-type="GRID">grid.4868.2</institution-id><institution>Wolfson Institute of Preventive Medicine, Queen Mary University of London,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Ku Ma, El Bieta" sort="Ku Ma, El Bieta" uniqKey="Ku Ma E" first="El Bieta" last="Ku Ma">El Bieta Ku Ma</name><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8024</institution-id><institution-id institution-id-type="GRID">grid.8391.3</institution-id><institution>University of Exeter Medical School,</institution></institution-wrap>Exeter, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Bao, Yanchun" sort="Bao, Yanchun" uniqKey="Bao Y" first="Yanchun" last="Bao">Yanchun Bao</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0942 6946</institution-id><institution-id institution-id-type="GRID">grid.8356.8</institution-id><institution>Institute for Social and Economic Research (ISER), University of Essex,</institution></institution-wrap>Colchester, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Smart, Melissa C" sort="Smart, Melissa C" uniqKey="Smart M" first="Melissa C." last="Smart">Melissa C. Smart</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0942 6946</institution-id><institution-id institution-id-type="GRID">grid.8356.8</institution-id><institution>Institute for Social and Economic Research (ISER), University of Essex,</institution></institution-wrap>Colchester, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Saum, Kai Uwe" sort="Saum, Kai Uwe" uniqKey="Saum K" first="Kai-Uwe" last="Saum">Kai-Uwe Saum</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0492 0584</institution-id><institution-id institution-id-type="GRID">grid.7497.d</institution-id><institution>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ),</institution></institution-wrap>Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Schottker, Ben" sort="Schottker, Ben" uniqKey="Schottker B" first="Ben" last="Schöttker">Ben Schöttker</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0492 0584</institution-id><institution-id institution-id-type="GRID">grid.7497.d</institution-id><institution>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ),</institution></institution-wrap>Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2190 4373</institution-id><institution-id institution-id-type="GRID">grid.7700.0</institution-id><institution>Network Aging Research (NAR), University of Heidelberg,</institution></institution-wrap>Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="Aff9">Institute of Health Care and Social Sciences, FOM University, Essen, Germany</nlm:aff></affiliation></author><author><name sortKey="Engmann, Jorgen" sort="Engmann, Jorgen" uniqKey="Engmann J" first="Jorgen" last="Engmann">Jorgen Engmann</name><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Department of Epidemiology and Public Health, University College London,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Kj Rgaard, Marie" sort="Kj Rgaard, Marie" uniqKey="Kj Rgaard M" first="Marie" last="Kj Rgaard">Marie Kj Rgaard</name><affiliation><nlm:aff id="Aff11"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4689 5540</institution-id><institution-id institution-id-type="GRID">grid.412244.5</institution-id><institution>Division of Internal Medicine, University Hospital of North Norway,</institution></institution-wrap>Tromsø, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="Aff12"><institution-wrap><institution-id institution-id-type="ISNI">0000000122595234</institution-id><institution-id institution-id-type="GRID">grid.10919.30</institution-id><institution>Endocrinology Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway,</institution></institution-wrap>Tromsø, Norway</nlm:aff></affiliation></author><author><name sortKey="Karhunen, Ville" sort="Karhunen, Ville" uniqKey="Karhunen V" first="Ville" last="Karhunen">Ville Karhunen</name><affiliation><nlm:aff id="Aff13"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Center for Life Course Health Research, University of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff14"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4685 4917</institution-id><institution-id institution-id-type="GRID">grid.412326.0</institution-id><institution>Oulu University Hospital,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Zhan, Yiqiang" sort="Zhan, Yiqiang" uniqKey="Zhan Y" first="Yiqiang" last="Zhan">Yiqiang Zhan</name><affiliation><nlm:aff id="Aff15"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1937 0626</institution-id><institution-id institution-id-type="GRID">grid.4714.6</institution-id><institution>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,</institution></institution-wrap>Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Lehtim Ki, Terho" sort="Lehtim Ki, Terho" uniqKey="Lehtim Ki T" first="Terho" last="Lehtim Ki">Terho Lehtim Ki</name><affiliation><nlm:aff id="Aff16"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2314 6254</institution-id><institution-id institution-id-type="GRID">grid.5509.9</institution-id><institution>Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere,</institution></institution-wrap>Tampere, Finland</nlm:aff></affiliation></author><author><name sortKey="Rovio, Suvi P" sort="Rovio, Suvi P" uniqKey="Rovio S" first="Suvi P." last="Rovio">Suvi P. Rovio</name><affiliation><nlm:aff id="Aff17"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2097 1371</institution-id><institution-id institution-id-type="GRID">grid.1374.1</institution-id><institution>Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku,</institution></institution-wrap>Turku, Finland</nlm:aff></affiliation></author><author><name sortKey="Byberg, Liisa" sort="Byberg, Liisa" uniqKey="Byberg L" first="Liisa" last="Byberg">Liisa Byberg</name><affiliation><nlm:aff id="Aff18"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Surgical Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="Lahti, Jari" sort="Lahti, Jari" uniqKey="Lahti J" first="Jari" last="Lahti">Jari Lahti</name><affiliation><nlm:aff id="Aff19"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0410 2071</institution-id><institution-id institution-id-type="GRID">grid.7737.4</institution-id><institution>Department of Psychology and Logopedics, University of Helsinki,</institution></institution-wrap>Helsinki, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff20"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0410 2071</institution-id><institution-id institution-id-type="GRID">grid.7737.4</institution-id><institution>Helsinki Collegium for Advanced Studies, University of Helsinki,</institution></institution-wrap>Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Marques Vidal, Pedro" sort="Marques Vidal, Pedro" uniqKey="Marques Vidal P" first="Pedro" last="Marques-Vidal">Pedro Marques-Vidal</name><affiliation><nlm:aff id="Aff21"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0423 4662</institution-id><institution-id institution-id-type="GRID">grid.8515.9</institution-id><institution>Department of Medicine, Internal Medicine, Lausanne University Hospital,</institution></institution-wrap>Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Sen, Abhijit" sort="Sen, Abhijit" uniqKey="Sen A" first="Abhijit" last="Sen">Abhijit Sen</name><affiliation><nlm:aff id="Aff22"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 1516 2393</institution-id><institution-id institution-id-type="GRID">grid.5947.f</institution-id><institution>Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU),</institution></institution-wrap>Trondheim, Norway</nlm:aff></affiliation></author><author><name sortKey="Perna, Laura" sort="Perna, Laura" uniqKey="Perna L" first="Laura" last="Perna">Laura Perna</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0492 0584</institution-id><institution-id institution-id-type="GRID">grid.7497.d</institution-id><institution>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ),</institution></institution-wrap>Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Schirmer, Henrik" sort="Schirmer, Henrik" uniqKey="Schirmer H" first="Henrik" last="Schirmer">Henrik Schirmer</name><affiliation><nlm:aff id="Aff23"><institution-wrap><institution-id institution-id-type="ISNI">0000000122595234</institution-id><institution-id institution-id-type="GRID">grid.10919.30</institution-id><institution>Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway,</institution></institution-wrap>Tromsø, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="Aff24"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9637 455X</institution-id><institution-id institution-id-type="GRID">grid.411279.8</institution-id><institution>Department of Cardiology, Akershus University Hospital,</institution></institution-wrap>Lørenskog, Norway</nlm:aff></affiliation></author><author><name sortKey="Singh Manoux, Archana" sort="Singh Manoux, Archana" uniqKey="Singh Manoux A" first="Archana" last="Singh-Manoux">Archana Singh-Manoux</name><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Department of Epidemiology and Public Health, University College London,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="Aff25"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0206 8146</institution-id><institution-id institution-id-type="GRID">grid.413133.7</institution-id><institution>INSERM, U1018, Centre for Research in Epidemiology and Population Health, Hôpital Paul Brousse,</institution></institution-wrap>Villejuif, France</nlm:aff></affiliation></author><author><name sortKey="Auvinen, Juha" sort="Auvinen, Juha" uniqKey="Auvinen J" first="Juha" last="Auvinen">Juha Auvinen</name><affiliation><nlm:aff id="Aff13"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Center for Life Course Health Research, University of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff14"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4685 4917</institution-id><institution-id institution-id-type="GRID">grid.412326.0</institution-id><institution>Oulu University Hospital,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Hutri K Honen, Nina" sort="Hutri K Honen, Nina" uniqKey="Hutri K Honen N" first="Nina" last="Hutri-K Hönen">Nina Hutri-K Hönen</name><affiliation><nlm:aff id="Aff26"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2314 6254</institution-id><institution-id institution-id-type="GRID">grid.5509.9</institution-id><institution>Department of Pediatrics, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere,</institution></institution-wrap>Tampere, Finland</nlm:aff></affiliation></author><author><name sortKey="K Honen, Mika" sort="K Honen, Mika" uniqKey="K Honen M" first="Mika" last="K Hönen">Mika K Hönen</name><affiliation><nlm:aff id="Aff27"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2314 6254</institution-id><institution-id institution-id-type="GRID">grid.5509.9</institution-id><institution>Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere,</institution></institution-wrap>Tampere, Finland</nlm:aff></affiliation></author><author><name sortKey="Kilander, Lena" sort="Kilander, Lena" uniqKey="Kilander L" first="Lena" last="Kilander">Lena Kilander</name><affiliation><nlm:aff id="Aff28"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Public Health and Caring Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="R Ikkonen, Katri" sort="R Ikkonen, Katri" uniqKey="R Ikkonen K" first="Katri" last="R Ikkönen">Katri R Ikkönen</name><affiliation><nlm:aff id="Aff19"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0410 2071</institution-id><institution-id institution-id-type="GRID">grid.7737.4</institution-id><institution>Department of Psychology and Logopedics, University of Helsinki,</institution></institution-wrap>Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Melhus, H Kan" sort="Melhus, H Kan" uniqKey="Melhus H" first="H Kan" last="Melhus">H Kan Melhus</name><affiliation><nlm:aff id="Aff29"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Medical Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="Ingelsson, Erik" sort="Ingelsson, Erik" uniqKey="Ingelsson E" first="Erik" last="Ingelsson">Erik Ingelsson</name><affiliation><nlm:aff id="Aff29"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Medical Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</nlm:aff></affiliation><affiliation><nlm:aff id="Aff30"><institution-wrap><institution-id institution-id-type="ISNI">0000000419368956</institution-id><institution-id institution-id-type="GRID">grid.168010.e</institution-id><institution>Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine,</institution></institution-wrap>Stanford, California, USA</nlm:aff></affiliation></author><author><name sortKey="Guessous, Idris" sort="Guessous, Idris" uniqKey="Guessous I" first="Idris" last="Guessous">Idris Guessous</name><affiliation><nlm:aff id="Aff31"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0721 9812</institution-id><institution-id institution-id-type="GRID">grid.150338.c</institution-id><institution>Unit of Population Epidemiology, Division of Primary Care Medicine, Department of Community Medicine, Primary Care and Emergency Medicine, Geneva University Hospitals,</institution></institution-wrap>Geneva, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff32"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 6502</institution-id><institution-id institution-id-type="GRID">grid.189967.8</institution-id><institution>Department of Epidemiology, Rollins School of Public Health, Emory University,</institution></institution-wrap>Atlanta, Georgia, USA</nlm:aff></affiliation><affiliation><nlm:aff id="Aff33"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2165 4204</institution-id><institution-id institution-id-type="GRID">grid.9851.5</institution-id><institution>Department of Ambulatory Care and Community Medicine, University of Lausanne,</institution></institution-wrap>Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Petrovic, Katja E" sort="Petrovic, Katja E" uniqKey="Petrovic K" first="Katja E" last="Petrovic">Katja E. Petrovic</name><affiliation><nlm:aff id="Aff34"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8988 2476</institution-id><institution-id institution-id-type="GRID">grid.11598.34</institution-id><institution>Division of General Neurology, Department of Neurology, General Hospital and Medical University of Graz,</institution></institution-wrap>Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Schmidt, Helena" sort="Schmidt, Helena" uniqKey="Schmidt H" first="Helena" last="Schmidt">Helena Schmidt</name><affiliation><nlm:aff id="Aff35"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8988 2476</institution-id><institution-id institution-id-type="GRID">grid.11598.34</institution-id><institution>Research Unit for Genetic Epidemiology, Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz,</institution></institution-wrap>Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Schmidt, Reinhold" sort="Schmidt, Reinhold" uniqKey="Schmidt R" first="Reinhold" last="Schmidt">Reinhold Schmidt</name><affiliation><nlm:aff id="Aff36"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8988 2476</institution-id><institution-id institution-id-type="GRID">grid.11598.34</institution-id><institution>Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz,</institution></institution-wrap>Graz, Austria</nlm:aff></affiliation></author><author><name sortKey="Vollenweider, Peter" sort="Vollenweider, Peter" uniqKey="Vollenweider P" first="Peter" last="Vollenweider">Peter Vollenweider</name><affiliation><nlm:aff id="Aff21"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0423 4662</institution-id><institution-id institution-id-type="GRID">grid.8515.9</institution-id><institution>Department of Medicine, Internal Medicine, Lausanne University Hospital,</institution></institution-wrap>Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Lind, Lars" sort="Lind, Lars" uniqKey="Lind L" first="Lars" last="Lind">Lars Lind</name><affiliation><nlm:aff id="Aff29"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Medical Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="Eriksson, Johan G" sort="Eriksson, Johan G" uniqKey="Eriksson J" first="Johan G." last="Eriksson">Johan G. Eriksson</name><affiliation><nlm:aff id="Aff37"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0410 2071</institution-id><institution-id institution-id-type="GRID">grid.7737.4</institution-id><institution>Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, University of Helsinki,</institution></institution-wrap>Helsinki, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff38"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0409 6302</institution-id><institution-id institution-id-type="GRID">grid.428673.c</institution-id><institution>Folkhälsan Research Center,</institution></institution-wrap>Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Michaelsson, Karl" sort="Michaelsson, Karl" uniqKey="Michaelsson K" first="Karl" last="Michaëlsson">Karl Michaëlsson</name><affiliation><nlm:aff id="Aff18"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Surgical Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="Raitakari, Olli T" sort="Raitakari, Olli T" uniqKey="Raitakari O" first="Olli T." last="Raitakari">Olli T. Raitakari</name><affiliation><nlm:aff id="Aff17"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2097 1371</institution-id><institution-id institution-id-type="GRID">grid.1374.1</institution-id><institution>Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku,</institution></institution-wrap>Turku, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff39"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 215X</institution-id><institution-id institution-id-type="GRID">grid.410552.7</institution-id><institution>Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital,</institution></institution-wrap>Turku, Finland</nlm:aff></affiliation></author><author><name sortKey="H Gg, Sara" sort="H Gg, Sara" uniqKey="H Gg S" first="Sara" last="H Gg">Sara H Gg</name><affiliation><nlm:aff id="Aff15"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1937 0626</institution-id><institution-id institution-id-type="GRID">grid.4714.6</institution-id><institution>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,</institution></institution-wrap>Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Pedersen, Nancy L" sort="Pedersen, Nancy L" uniqKey="Pedersen N" first="Nancy L." last="Pedersen">Nancy L. Pedersen</name><affiliation><nlm:aff id="Aff15"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1937 0626</institution-id><institution-id institution-id-type="GRID">grid.4714.6</institution-id><institution>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,</institution></institution-wrap>Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Herzig, Karl Heinz" sort="Herzig, Karl Heinz" uniqKey="Herzig K" first="Karl-Heinz" last="Herzig">Karl-Heinz Herzig</name><affiliation><nlm:aff id="Aff40"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Research Unit of Biomedicine, University of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff41"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Biocenter Oulu, University of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff42"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4685 4917</institution-id><institution-id institution-id-type="GRID">grid.412326.0</institution-id><institution>Medical Research Center (MRC) and Oulu University Hospital,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff43"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2205 0971</institution-id><institution-id institution-id-type="GRID">grid.22254.33</institution-id><institution>Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences,</institution></institution-wrap>Poznan, Poland</nlm:aff></affiliation></author><author><name sortKey="J Rvelin, Marjo Riitta" sort="J Rvelin, Marjo Riitta" uniqKey="J Rvelin M" first="Marjo-Riitta" last="J Rvelin">Marjo-Riitta J Rvelin</name><affiliation><nlm:aff id="Aff13"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Center for Life Course Health Research, University of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff44"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2113 8111</institution-id><institution-id institution-id-type="GRID">grid.7445.2</institution-id><institution>Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London,</institution></institution-wrap>London, UK</nlm:aff></affiliation></author><author><name sortKey="Veijola, Juha" sort="Veijola, Juha" uniqKey="Veijola J" first="Juha" last="Veijola">Juha Veijola</name><affiliation><nlm:aff id="Aff42"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4685 4917</institution-id><institution-id institution-id-type="GRID">grid.412326.0</institution-id><institution>Medical Research Center (MRC) and Oulu University Hospital,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff45"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Research Unit of Clinical Neuroscience, Department of Psychiatry, University of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff46"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4685 4917</institution-id><institution-id institution-id-type="GRID">grid.412326.0</institution-id><institution>Department of Psychiatry, University Hospital of Oulu,</institution></institution-wrap>Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Kivimaki, Mika" sort="Kivimaki, Mika" uniqKey="Kivimaki M" first="Mika" last="Kivimaki">Mika Kivimaki</name><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Department of Epidemiology and Public Health, University College London,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="Aff47"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0410 2071</institution-id><institution-id institution-id-type="GRID">grid.7737.4</institution-id><institution>Clinicum, University of Helsinki,</institution></institution-wrap>Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Jorde, Rolf" sort="Jorde, Rolf" uniqKey="Jorde R" first="Rolf" last="Jorde">Rolf Jorde</name><affiliation><nlm:aff id="Aff11"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4689 5540</institution-id><institution-id institution-id-type="GRID">grid.412244.5</institution-id><institution>Division of Internal Medicine, University Hospital of North Norway,</institution></institution-wrap>Tromsø, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="Aff12"><institution-wrap><institution-id institution-id-type="ISNI">0000000122595234</institution-id><institution-id institution-id-type="GRID">grid.10919.30</institution-id><institution>Endocrinology Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway,</institution></institution-wrap>Tromsø, Norway</nlm:aff></affiliation></author><author><name sortKey="Brenner, Hermann" sort="Brenner, Hermann" uniqKey="Brenner H" first="Hermann" last="Brenner">Hermann Brenner</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0492 0584</institution-id><institution-id institution-id-type="GRID">grid.7497.d</institution-id><institution>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ),</institution></institution-wrap>Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2190 4373</institution-id><institution-id institution-id-type="GRID">grid.7700.0</institution-id><institution>Network Aging Research (NAR), University of Heidelberg,</institution></institution-wrap>Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Kumari, Meena" sort="Kumari, Meena" uniqKey="Kumari M" first="Meena" last="Kumari">Meena Kumari</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0942 6946</institution-id><institution-id institution-id-type="GRID">grid.8356.8</institution-id><institution>Institute for Social and Economic Research (ISER), University of Essex,</institution></institution-wrap>Colchester, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Department of Epidemiology and Public Health, University College London,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Power, Chris" sort="Power, Chris" uniqKey="Power C" first="Chris" last="Power">Chris Power</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Llewellyn, David J" sort="Llewellyn, David J" uniqKey="Llewellyn D" first="David J." last="Llewellyn">David J. Llewellyn</name><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8024</institution-id><institution-id institution-id-type="GRID">grid.8391.3</institution-id><institution>University of Exeter Medical School,</institution></institution-wrap>Exeter, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Hypponen, Elina" sort="Hypponen, Elina" uniqKey="Hypponen E" first="Elina" last="Hyppönen">Elina Hyppönen</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8994 5086</institution-id><institution-id institution-id-type="GRID">grid.1026.5</institution-id><institution>Centre for Population Health Research, Sansom Institute, University of South Australia,</institution></institution-wrap>Adelaide, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health,</institution></institution-wrap>London, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="Aff48"><institution-wrap><institution-id institution-id-type="GRID">grid.430453.5</institution-id><institution>South Australian Health and Medical Research Institute,</institution></institution-wrap>Adelaide, Australia</nlm:aff></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">The causal nature of the association between hypovitaminosis D and poor cognitive function in mid- to later-life is uncertain. Using a Mendelian randomisation(MR) approach, we examined the causal relationship between 25(OH)D and cognitive function. Data came from 172,349 participants from 17 cohorts. <italic>DHCR7</italic>(rs12785878), <italic>CYP2R1</italic> rs12794714) and their combined <italic>synthesis score</italic> were chosen to proxy 25(OH)D. Cognitive tests were standardised into global and memory scores. Analyses were stratified by 25(OH)D tertiles, sex and age. Random effects meta-analyses assessed associations between 25(OH)D and cognitive function. Associations of serum 25(OH)D with global and memory-related cognitive function were non-linear (lower cognitive scores for both low and high 25(OH)D, <italic>p</italic><sub>curvature</sub> ≤ 0.006), with much of the curvature attributed to a single study. <italic>DHCR7</italic>, <italic>CYP2R1</italic>, and the <italic>synthesis score</italic> were associated with small reductions in 25(OH)D per vitamin D-decreasing allele. However, coefficients for associations with global or memory-related cognitive function were non-significant and in opposing directions for <italic>DHCR7</italic> and <italic>CYP2R1</italic>, with no overall association observed for the <italic>synthesis score</italic>. Coefficients for the <italic>synthesis score</italic> and global and memory cognition were similar when stratified by 25(OH)D tertiles, sex and age. We found no evidence for serum 25(OH)D concentration as a causal factor for cognitive performance in mid- to later life.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Prince, M" uniqKey="Prince M">M Prince</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smith, Ad" uniqKey="Smith A">AD Smith</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Annweiler, C" uniqKey="Annweiler C">C Annweiler</name></author><author><name sortKey="Beauchet, O" uniqKey="Beauchet O">O Beauchet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Annweiler, C" uniqKey="Annweiler C">C Annweiler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Balion, C" uniqKey="Balion C">C Balion</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Etgen, T" uniqKey="Etgen T">T Etgen</name></author><author><name sortKey="Sander, D" uniqKey="Sander D">D Sander</name></author><author><name sortKey="Bickel, H" uniqKey="Bickel H">H Bickel</name></author><author><name sortKey="Sander, K" uniqKey="Sander K">K Sander</name></author><author><name sortKey="Forstl, H" uniqKey="Forstl H">H Förstl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Garcion, E" uniqKey="Garcion E">E Garcion</name></author><author><name sortKey="Wion Barbot, N" uniqKey="Wion Barbot N">N Wion-Barbot</name></author><author><name sortKey="Montero Menei, Cn" uniqKey="Montero Menei C">CN Montero-Menei</name></author><author><name sortKey="Berger, F" uniqKey="Berger F">F Berger</name></author><author><name sortKey="Wion, D" uniqKey="Wion D">D Wion</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brown, J" uniqKey="Brown J">J Brown</name></author><author><name sortKey="Bianco, Ji" uniqKey="Bianco J">JI 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">29038561</article-id><article-id pub-id-type="pmc">5643555</article-id><article-id pub-id-type="publisher-id">13189</article-id><article-id pub-id-type="doi">10.1038/s41598-017-13189-3</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Vitamin D and cognitive function: A Mendelian randomisation study</article-title></title-group><contrib-group><contrib contrib-type="author" 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contrib-type="author"><name><surname>Herzig</surname><given-names>Karl-Heinz</given-names></name><xref ref-type="aff" rid="Aff40">40</xref><xref ref-type="aff" rid="Aff41">41</xref><xref ref-type="aff" rid="Aff42">42</xref><xref ref-type="aff" rid="Aff43">43</xref></contrib><contrib contrib-type="author"><name><surname>Järvelin</surname><given-names>Marjo-Riitta</given-names></name><xref ref-type="aff" rid="Aff13">13</xref><xref ref-type="aff" rid="Aff44">44</xref></contrib><contrib contrib-type="author"><name><surname>Veijola</surname><given-names>Juha</given-names></name><xref ref-type="aff" rid="Aff42">42</xref><xref ref-type="aff" rid="Aff45">45</xref><xref ref-type="aff" rid="Aff46">46</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-4699-5627</contrib-id><name><surname>Kivimaki</surname><given-names>Mika</given-names></name><xref ref-type="aff" rid="Aff10">10</xref><xref ref-type="aff" rid="Aff47">47</xref></contrib><contrib contrib-type="author"><name><surname>Jorde</surname><given-names>Rolf</given-names></name><xref ref-type="aff" rid="Aff11">11</xref><xref ref-type="aff" rid="Aff12">12</xref></contrib><contrib contrib-type="author"><name><surname>Brenner</surname><given-names>Hermann</given-names></name><xref ref-type="aff" rid="Aff7">7</xref><xref ref-type="aff" rid="Aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Kumari</surname><given-names>Meena</given-names></name><xref ref-type="aff" rid="Aff6">6</xref><xref ref-type="aff" rid="Aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Power</surname><given-names>Chris</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Llewellyn</surname><given-names>David J.</given-names></name><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Hyppönen</surname><given-names>Elina</given-names></name><address><email>elina.hypponen@unisa.edu.au</email></address><xref ref-type="aff" rid="Aff3">3</xref><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff48">48</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000000122478951</institution-id><institution-id institution-id-type="GRID">grid.14105.31</institution-id><institution>MRC Lifelong Health and Ageing at UCL,</institution></institution-wrap>London, United Kingdom</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health,</institution></institution-wrap>London, United Kingdom</aff><aff 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institution-id-type="ISNI">0000 0001 2314 6254</institution-id><institution-id institution-id-type="GRID">grid.5509.9</institution-id><institution>Department of Pediatrics, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere,</institution></institution-wrap>Tampere, Finland</aff><aff id="Aff27"><label>27</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2314 6254</institution-id><institution-id institution-id-type="GRID">grid.5509.9</institution-id><institution>Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere,</institution></institution-wrap>Tampere, Finland</aff><aff id="Aff28"><label>28</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Public Health and Caring Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</aff><aff id="Aff29"><label>29</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9457</institution-id><institution-id institution-id-type="GRID">grid.8993.b</institution-id><institution>Department of Medical Sciences, Uppsala University,</institution></institution-wrap>Uppsala, Sweden</aff><aff id="Aff30"><label>30</label><institution-wrap><institution-id institution-id-type="ISNI">0000000419368956</institution-id><institution-id institution-id-type="GRID">grid.168010.e</institution-id><institution>Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine,</institution></institution-wrap>Stanford, California, USA</aff><aff id="Aff31"><label>31</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0721 9812</institution-id><institution-id institution-id-type="GRID">grid.150338.c</institution-id><institution>Unit of Population Epidemiology, Division of Primary Care Medicine, Department of Community Medicine, Primary Care and Emergency Medicine, Geneva University Hospitals,</institution></institution-wrap>Geneva, Switzerland</aff><aff id="Aff32"><label>32</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 6502</institution-id><institution-id institution-id-type="GRID">grid.189967.8</institution-id><institution>Department of Epidemiology, Rollins School of Public Health, Emory University,</institution></institution-wrap>Atlanta, Georgia, USA</aff><aff id="Aff33"><label>33</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2165 4204</institution-id><institution-id institution-id-type="GRID">grid.9851.5</institution-id><institution>Department of Ambulatory Care and Community Medicine, University of Lausanne,</institution></institution-wrap>Lausanne, Switzerland</aff><aff id="Aff34"><label>34</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8988 2476</institution-id><institution-id institution-id-type="GRID">grid.11598.34</institution-id><institution>Division of General Neurology, Department of Neurology, General Hospital and Medical University of Graz,</institution></institution-wrap>Graz, Austria</aff><aff id="Aff35"><label>35</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8988 2476</institution-id><institution-id institution-id-type="GRID">grid.11598.34</institution-id><institution>Research Unit for Genetic Epidemiology, Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz,</institution></institution-wrap>Graz, Austria</aff><aff id="Aff36"><label>36</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8988 2476</institution-id><institution-id institution-id-type="GRID">grid.11598.34</institution-id><institution>Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz,</institution></institution-wrap>Graz, Austria</aff><aff id="Aff37"><label>37</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0410 2071</institution-id><institution-id institution-id-type="GRID">grid.7737.4</institution-id><institution>Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, University of Helsinki,</institution></institution-wrap>Helsinki, Finland</aff><aff id="Aff38"><label>38</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0409 6302</institution-id><institution-id institution-id-type="GRID">grid.428673.c</institution-id><institution>Folkhälsan Research Center,</institution></institution-wrap>Helsinki, Finland</aff><aff id="Aff39"><label>39</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 215X</institution-id><institution-id institution-id-type="GRID">grid.410552.7</institution-id><institution>Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital,</institution></institution-wrap>Turku, Finland</aff><aff id="Aff40"><label>40</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Research Unit of Biomedicine, University of Oulu,</institution></institution-wrap>Oulu, Finland</aff><aff id="Aff41"><label>41</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Biocenter Oulu, University of Oulu,</institution></institution-wrap>Oulu, Finland</aff><aff id="Aff42"><label>42</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4685 4917</institution-id><institution-id institution-id-type="GRID">grid.412326.0</institution-id><institution>Medical Research Center (MRC) and Oulu University Hospital,</institution></institution-wrap>Oulu, Finland</aff><aff id="Aff43"><label>43</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2205 0971</institution-id><institution-id institution-id-type="GRID">grid.22254.33</institution-id><institution>Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences,</institution></institution-wrap>Poznan, Poland</aff><aff id="Aff44"><label>44</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2113 8111</institution-id><institution-id institution-id-type="GRID">grid.7445.2</institution-id><institution>Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London,</institution></institution-wrap>London, UK</aff><aff id="Aff45"><label>45</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 4873</institution-id><institution-id institution-id-type="GRID">grid.10858.34</institution-id><institution>Research Unit of Clinical Neuroscience, Department of Psychiatry, University of Oulu,</institution></institution-wrap>Oulu, Finland</aff><aff id="Aff46"><label>46</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 4685 4917</institution-id><institution-id institution-id-type="GRID">grid.412326.0</institution-id><institution>Department of Psychiatry, University Hospital of Oulu,</institution></institution-wrap>Oulu, Finland</aff><aff id="Aff47"><label>47</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0410 2071</institution-id><institution-id institution-id-type="GRID">grid.7737.4</institution-id><institution>Clinicum, University of Helsinki,</institution></institution-wrap>Helsinki, Finland</aff><aff id="Aff48"><label>48</label><institution-wrap><institution-id institution-id-type="GRID">grid.430453.5</institution-id><institution>South Australian Health and Medical Research Institute,</institution></institution-wrap>Adelaide, Australia</aff></contrib-group><pub-date pub-type="epub"><day>16</day><month>10</month><year>2017</year></pub-date><pub-date pub-type="pmc-release"><day>16</day><month>10</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>7</volume><elocation-id>13230</elocation-id><history><date date-type="received"><day>24</day><month>5</month><year>2017</year></date><date date-type="accepted"><day>19</day><month>9</month><year>2017</year></date></history><permissions><copyright-statement>© The Author(s) 2017</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">The causal nature of the association between hypovitaminosis D and poor cognitive function in mid- to later-life is uncertain. Using a Mendelian randomisation(MR) approach, we examined the causal relationship between 25(OH)D and cognitive function. Data came from 172,349 participants from 17 cohorts. <italic>DHCR7</italic>(rs12785878), <italic>CYP2R1</italic> rs12794714) and their combined <italic>synthesis score</italic> were chosen to proxy 25(OH)D. Cognitive tests were standardised into global and memory scores. Analyses were stratified by 25(OH)D tertiles, sex and age. Random effects meta-analyses assessed associations between 25(OH)D and cognitive function. Associations of serum 25(OH)D with global and memory-related cognitive function were non-linear (lower cognitive scores for both low and high 25(OH)D, <italic>p</italic><sub>curvature</sub> ≤ 0.006), with much of the curvature attributed to a single study. <italic>DHCR7</italic>, <italic>CYP2R1</italic>, and the <italic>synthesis score</italic> were associated with small reductions in 25(OH)D per vitamin D-decreasing allele. However, coefficients for associations with global or memory-related cognitive function were non-significant and in opposing directions for <italic>DHCR7</italic> and <italic>CYP2R1</italic>, with no overall association observed for the <italic>synthesis score</italic>. Coefficients for the <italic>synthesis score</italic> and global and memory cognition were similar when stratified by 25(OH)D tertiles, sex and age. We found no evidence for serum 25(OH)D concentration as a causal factor for cognitive performance in mid- to later life.</p></abstract><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2017</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1" sec-type="introduction"><title>Introduction</title><p id="Par2">The profound effect of an ageing population is evidenced by estimates suggesting 65·7 million people worldwide will be affected by dementia by 2030, increasing to 115·4 million by 2050<sup><xref ref-type="bibr" rid="CR1">1</xref></sup>. The latency period from the onset of symptoms to clinical diagnosis is typically very long and cognitive changes can be observed decades before diagnosis<sup><xref ref-type="bibr" rid="CR2">2</xref></sup>. So, for the development of efficient primary prevention strategies, it is essential to identify risk factors that operate at the early pre-clinical stage.</p><p id="Par3">Hypovitaminosis D is hypothesised to be one such risk factor. Low 25-hydroxyvitamin D [25(OH)D] levels are prevalent in older individuals<sup><xref ref-type="bibr" rid="CR3">3</xref></sup>, and adults with cognitive difficulties have been shown to have hypovitaminosis D<sup><xref ref-type="bibr" rid="CR4">4</xref>–<xref ref-type="bibr" rid="CR6">6</xref></sup>. There is a biologically plausible link between vitamin D and cognitive function. The vitamin D receptor (VDR), vitamin D metabolites and enzymes required for vitamin D activation have been found in the brain and central nervous system<sup><xref ref-type="bibr" rid="CR7">7</xref></sup>. Additionally, experimental studies have demonstrated that active vitamin D may influence brain and neuron development<sup><xref ref-type="bibr" rid="CR8">8</xref></sup>, and have neuroprotective potential and antioxidant effects<sup><xref ref-type="bibr" rid="CR7">7</xref></sup>. Studies on VDR knockout mice have demonstrated that hypovitaminosis D may play a role in accelerated ageing, behavioural, social, motor and sensory deficits<sup><xref ref-type="bibr" rid="CR9">9</xref>–<xref ref-type="bibr" rid="CR12">12</xref></sup>, all of which can contribute to cognitive decline.</p><p id="Par4">A number of observational studies have linked hypovitaminosis D with cognitive impairment and/or dementia<sup><xref ref-type="bibr" rid="CR5">5</xref>,<xref ref-type="bibr" rid="CR6">6</xref>,<xref ref-type="bibr" rid="CR13">13</xref>,<xref ref-type="bibr" rid="CR14">14</xref></sup>. In 2012, a meta-analysis including eight cross-sectional studies (<italic>n</italic> = 2,740) found that mean scores on the Mini-Mental State Examination (MMSE) were lower among individuals with <50 nmol/l compared with ≥50 nmol/l 25(OH)D<sup><xref ref-type="bibr" rid="CR5">5</xref></sup>. The authors also demonstrated that 25(OH)D concentrations were on average 6·2 nmol/l lower in Alzheimer’s disease patients compared with controls (<italic>n</italic> = 502)<sup><xref ref-type="bibr" rid="CR5">5</xref></sup>. Another meta-analysis in 2012, including five cross-sectional and two longitudinal studies (<italic>n</italic> = 7,688) suggested that the risk of cognitive impairment was doubled in participants with low vitamin D status compared to those with normal levels<sup><xref ref-type="bibr" rid="CR6">6</xref></sup>. A systematic review in 2013 found that low vitamin D status was associated with worse cognitive function or a higher incidence of dementia in 72% of the 25 cross-sectional studies and 67% of the six prospective studies included<sup><xref ref-type="bibr" rid="CR13">13</xref></sup>. In 2017, a meta-analysis including five longitudinal studies supported the hypothesis that 25(OH)D concentrations <25 nmol/l may contribute to the development of dementia<sup><xref ref-type="bibr" rid="CR14">14</xref></sup>.</p><p id="Par5">Results from randomised controlled trials (RCTs) have not been as promising<sup><xref ref-type="bibr" rid="CR15">15</xref>–<xref ref-type="bibr" rid="CR18">18</xref></sup>. However, null findings from these trials may be due to a number of reasons including: short follow-up time<sup><xref ref-type="bibr" rid="CR16">16</xref>,<xref ref-type="bibr" rid="CR18">18</xref></sup>, inclusion of younger participants<sup><xref ref-type="bibr" rid="CR16">16</xref></sup>, inclusion of supraphysiological doses<sup><xref ref-type="bibr" rid="CR18">18</xref></sup>, vitamin D being used in combination with other substances<sup><xref ref-type="bibr" rid="CR15">15</xref>,<xref ref-type="bibr" rid="CR17">17</xref></sup>, in low doses<sup><xref ref-type="bibr" rid="CR17">17</xref></sup> or, high baseline 25(OH)D status<sup><xref ref-type="bibr" rid="CR15">15</xref>,<xref ref-type="bibr" rid="CR16">16</xref></sup>.</p><p id="Par6">In light of these findings, in 2014 a group of international experts came to the consensus that hypovitaminosis D should be considered a risk factor for cognitive decline and dementia as it may change the clinical presentation of dementia due to accompanying comorbidities, but that 25(OH)D should not be used as a diagnostic or prognostic biomarker<sup><xref ref-type="bibr" rid="CR19">19</xref></sup>. The authors concluded that vitamin D supplementation should be part of the care management of older adults with cognitive disorders<sup><xref ref-type="bibr" rid="CR19">19</xref></sup>. However, whether vitamin D plays a causal role in cognitive decline directly or through its impact on comorbidities, or whether it is a consequence of cognitive decline remains unclear.</p><p id="Par7">Determining the nature of the true relationship between vitamin D and cognitive function is challenging due to study design issues. For instance, even if well-conducted, observational studies may not capture all unmeasured confounding and there is a possibility of reverse causality<sup><xref ref-type="bibr" rid="CR20">20</xref></sup>. RCTs are the gold standard approach for inferring a causal association, but they also have their limitations<sup><xref ref-type="bibr" rid="CR20">20</xref></sup>. Mendelian Randomisation (MR) is an approach that uses a genetic variant, which is associated with the exposure of interest, to estimate the causal relationship between an exposure and outcome<sup><xref ref-type="bibr" rid="CR20">20</xref></sup>. This method can help to overcome some limitations of observational studies as it relies on the random assignment of genetic variants from parents to offspring to reduce the possibility of confounding<sup><xref ref-type="bibr" rid="CR20">20</xref></sup>. Furthermore, since the genetic variant is established at conception, the possibility of reverse causality is minimised<sup><xref ref-type="bibr" rid="CR20">20</xref></sup>. If hypovitaminosis D is causally related to worse cognitive function, the genetic variant associated with vitamin D status, should be associated with cognitive function. Using an MR approach, a recent study provided some support for a beneficial role of 25(OH)D in reducing the risk of dementia<sup><xref ref-type="bibr" rid="CR21">21</xref></sup>.</p><p id="Par8">We conducted a study to examine the causal nature of the association between vitamin D status, as measured by 25(OH)D, and cognitive function in mid- to later-life using a MR approach.</p></sec><sec id="Sec2" sec-type="materials|methods"><title>Methods</title><sec id="Sec3"><title>Participants</title><p id="Par9">Information came from 17 cohorts: 1958 British birth cohort (1958BC); Austria Stroke Prevention Study (ASPS); The CoLaus Study (CoLaus); English Longitudinal Study of Ageing (ELSA); Epidemiologic study assessing prevention, early detection, and treatment of chronic diseases among older adults (ESTHER); Helsinki Birth Cohort Study (HBCS); Health and Retirement Study (HRS); Northern Finland Birth Cohort 1966 (NFBC1966); The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS); Swedish Twin Registry (STR); The Tromsø Study (Tromsø); TwinGene; UK Biobank; The UK Household Longitudinal Study (<italic>Understanding Society</italic>, UKHLS); Uppsala Longitudinal Study of Adult Men (ULSAM); Whitehall II (WII); and Young Finns Study (YFS). In all studies, data were restricted to White/European participants with genetic and cognitive data (<italic>n</italic> = 172,349, Table <xref rid="Tab1" ref-type="table">1</xref>). Information on 25(OH)D concentrations was available in nine studies (<italic>n</italic> = 26,856). All participants provided informed consent and ethical approval was granted by local research ethics committees. An expanded description is provided in supplementary text.<table-wrap id="Tab1"><label>Table 1</label><caption><p>Participant characteristics.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2"></th><th><bold>Total</bold></th><th><bold>Males</bold></th><th><bold>Age, yrs</bold></th><th><bold>Age</bold> ≥ <bold>65yrs</bold></th><th><bold>25(OH)D, nmol/l</bold></th><th><bold><italic>CYP2R1</italic></bold><bold>, MAF</bold></th><th><bold><italic>DHCR7</italic></bold><bold>, MAF</bold></th></tr><tr><th><bold>N</bold> = <bold>172,349</bold></th><th><bold>(%)</bold></th><th><bold>(median, IQR)</bold></th><th><bold>(%)</bold></th><th><bold>(median, IQR)</bold></th><th><bold>(%)</bold></th><th><bold>(%)</bold></th></tr></thead><tbody><tr><td colspan="8"><bold><italic>Studies with 25(OH)D (N</italic></bold> = <bold><italic>28,070</italic></bold>)</td></tr><tr><td>1958BC</td><td>5,633</td><td>49·1</td><td>50 (NA)</td><td>0</td><td>57·0 (33·9)</td><td>43·0</td><td>22·2</td></tr><tr><td>CoLaus</td><td>875</td><td>45·1</td><td>70 (6)</td><td>100</td><td>47·3 (33·6)</td><td>47·1</td><td>27·9</td></tr><tr><td>ESTHER</td><td>8,080</td><td>43·0*</td><td>74 (4)*</td><td>100*</td><td>45·1 (27·1)</td><td>46·2</td><td>25·7</td></tr><tr><td>HBCS</td><td>1,059</td><td>59·1</td><td>67·6 (3·6)</td><td>91·8</td><td>61 (24)</td><td>38·5</td><td>38·0</td></tr><tr><td>NFBC66</td><td>3,488</td><td>43·5</td><td>46·5 (0·9)</td><td>0</td><td>50·2 (20·8)</td><td>40·8</td><td>38·9</td></tr><tr><td>PIVUS</td><td>891</td><td>50·3</td><td>70·1 (0·2)</td><td>100</td><td>56 (26·5)</td><td>39·9</td><td>35·0</td></tr><tr><td>Tromsø</td><td>4,766</td><td>55·4</td><td>69 (11)</td><td>76·8</td><td>56·5 (25·9)</td><td>41·2</td><td>38·6</td></tr><tr><td>ULSAM</td><td>1,118</td><td>100</td><td>71 (0·9)</td><td>100</td><td>68·2 (24·7)</td><td>39·4</td><td>33·4</td></tr><tr><td>YFS</td><td>2,160</td><td>45·1</td><td>43 (9)</td><td>0</td><td>57 (25)</td><td>38·2</td><td>40·4</td></tr><tr><td colspan="8"><bold><italic>Studies without 25(OH)D (N</italic></bold> = <bold><italic>144,279</italic></bold>)</td></tr><tr><td>ASPS</td><td>780</td><td>43·3</td><td>64.7 (11)</td><td>49·2</td><td>NA</td><td>43·7</td><td>29·3</td></tr><tr><td>ELSA</td><td>5,382</td><td>45·6</td><td>65 (15)</td><td>50·6</td><td>NA</td><td>43·2</td><td>22·4</td></tr><tr><td>HRS</td><td>9,930</td><td>41·4</td><td>68 (15)</td><td>62</td><td>NA</td><td>43·8</td><td>27·0</td></tr><tr><td>STR</td><td>969</td><td>44·7</td><td>72.1 (10·1)</td><td>77·2</td><td>NA</td><td>38·8</td><td>30·0</td></tr><tr><td>TwinGene</td><td>2,362</td><td>51·1</td><td>69 (6)</td><td>100</td><td>NA</td><td>40·0</td><td>33·2</td></tr><tr><td>UKBiobank</td><td>111,936</td><td>47·5</td><td>58 (12)</td><td>19·7</td><td>NA</td><td>42·2</td><td>21·0</td></tr><tr><td>UKHLS</td><td>8,577</td><td>43·7</td><td>54 (24)</td><td>28·0</td><td>NA</td><td>42·4</td><td>21·6</td></tr><tr><td>WII</td><td>4,343</td><td>76·2</td><td>59·7 (10)</td><td>28·7</td><td>NA</td><td>42·5</td><td>22·7</td></tr></tbody></table><table-wrap-foot><p>IQR: Interquartile range; MAF: minor allele frequency.</p><p>1958BC: 1958 British birth cohort;</p><p>COLAUS: The Colaus study;</p><p>ESTHER: Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen in der älteren Bevölkerung;</p><p>HBCS: Helsinki Birth Cohort Study;</p><p>NFBC66: Northern Finland birth cohort 1966;</p><p>PIVUS: The Prospective Investigation of the Vasculature in Uppsala Seniors;</p><p>TROMSO: The Tromsø Study;</p><p>ULSAM: Uppsala Longitudinal Study of Adult Men;</p><p>YFS: Young Finns;</p><p>ASPS: Austria Stroke Prevention Study;</p><p>ELSA: English Longitudinal Study of Ageing;</p><p>HRS: Health and Retirement Study;</p><p>STR: Swedish Twin Registry;</p><p>TwinGene: Swedish Twin Registry;</p><p>UKBiobank: UK Biobank;</p><p>UKHLS: The UK Household Longitudinal Study (Understanding Society);</p><p>WII: Whitehall II</p><p>* N’s based on participants with cognitive data.</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec4"><title>Genetic variants</title><p id="Par10">We used two single nucleotide polymorphisms (SNPs) based on their demonstrated associations with 25(OH)D concentrations: rs12785878 (vitamin D-decreasing allele, G), located near gene coding 7-dehydrocholesterol reductase (<italic>DHCR7</italic>), and rs12794714 (vitamin D-decreasing allele, A) near 25-hydroxylase (<italic>CYP2R1</italic>)<sup><xref ref-type="bibr" rid="CR22">22</xref>,<xref ref-type="bibr" rid="CR23">23</xref></sup>. When these SNPs were not accessible, proxy SNPs in perfect linkage disequilibrium were used (Supplementary Table <xref rid="MOESM1" ref-type="media">1</xref>). The assumptions for the use of these SNPs to proxy vitamin D status in MR studies have been assessed in a previous study using data from 1958BC<sup><xref ref-type="bibr" rid="CR24">24</xref></sup>. Data on <italic>DHCR7</italic> and <italic>CYP2R1</italic> were available in all cohorts. For analysis purposes, both <italic>DHCR7</italic> and <italic>CYP2R1</italic> genotypes were coded as 0-2 depending on presence of alleles associated with decreasing 25(OH)D concentrations, where homozygous genotypes were coded as 2. A score was created by summing <italic>DHCR7</italic> and <italic>CYP2R1</italic> on the basis of their effect alleles<sup><xref ref-type="bibr" rid="CR24">24</xref></sup>. The score is referred to as the <italic>synthesis score</italic> since it contains the SNPs involved in the synthesis of 25(OH)D<sup><xref ref-type="bibr" rid="CR24">24</xref></sup>. The few participants with 3 or 4 25(OH)D-decreasing alleles (ranging from 9·6% in 1958BC to 17·4% in Tromsø) were grouped. Genotyping techniques are described in supplementary materials. Quality checks of each SNP including minor allele frequencies and Hardy Weinberg equilibrium are reported in Supplementary Table <xref rid="MOESM1" ref-type="media">1</xref>. Minor allele frequencies were compared with HapMap data and were found to be approximately similar.</p></sec><sec id="Sec5"><title>25-Hydroxyvitamin D</title><p id="Par11">25(OH)D concentrations were available for nine studies, with details for measurement methods provided in the supplementary text. In order to examine analyses stratified by 25(OH)D concentrations, sex and study specific 25(OH)D tertiles(T) were created (Supplementary Table <xref rid="MOESM1" ref-type="media">2</xref>). 25(OH)D was found to be skewed, therefore natural log (ln) transformation was applied to approximate a normal distribution when 25(OH)D was the outcome in analyses.</p></sec><sec id="Sec6"><title>Global and memory cognitive function</title><p id="Par12">Details of cognitive tests in each cohort, grouped to represent global and/or memory cognitive function, can be found in supplementary materials. Each test was standardised to produce a mean of zero and a standard deviation of one. To obtain a summary score for global/memory cognitive function, relevant tests were summed and re-standardised. ULSAM and CoLaus had information on global cognitive function only.</p></sec><sec id="Sec7"><title>Covariates</title><p id="Par13">Results in all studies were adjusted for sex, age (in years), month of blood collection for 25(OH)D, and, education and depressive symptoms which were considered potential confounders <italic>a priori</italic>. A description of how education and depressive symptoms were measured in each cohort is outlined in supplementary materials.</p></sec><sec id="Sec8"><title>Statistical analyses</title><p id="Par14">Within each study, linear regression models were used to assess the following: 1) phenotypic associations i.e. serum 25(OH)D and cognitive function adjusted for age, sex, month of 25(OH)D blood collection, educational attainment and depressive symptoms where possible; 2) associations between SNPs/<italic>synthesis score</italic> and cognitive function adjusted for age, sex, education, depressive symptoms and principle components (to account for population stratification) where specified in supplementary materials. The presence of non-linear phenotypic associations were assessed by including a quadratic term of 25(OH)D in the regression model. Interaction by age and sex was also assessed.</p><p id="Par15">Results from within-study analyses were combined using random effects meta-analyses. Analyses were stratified by 25(OH)D-tertiles, sex and age (<65 years vs. ≥65 years). I-square tests were used to indicate heterogeneity between cohorts.</p><p id="Par16">Meta-regression was used to examine heterogeneity between the cohorts using results from the meta-analysed phenotypic analyses. Study characteristics that were hypothesised <italic>a priori</italic> to affect the association included sex, age (<65 years vs. ≥65 years), vitamin D assay (mass spectrometry or immunoassay) and country region [categorised as UK, Nordic (Finland, Sweden, Norway), central Europe (Austria, Germany, Switzerland) and the US].</p><p id="Par17">To examine the strength and suitability of the SNPs/<italic>synthesis score</italic> as instruments for MR studies, associations between the SNPs/<italic>synthesis score</italic> and ln25(OH)D (adjusted for age, sex, month of 25(OH)D collection and study-specific components where specified) were examined, and F-statistics were calculated. The F-statistic was approximated from the proportion of variation in the model (R<sup>2</sup>) assessing 25(OH)D which is explained by the SNPs/<italic>synthesis score</italic> [F-stat = (R<sup>2</sup>*(<italic>n</italic> − 2))/(1 − R<sup>2</sup>)]. The adjusted R<sup>2</sup> in each cohort was weighted by the sample size of each cohort. The F-statistic should ideally be greater than ten in order for an instrument to be considered strong enough to use<sup><xref ref-type="bibr" rid="CR25">25</xref></sup>.</p><p id="Par18">Participants from UK Biobank were used to investigate cognitive domain-specific effects (using standardised fluid intelligence, pairs matching and reaction time tests) of the SNPs/<italic>synthesis score</italic>.</p><p id="Par19">Finally, a power calculation was conducted to determine the smallest effect size that our study able to detect at a two-sided alpha level of 0·05 and at a power of 0.80. Power analysis was performed using Quanto 1.2 (University of Southern California, USA).</p><p id="Par20">Meta-analyses were conducted at the Centre for Population Health Research (University of South Australia) using STATA version 14.</p></sec></sec><sec id="Sec9" sec-type="results"><title>Results</title><p id="Par21">A total of 172,349 participants had complete data for the SNPs and completed at least one cognitive test. Participants from eight cohorts had no information on 25(OH)D concentrations, while two studies had no information on memory-related cognitive function. Basic characteristics of all studies are presented in Table <xref rid="Tab1" ref-type="table">1</xref>.</p><sec id="Sec10"><title>Phenotypic association between serum 25(OH)D and cognitive function</title><p id="Par22">In meta-analyses of the nine eligible studies, there was no evidence of interaction by sex or age on phenotypic associations (<italic>p</italic> ≥ 0·06, Supplementary Table <xref rid="MOESM1" ref-type="media">3</xref>). There was evidence of a non-linear relationship between serum 25(OH)D and cognitive function, <italic>p</italic> ≤ 0·006 (Supplementary Table <xref rid="MOESM1" ref-type="media">3</xref>) after adjustment for age, sex, month of blood collection, educational attainment and depressive symptoms. However, this non-linear association was driven by a single study and weakened following its’ exclusion from the meta-analyses (Table <xref rid="Tab2" ref-type="table">2</xref>). When stratified by 25(OH)D tertiles, participants in T2 and T3 had higher scores in global cognition compared with those in T1 (0·05 SD, 95%CI 0·01, 0·09; p = 0·02 and 0·07 SD, −0·01, −0·15; p = 0·07, respectively), while no clear differences were not seen for memory cognition (P ≥ 0·11 for both comparisons). There were no overall differences in phenotypic associations by sex, country or vitamin D assay, while associations appeared somewhat stronger among those aged 65 years or above compared to younger participants (Supplementary Table <xref rid="MOESM1" ref-type="media">4</xref>).<table-wrap id="Tab2"><label>Table 2</label><caption><p>Association of sex-specific 25(OH)D tertiles with cognition.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2"></th><th colspan="5">Global Cognition</th><th colspan="5">Memory Cognition</th></tr><tr><th>N</th><th>Beta (95% C.I.)</th><th>p</th><th>I<sup>2</sup>(%)</th><th>p<sub>hetero</sub></th><th>n</th><th>Beta (95% C.I.)</th><th>p</th><th>I<sup>2</sup>(%)</th><th>p<sub>hetero</sub></th></tr></thead><tbody><tr><td><bold>25(OH)D T1</bold></td><td>4,961</td><td>Reference</td><td></td><td></td><td></td><td>44,482</td><td>Reference</td><td></td><td></td><td></td></tr><tr><td><bold>25(OH)D T2</bold></td><td>5,269</td><td>0·05 (0·01, 0·09)</td><td>0·02</td><td>17·48</td><td>0·29</td><td>44,772</td><td>0·04 (−0·01, 0·09)</td><td>00·11</td><td>34·29</td><td>0·17</td></tr><tr><td><bold>25(OH)D T3</bold></td><td>5,293</td><td>0·07 (−0·01, 0·15)</td><td>0·07</td><td>74·05</td><td><0·001</td><td>44,827</td><td>0·02 (−0·07, 0·11)</td><td>0·64</td><td>76·84</td><td><0·001</td></tr><tr><td></td><td></td><td colspan="4">p<sub>trend</sub> = 0·15</td><td></td><td colspan="4">p<sub>trend</sub> = 0·89</td></tr><tr><td></td><td></td><td colspan="4">p<sup>*</sup><sub>curvature</sub> = 0·001</td><td></td><td colspan="4">p<sup>┼</sup><sub>curvature</sub> = 0·01</td></tr></tbody></table><table-wrap-foot><p><sup>*</sup>excluding 1958BC, p<sub>curvature</sub> = 0·04; <sup>┼</sup>excluding 1958BC, p<sub>curvature</sub> = 0·16.</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec11"><title>Mendelian randomisation: association between SNPs/synthesis score and cognitive function</title><p id="Par23">There were no associations between 25(OH)D-related SNPs/<italic>synthesis score</italic> with global or memory cognition (Fig. <xref rid="Fig1" ref-type="fig">1</xref>, Supplementary Table <xref rid="MOESM1" ref-type="media">5</xref>). Furthermore, there was no evidence for an association between SNPs/<italic>synthesis score</italic> with either cognitive measure stratifying by sex, age and 25(OH)D tertiles (Supplementary Figure <xref rid="MOESM1" ref-type="media">1</xref>). Genetic associations with cognitive function did not vary by age, sex or country (Supplementary Table <xref rid="MOESM1" ref-type="media">4</xref>).<fig id="Fig1"><label>Figure 1</label><caption><p>Association of <italic>CYP2R1</italic>, <italic>DHCR7</italic> and <italic>synthesis score</italic> with global and memory cognition.</p></caption><graphic xlink:href="41598_2017_13189_Fig1_HTML" id="d29e2306"></graphic></fig></p><p id="Par24">Information for pairs matching (<italic>n</italic> = 110,545), reaction time (<italic>n</italic> = 109,911), reasoning (<italic>n</italic> = 35,603), and prospective memory (<italic>n</italic> = 36,311) was available for the UK Biobank. We conducted domain specific analyses against all the four outcomes, but observed no associations with the SNPs/<italic>synthesis score</italic> (Supplementary Figure <xref rid="MOESM1" ref-type="media">2</xref>).</p></sec><sec id="Sec12"><title>Instrument validation: association between SNPs/synthesis score and 25(OH)D</title><p id="Par25">The SNPs/<italic>synthesis score</italic> were associated with 25(OH)D (Fig. <xref rid="Fig2" ref-type="fig">2</xref>, Supplementary Table <xref rid="MOESM1" ref-type="media">6</xref>). 25(OH)D concentrations were 2·7% (95% CI 0·7% to 4·1%), 3·3% (95% CI 0·5% to 4·3%), and 3·1% (95% CI 0·5% to 4·0%) lower per vitamin D-decreasing allele for <italic>DHCR7</italic>, <italic>CYP2R1</italic> and the <italic>synthesis score</italic> respectively. The weighted F-statistic was 54·13 (R<sup>2</sup> = 0.003), 71·69 (R<sup>2</sup> = 0.004) and 113·50 (R<sup>2</sup> = 0.006) for <italic>DHCR7</italic>, <italic>CYP2R1</italic> and the <italic>synthesis score</italic> respectively. Since these F-statistics are >10, the SNPs/<italic>synthesis score</italic> can be considered strong proxies for 25(OH)D in MR analyses<sup><xref ref-type="bibr" rid="CR25">25</xref></sup>.<fig id="Fig2"><label>Figure 2</label><caption><p>Association of <italic>CYP2R1</italic>, <italic>DHCR7</italic> and <italic>synthesis score</italic> with 25-hydroxyvitamin D (25(OH)D).</p></caption><graphic xlink:href="41598_2017_13189_Fig2_HTML" id="d29e2396"></graphic></fig></p></sec><sec id="Sec13"><title>Power calculation</title><p id="Par26">With a sample size of 153,187, a power of 0·80, and a two-sided alpha level of 0·05, we are sufficiently powered to detect a 0·0125 SD change in the cognitive score per vitamin D-decreasing allele. For the smallest stratum with <italic>n</italic> = 4,957, our study is powered to detect an effect size of 0·058 SD or larger (Supplementary Table <xref rid="MOESM1" ref-type="media">7</xref>). Converted to the reflect the association between serum 25(OH)D and a standardised cognitive outcome, this corresponds to a 0.09 SD and 0.51 SD difference by 1 SD change in log 25(OH)D for the full and minimum sample, respectively.</p></sec></sec><sec id="Sec14" sec-type="discussion"><title>Discussion</title><p id="Par27">Using data from 17 studies with information for up to 172,349 participants, we failed to find any evidence for a causal association between vitamin D and cognitive function, with sub-group analyses stratifying by age, sex and 25(OH)D tertiles providing a consistent lack of evidence for causality. These findings suggest that the non-linear phenotypic association between serum 25(OH)D and cognitive function (where cognitive scores were lower for both low and high 25(OH)D concentrations), which was also confirmed in our datasets, may be due to reverse causation or confounding.</p><p id="Par28">There are a limited number of RCTs assessing the effect of vitamin D supplementation on cognitive function<sup><xref ref-type="bibr" rid="CR15">15</xref>–<xref ref-type="bibr" rid="CR18">18</xref></sup>. In line with our study, these have provided little evidence for causality. In particular, our MR findings were supportive of results from the biggest RCT to date which was carried out among older women (≥65 years, <italic>n</italic> = 4,143) participating in the Women’s Health Initiative<sup><xref ref-type="bibr" rid="CR15">15</xref></sup>. In that RCT, over a mean follow-up of 7·8 years, there was no effect of supplementation with 400 IU/day vitamin D3 and 1,000 mg/day calcium on cognitive impairment. However, it has been argued that the inclusion of calcium, which can be harmful for the brain, may have weakened the result, and baseline concentrations of 25(OH)D among participants may have been adequate to meet their cognitive requirements<sup><xref ref-type="bibr" rid="CR26">26</xref></sup>. Two pre-post studies have been conducted<sup><xref ref-type="bibr" rid="CR27">27</xref>,<xref ref-type="bibr" rid="CR28">28</xref></sup>. One found no effect of four weeks of vitamin D2 supplementation on cognitive function among institutionalised older adults<sup><xref ref-type="bibr" rid="CR27">27</xref></sup>. In contrast with our findings, the other study demonstrated an improvement in the cognitive performance among 20 older adults after 16 months of 800 IU/day vitamin D3 supplementation compared with controls (<italic>n</italic> = 24)<sup><xref ref-type="bibr" rid="CR28">28</xref></sup>. However, the non-random pre-post design of these studies is a limitation as potential unmeasured confounding cannot be ruled out.</p><p id="Par29">One earlier genetic study suggested a beneficial effect of 25(OH)D on reducing the risk of Alzheimer’s disease<sup><xref ref-type="bibr" rid="CR21">21</xref></sup>. However, in this study the beneficial association with Alzheimer’s disease was due to a significant association with a variant in the <italic>GC</italic> gene coding variations in the vitamin D binding protein, while in line with our study, no associations were seen for <italic>DHCR7</italic>, or <italic>CYP2R1</italic>. As we have described earlier, while associated with 25(OH)D concentrations, <italic>GC</italic> is not suitable for the use as its’ proxy marker in Mendelian randomisation analyses, given likely influences on bioavailability of 25(OH)D<sup><xref ref-type="bibr" rid="CR29">29</xref></sup>. Indeed, the success of an MR study relies upon the ability of the genetic variant to accurately proxy the exposure of interest<sup><xref ref-type="bibr" rid="CR20">20</xref></sup>. In line with previous studies<sup><xref ref-type="bibr" rid="CR22">22</xref>–<xref ref-type="bibr" rid="CR24">24</xref></sup> we used two variants which have been consistently associated with circulating 25(OH)D concentrations. Both variants are located upstream of the 25(OH)D metabolite, with <italic>DHCR7</italic> influencing substrate availability and <italic>CYP2R1</italic> coding the 25-OH-hydroxylate. Analyses stratifying by 25(OH)D concentrations suggested that the association between <italic>CYP2R1</italic> and 25(OH)D is restricted to participants with the highest group. While this could suggest that the <italic>CYP2R1</italic> variant has a rate-limiting effect on 25(OH)D synthesis for individuals with the high 25(OH)D concentrations, it is also possible that the apparent difference is due to the wide range of 25(OH)D concentrations for individuals in the highest tertile in this study. Stratification by 25(OH)D tertiles could also have led to collider bias, i.e. when the association of two variables (i.e. genetic variant and cognitive function), changes upon conditioning on a third variable (i.e. 25(OH)D), when this third variable is affected by the other two. Therefore, cautious interpretation is required when stratifying MR analyses by 25(OH)D.</p><p id="Par30">Interpreting the association between vitamin D and cognitive function is complicated. Dementia is often accompanied by a range of other chronic diseases/disorders, where cognitive decline may enhance chronic disease and vice-versa<sup><xref ref-type="bibr" rid="CR19">19</xref></sup>. Vitamin D supplementation has been shown to reduce mortality risk<sup><xref ref-type="bibr" rid="CR30">30</xref></sup>. Hypovitaminosis D has been associated with a number of conditions including osteoporosis, vascular disease and reduced olfactory function<sup><xref ref-type="bibr" rid="CR31">31</xref></sup>, which can precipitate the progression of dementia. Therefore it is plausible that the potential cognitive benefits of vitamin D identified in observational studies may be mediated by improvements in accompanying chronic diseases.</p><p id="Par31">Results should be interpreted with limitations in mind. It has been suggested that there are sensitive periods i.e. foetal development, growth and senescence during which vitamin D is of particular significance to neurocognition<sup><xref ref-type="bibr" rid="CR19">19</xref></sup>. Our study looked at effects on cognitive function in mid- to later-life, and while we found no evidence stratifying by age group (i.e. <65 versus ≥65 years), we could not assess the association in younger or very old individuals. Nevertheless, the use of genetic variants to proxy 25(OH)D status assumes that we have represented lifetime 25(OH)D status<sup><xref ref-type="bibr" rid="CR20">20</xref></sup>. Generalisability of the study results is restricted to caucasian populations. Cognition was assessed using different tests between the cohorts therefore a composite measure of global cognitive function was used to obtain a more uniform representation of cognitive function; this may have masked some domain specific effects. Since our previous study emphasised the role of vitamin D in cognitive function, a separate memory function score was created to account for any discriminating effects of vitamin D<sup><xref ref-type="bibr" rid="CR32">32</xref></sup>. A recent study suggested that vitamin D may be associated with speed of processing and executive functioning<sup><xref ref-type="bibr" rid="CR33">33</xref></sup>, we found no evidence for domain-specific effects using data from UK Biobank. MR studies require large sample sizes partly due to the very small amount of variation in the exposure explained by genetic instruments<sup><xref ref-type="bibr" rid="CR20">20</xref></sup>. According to the power calculation, our study was sufficiently powered to detect relatively small effects. Nevertheless, it should be acknowledged that our analyses may have been underpowered to detect small causal effects operating at the extremes of 25(OH)D distribution.</p></sec><sec id="Sec15" sec-type="conclusion"><title>Conclusion</title><p id="Par32">We found no evidence for a causal association between 25(OH)D concentrations and cognitive performance in mid- to later-life.</p></sec><sec sec-type="supplementary-material"><title>Electronic supplementary material</title><sec id="Sec16"><p><supplementary-material content-type="local-data" id="MOESM1"><media xlink:href="41598_2017_13189_MOESM1_ESM.pdf"><caption><p>Supplementary material</p></caption></media></supplementary-material></p></sec></sec></body><back><fn-group><fn><p><bold>Electronic supplementary material</bold></p><p><bold>Supplementary information</bold> accompanies this paper at 10.1038/s41598-017-13189-3.</p></fn><fn><p><bold>Publisher's note:</bold> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group><ack><title>Acknowledgements</title><p>Primary project funding came from The Judith Jane Mason & Harold Stannett Williams Memorial Foundation, other resources are listed in the supplementary material. Funders played no role in the design, analysis or reporting of the study.</p></ack><notes notes-type="author-contribution"><title>Author Contributions</title><p>Wrote the paper: J.M., E.H. Study supervision: E.H., C.P., D.L., H.B., M.Ki., M.Ku., M.R.J., N.L.P., O.T.R., S.H. Data analysis: J.M., A.Z., A.C., A.S., B.S., E.K., J.E., J.L., K.S., L.B., M.Kj., M.S., O.T.R., P.M.V., S.R., T.L., V.K., Y.B., Y.Z. Provision of administrative technical or material support: HSchi, M.Kä., M.Ki., N.H.K., N.L.P., O.T.R., R.J., S.H., S.R., T.L. Data collection: E.H., C.P., A.S.M., E.I., H.B., H.Schi., H.Schm., J.G.E., J.V., K.R., L.L., M.Kä., M.ki., M.R.J., N.H.K., N.L.P., O.T.R., R.J., R.S., S.H., S.R., T.L. Interpretation, manuscript revision and approval of submission: J.M., E.H., A.Z., A.C., C.P., D.L., E.K., Y.B. M.S., K.S., J.E., M.Kj., V.K., Y.Z., T.L., S.R., L.B., J.L., P.M.V., A.S., L.P., H.Schi., A.S.M., J.A., N.H.K., M.K., L.K., K.R., H.M., E.I., I.G., K.E.P., H.Schm., R.S., P.V., L.L., J.G.E., K.M., O.T.R., S.H., N.L.P., K.H.H., M.R.J., J.V., M.Ki., R.J., H.B., M.ku.</p></notes><notes notes-type="COI-statement"><sec id="FPar1"><title>Competing Interests</title><p id="Par33">EI is a scientific advisor for Precision Wellness, Cellink and Olink Proteomics for work unrelated to the present project. 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