Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases
Identifieur interne : 000360 ( Pmc/Corpus ); précédent : 000359; suivant : 000361Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases
Auteurs : Rita Guerreiro ; Valentina Escott-Price ; Lee Darwent ; Laura Parkkinen ; Olaf Ansorge ; Dena G. Hernandez ; Michael A. Nalls ; Lorraine Clark ; Lawrence Honig ; Karen Marder ; Wiesje Van Der Flier ; Henne Holstege ; Eva Louwersheimer ; Afina Lemstra ; Philip Scheltens ; Ekaterina Rogaeva ; Peter St George-Hyslop ; Elisabet Londos ; Henrik Zetterberg ; Sara Ortega-Cubero ; Pau Pastor ; Tanis J. Ferman ; Neill R. Graff-Radford ; Owen A. Ross ; Imelda Barber ; Anne Braae ; Kristelle Brown ; Kevin Morgan ; Walter Maetzler ; Daniela Berg ; Claire Troakes ; Safa Al-Sarraj ; Tammaryn Lashley ; Yaroslau Compta ; Tamas Revesz ; Andrew Lees ; Nigel J. Cairns ; Glenda M. Halliday ; David Mann ; Stuart Pickering-Brown ; John Powell ; Katie Lunnon ; Michelle K. Lupton ; Dennis Dickson ; John Hardy ; Andrew Singleton ; Jose BrasSource :
- Neurobiology of Aging [ 0197-4580 ] ; 2016.
Abstract
The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the
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DOI: 10.1016/j.neurobiolaging.2015.10.028
PubMed: 26643944
PubMed Central: 4759606
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases</title><author><name sortKey="Guerreiro, Rita" sort="Guerreiro, Rita" uniqKey="Guerreiro R" first="Rita" last="Guerreiro">Rita Guerreiro</name><affiliation><nlm:aff id="aff1">Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK</nlm:aff></affiliation></author><author><name sortKey="Escott Price, Valentina" sort="Escott Price, Valentina" uniqKey="Escott Price V" first="Valentina" last="Escott-Price">Valentina Escott-Price</name><affiliation><nlm:aff id="aff2">MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK</nlm:aff></affiliation></author><author><name sortKey="Darwent, Lee" sort="Darwent, Lee" uniqKey="Darwent L" first="Lee" last="Darwent">Lee Darwent</name><affiliation><nlm:aff id="aff1">Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK</nlm:aff></affiliation></author><author><name sortKey="Parkkinen, Laura" sort="Parkkinen, Laura" uniqKey="Parkkinen L" first="Laura" last="Parkkinen">Laura Parkkinen</name><affiliation><nlm:aff id="aff3">Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Ansorge, Olaf" sort="Ansorge, Olaf" uniqKey="Ansorge O" first="Olaf" last="Ansorge">Olaf Ansorge</name><affiliation><nlm:aff id="aff3">Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Hernandez, Dena G" sort="Hernandez, Dena G" uniqKey="Hernandez D" first="Dena G." last="Hernandez">Dena G. Hernandez</name><affiliation><nlm:aff id="aff4">Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Nalls, Michael A" sort="Nalls, Michael A" uniqKey="Nalls M" first="Michael A." last="Nalls">Michael A. Nalls</name><affiliation><nlm:aff id="aff4">Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA</nlm:aff></affiliation></author><author><name sortKey="Clark, Lorraine" sort="Clark, Lorraine" uniqKey="Clark L" first="Lorraine" last="Clark">Lorraine Clark</name><affiliation><nlm:aff id="aff6">Taub Institute for Alzheimer Disease and the Aging Brain, Columbia University, New York, NY, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Department of Pathology and Cell Biology, Columbia University, New York, NY, USA</nlm:aff></affiliation></author><author><name sortKey="Honig, Lawrence" sort="Honig, Lawrence" uniqKey="Honig L" first="Lawrence" last="Honig">Lawrence Honig</name><affiliation><nlm:aff id="aff6">Taub Institute for Alzheimer Disease and the Aging Brain, Columbia University, New York, NY, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Department of Pathology and Cell Biology, Columbia University, New York, NY, USA</nlm:aff></affiliation></author><author><name sortKey="Marder, Karen" sort="Marder, Karen" uniqKey="Marder K" first="Karen" last="Marder">Karen Marder</name><affiliation><nlm:aff id="aff6">Taub Institute for Alzheimer Disease and the Aging Brain, Columbia University, New York, NY, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">Department of Neurology, Columbia University, New York, NY, USA</nlm:aff></affiliation></author><author><name sortKey="Van Der Flier, Wiesje" sort="Van Der Flier, Wiesje" uniqKey="Van Der Flier W" first="Wiesje" last="Van Der Flier">Wiesje Van Der Flier</name><affiliation><nlm:aff id="aff9">Department Of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Holstege, Henne" sort="Holstege, Henne" uniqKey="Holstege H" first="Henne" last="Holstege">Henne Holstege</name><affiliation><nlm:aff id="aff9">Department Of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Louwersheimer, Eva" sort="Louwersheimer, Eva" uniqKey="Louwersheimer E" first="Eva" last="Louwersheimer">Eva Louwersheimer</name><affiliation><nlm:aff id="aff9">Department Of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Lemstra, Afina" sort="Lemstra, Afina" uniqKey="Lemstra A" first="Afina" last="Lemstra">Afina Lemstra</name><affiliation><nlm:aff id="aff9">Department Of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Scheltens, Philip" sort="Scheltens, Philip" uniqKey="Scheltens P" first="Philip" last="Scheltens">Philip Scheltens</name><affiliation><nlm:aff id="aff9">Department Of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name><affiliation><nlm:aff id="aff10">Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada</nlm:aff></affiliation></author><author><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name><affiliation><nlm:aff id="aff10">Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Cambridge Institute for Medical Research, and Cambridge National Institute of Health Research Biomedical Research Unit in Dementia, University of Cambridge, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Londos, Elisabet" sort="Londos, Elisabet" uniqKey="Londos E" first="Elisabet" last="Londos">Elisabet Londos</name><affiliation><nlm:aff id="aff12">Clinical Memory Research Unit, Institute of Clinical Sciences Malmö, Lund University, Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Zetterberg, Henrik" sort="Zetterberg, Henrik" uniqKey="Zetterberg H" first="Henrik" last="Zetterberg">Henrik Zetterberg</name><affiliation><nlm:aff id="aff13">Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden</nlm:aff></affiliation><affiliation><nlm:aff id="aff1">Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK</nlm:aff></affiliation></author><author><name sortKey="Ortega Cubero, Sara" sort="Ortega Cubero, Sara" uniqKey="Ortega Cubero S" first="Sara" last="Ortega-Cubero">Sara Ortega-Cubero</name><affiliation><nlm:aff id="aff14">Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, (CIMA), University of Navarra, Pamplona, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="aff15">CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Pastor, Pau" sort="Pastor, Pau" uniqKey="Pastor P" first="Pau" last="Pastor">Pau Pastor</name><affiliation><nlm:aff id="aff14">Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, (CIMA), University of Navarra, Pamplona, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="aff15">CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="aff16">Memory and Movement Disorders Units, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Ferman, Tanis J" sort="Ferman, Tanis J" uniqKey="Ferman T" first="Tanis J." last="Ferman">Tanis J. Ferman</name><affiliation><nlm:aff id="aff17">Departments of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA</nlm:aff></affiliation></author><author><name sortKey="Graff Radford, Neill R" sort="Graff Radford, Neill R" uniqKey="Graff Radford N" first="Neill R." last="Graff-Radford">Neill R. Graff-Radford</name><affiliation><nlm:aff id="aff18">Department of Neurology, Mayo Clinic, Jacksonville, FL, USA</nlm:aff></affiliation></author><author><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A." last="Ross">Owen A. Ross</name><affiliation><nlm:aff id="aff19">Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</nlm:aff></affiliation></author><author><name sortKey="Barber, Imelda" sort="Barber, Imelda" uniqKey="Barber I" first="Imelda" last="Barber">Imelda Barber</name><affiliation><nlm:aff id="aff20">Translation Cell Sciences—Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK</nlm:aff></affiliation></author><author><name sortKey="Braae, Anne" sort="Braae, Anne" uniqKey="Braae A" first="Anne" last="Braae">Anne Braae</name><affiliation><nlm:aff id="aff20">Translation Cell Sciences—Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK</nlm:aff></affiliation></author><author><name sortKey="Brown, Kristelle" sort="Brown, Kristelle" uniqKey="Brown K" first="Kristelle" last="Brown">Kristelle Brown</name><affiliation><nlm:aff id="aff20">Translation Cell Sciences—Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK</nlm:aff></affiliation></author><author><name sortKey="Morgan, Kevin" sort="Morgan, Kevin" uniqKey="Morgan K" first="Kevin" last="Morgan">Kevin Morgan</name><affiliation><nlm:aff id="aff20">Translation Cell Sciences—Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK</nlm:aff></affiliation></author><author><name sortKey="Maetzler, Walter" sort="Maetzler, Walter" uniqKey="Maetzler W" first="Walter" last="Maetzler">Walter Maetzler</name><affiliation><nlm:aff id="aff21">Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, Center of Neurology, University of Tuebingen, and DZNE, German Center for Neurodegenerative Diseases, Tuebingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Berg, Daniela" sort="Berg, Daniela" uniqKey="Berg D" first="Daniela" last="Berg">Daniela Berg</name><affiliation><nlm:aff id="aff21">Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, Center of Neurology, University of Tuebingen, and DZNE, German Center for Neurodegenerative Diseases, Tuebingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Troakes, Claire" sort="Troakes, Claire" uniqKey="Troakes C" first="Claire" last="Troakes">Claire Troakes</name><affiliation><nlm:aff id="aff22">MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Department of Clinical Neuroscience, King's College London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Al Sarraj, Safa" sort="Al Sarraj, Safa" uniqKey="Al Sarraj S" first="Safa" last="Al-Sarraj">Safa Al-Sarraj</name><affiliation><nlm:aff id="aff22">MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Department of Clinical Neuroscience, King's College London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Lashley, Tammaryn" sort="Lashley, Tammaryn" uniqKey="Lashley T" first="Tammaryn" last="Lashley">Tammaryn Lashley</name><affiliation><nlm:aff id="aff23">Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</nlm:aff></affiliation></author><author><name sortKey="Compta, Yaroslau" sort="Compta, Yaroslau" uniqKey="Compta Y" first="Yaroslau" last="Compta">Yaroslau Compta</name><affiliation><nlm:aff id="aff23">Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff24">Parkinson's Disease & Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clínic/University of Barcelona/IDIBAPS, Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Revesz, Tamas" sort="Revesz, Tamas" uniqKey="Revesz T" first="Tamas" last="Revesz">Tamas Revesz</name><affiliation><nlm:aff id="aff23">Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</nlm:aff></affiliation></author><author><name sortKey="Lees, Andrew" sort="Lees, Andrew" uniqKey="Lees A" first="Andrew" last="Lees">Andrew Lees</name><affiliation><nlm:aff id="aff23">Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</nlm:aff></affiliation></author><author><name sortKey="Cairns, Nigel J" sort="Cairns, Nigel J" uniqKey="Cairns N" first="Nigel J." last="Cairns">Nigel J. Cairns</name><affiliation><nlm:aff id="aff25">Department of Neurology, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA</nlm:aff></affiliation></author><author><name sortKey="Halliday, Glenda M" sort="Halliday, Glenda M" uniqKey="Halliday G" first="Glenda M." last="Halliday">Glenda M. Halliday</name><affiliation><nlm:aff id="aff26">Neuroscience Research Australia, Sydney, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff27">School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia</nlm:aff></affiliation></author><author><name sortKey="Mann, David" sort="Mann, David" uniqKey="Mann D" first="David" last="Mann">David Mann</name><affiliation><nlm:aff id="aff28">Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK</nlm:aff></affiliation></author><author><name sortKey="Pickering Brown, Stuart" sort="Pickering Brown, Stuart" uniqKey="Pickering Brown S" first="Stuart" last="Pickering-Brown">Stuart Pickering-Brown</name><affiliation><nlm:aff id="aff28">Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK</nlm:aff></affiliation></author><author><name sortKey="Powell, John" sort="Powell, John" uniqKey="Powell J" first="John" last="Powell">John Powell</name><affiliation><nlm:aff id="aff29">Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Lunnon, Katie" sort="Lunnon, Katie" uniqKey="Lunnon K" first="Katie" last="Lunnon">Katie Lunnon</name><affiliation><nlm:aff id="aff30">Institute of Clinical and Biomedical Science, University of Exeter Medical School, University of Exeter, Exeter, UK</nlm:aff></affiliation></author><author><name sortKey="Lupton, Michelle K" sort="Lupton, Michelle K" uniqKey="Lupton M" first="Michelle K." last="Lupton">Michelle K. Lupton</name><affiliation><nlm:aff id="aff29">Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Dickson, Dennis" sort="Dickson, Dennis" uniqKey="Dickson D" first="Dennis" last="Dickson">Dennis Dickson</name><affiliation><nlm:aff id="aff19">Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</nlm:aff></affiliation></author><author><name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name><affiliation><nlm:aff id="aff31">Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</nlm:aff></affiliation></author><author><name sortKey="Singleton, Andrew" sort="Singleton, Andrew" uniqKey="Singleton A" first="Andrew" last="Singleton">Andrew Singleton</name><affiliation><nlm:aff id="aff4">Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA</nlm:aff></affiliation></author><author><name sortKey="Bras, Jose" sort="Bras, Jose" uniqKey="Bras J" first="Jose" last="Bras">Jose Bras</name><affiliation><nlm:aff id="aff1">Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26643944</idno><idno type="pmc">4759606</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759606</idno><idno type="RBID">PMC:4759606</idno><idno type="doi">10.1016/j.neurobiolaging.2015.10.028</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000360</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000360</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases</title><author><name sortKey="Guerreiro, Rita" sort="Guerreiro, Rita" uniqKey="Guerreiro R" first="Rita" last="Guerreiro">Rita Guerreiro</name><affiliation><nlm:aff id="aff1">Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK</nlm:aff></affiliation></author><author><name sortKey="Escott Price, Valentina" sort="Escott Price, Valentina" uniqKey="Escott Price V" first="Valentina" last="Escott-Price">Valentina Escott-Price</name><affiliation><nlm:aff id="aff2">MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK</nlm:aff></affiliation></author><author><name sortKey="Darwent, Lee" sort="Darwent, Lee" uniqKey="Darwent L" first="Lee" last="Darwent">Lee Darwent</name><affiliation><nlm:aff id="aff1">Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK</nlm:aff></affiliation></author><author><name sortKey="Parkkinen, Laura" sort="Parkkinen, Laura" uniqKey="Parkkinen L" first="Laura" last="Parkkinen">Laura Parkkinen</name><affiliation><nlm:aff id="aff3">Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Ansorge, Olaf" sort="Ansorge, Olaf" uniqKey="Ansorge O" first="Olaf" last="Ansorge">Olaf Ansorge</name><affiliation><nlm:aff id="aff3">Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Hernandez, Dena G" sort="Hernandez, Dena G" uniqKey="Hernandez D" first="Dena G." last="Hernandez">Dena G. Hernandez</name><affiliation><nlm:aff id="aff4">Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Nalls, Michael A" sort="Nalls, Michael A" uniqKey="Nalls M" first="Michael A." last="Nalls">Michael A. Nalls</name><affiliation><nlm:aff id="aff4">Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA</nlm:aff></affiliation></author><author><name sortKey="Clark, Lorraine" sort="Clark, Lorraine" uniqKey="Clark L" first="Lorraine" last="Clark">Lorraine Clark</name><affiliation><nlm:aff id="aff6">Taub Institute for Alzheimer Disease and the Aging Brain, Columbia University, New York, NY, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Department of Pathology and Cell Biology, Columbia University, New York, NY, USA</nlm:aff></affiliation></author><author><name sortKey="Honig, Lawrence" sort="Honig, Lawrence" uniqKey="Honig L" first="Lawrence" last="Honig">Lawrence Honig</name><affiliation><nlm:aff id="aff6">Taub Institute for Alzheimer Disease and the Aging Brain, Columbia University, New York, NY, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Department of Pathology and Cell Biology, Columbia University, New York, NY, USA</nlm:aff></affiliation></author><author><name sortKey="Marder, Karen" sort="Marder, Karen" uniqKey="Marder K" first="Karen" last="Marder">Karen Marder</name><affiliation><nlm:aff id="aff6">Taub Institute for Alzheimer Disease and the Aging Brain, Columbia University, New York, NY, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">Department of Neurology, Columbia University, New York, NY, USA</nlm:aff></affiliation></author><author><name sortKey="Van Der Flier, Wiesje" sort="Van Der Flier, Wiesje" uniqKey="Van Der Flier W" first="Wiesje" last="Van Der Flier">Wiesje Van Der Flier</name><affiliation><nlm:aff id="aff9">Department Of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Holstege, Henne" sort="Holstege, Henne" uniqKey="Holstege H" first="Henne" last="Holstege">Henne Holstege</name><affiliation><nlm:aff id="aff9">Department Of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Louwersheimer, Eva" sort="Louwersheimer, Eva" uniqKey="Louwersheimer E" first="Eva" last="Louwersheimer">Eva Louwersheimer</name><affiliation><nlm:aff id="aff9">Department Of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Lemstra, Afina" sort="Lemstra, Afina" uniqKey="Lemstra A" first="Afina" last="Lemstra">Afina Lemstra</name><affiliation><nlm:aff id="aff9">Department Of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Scheltens, Philip" sort="Scheltens, Philip" uniqKey="Scheltens P" first="Philip" last="Scheltens">Philip Scheltens</name><affiliation><nlm:aff id="aff9">Department Of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name><affiliation><nlm:aff id="aff10">Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada</nlm:aff></affiliation></author><author><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name><affiliation><nlm:aff id="aff10">Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Cambridge Institute for Medical Research, and Cambridge National Institute of Health Research Biomedical Research Unit in Dementia, University of Cambridge, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Londos, Elisabet" sort="Londos, Elisabet" uniqKey="Londos E" first="Elisabet" last="Londos">Elisabet Londos</name><affiliation><nlm:aff id="aff12">Clinical Memory Research Unit, Institute of Clinical Sciences Malmö, Lund University, Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Zetterberg, Henrik" sort="Zetterberg, Henrik" uniqKey="Zetterberg H" first="Henrik" last="Zetterberg">Henrik Zetterberg</name><affiliation><nlm:aff id="aff13">Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden</nlm:aff></affiliation><affiliation><nlm:aff id="aff1">Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK</nlm:aff></affiliation></author><author><name sortKey="Ortega Cubero, Sara" sort="Ortega Cubero, Sara" uniqKey="Ortega Cubero S" first="Sara" last="Ortega-Cubero">Sara Ortega-Cubero</name><affiliation><nlm:aff id="aff14">Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, (CIMA), University of Navarra, Pamplona, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="aff15">CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Pastor, Pau" sort="Pastor, Pau" uniqKey="Pastor P" first="Pau" last="Pastor">Pau Pastor</name><affiliation><nlm:aff id="aff14">Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, (CIMA), University of Navarra, Pamplona, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="aff15">CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="aff16">Memory and Movement Disorders Units, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Ferman, Tanis J" sort="Ferman, Tanis J" uniqKey="Ferman T" first="Tanis J." last="Ferman">Tanis J. Ferman</name><affiliation><nlm:aff id="aff17">Departments of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA</nlm:aff></affiliation></author><author><name sortKey="Graff Radford, Neill R" sort="Graff Radford, Neill R" uniqKey="Graff Radford N" first="Neill R." last="Graff-Radford">Neill R. Graff-Radford</name><affiliation><nlm:aff id="aff18">Department of Neurology, Mayo Clinic, Jacksonville, FL, USA</nlm:aff></affiliation></author><author><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A." last="Ross">Owen A. Ross</name><affiliation><nlm:aff id="aff19">Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</nlm:aff></affiliation></author><author><name sortKey="Barber, Imelda" sort="Barber, Imelda" uniqKey="Barber I" first="Imelda" last="Barber">Imelda Barber</name><affiliation><nlm:aff id="aff20">Translation Cell Sciences—Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK</nlm:aff></affiliation></author><author><name sortKey="Braae, Anne" sort="Braae, Anne" uniqKey="Braae A" first="Anne" last="Braae">Anne Braae</name><affiliation><nlm:aff id="aff20">Translation Cell Sciences—Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK</nlm:aff></affiliation></author><author><name sortKey="Brown, Kristelle" sort="Brown, Kristelle" uniqKey="Brown K" first="Kristelle" last="Brown">Kristelle Brown</name><affiliation><nlm:aff id="aff20">Translation Cell Sciences—Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK</nlm:aff></affiliation></author><author><name sortKey="Morgan, Kevin" sort="Morgan, Kevin" uniqKey="Morgan K" first="Kevin" last="Morgan">Kevin Morgan</name><affiliation><nlm:aff id="aff20">Translation Cell Sciences—Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK</nlm:aff></affiliation></author><author><name sortKey="Maetzler, Walter" sort="Maetzler, Walter" uniqKey="Maetzler W" first="Walter" last="Maetzler">Walter Maetzler</name><affiliation><nlm:aff id="aff21">Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, Center of Neurology, University of Tuebingen, and DZNE, German Center for Neurodegenerative Diseases, Tuebingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Berg, Daniela" sort="Berg, Daniela" uniqKey="Berg D" first="Daniela" last="Berg">Daniela Berg</name><affiliation><nlm:aff id="aff21">Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, Center of Neurology, University of Tuebingen, and DZNE, German Center for Neurodegenerative Diseases, Tuebingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Troakes, Claire" sort="Troakes, Claire" uniqKey="Troakes C" first="Claire" last="Troakes">Claire Troakes</name><affiliation><nlm:aff id="aff22">MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Department of Clinical Neuroscience, King's College London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Al Sarraj, Safa" sort="Al Sarraj, Safa" uniqKey="Al Sarraj S" first="Safa" last="Al-Sarraj">Safa Al-Sarraj</name><affiliation><nlm:aff id="aff22">MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Department of Clinical Neuroscience, King's College London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Lashley, Tammaryn" sort="Lashley, Tammaryn" uniqKey="Lashley T" first="Tammaryn" last="Lashley">Tammaryn Lashley</name><affiliation><nlm:aff id="aff23">Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</nlm:aff></affiliation></author><author><name sortKey="Compta, Yaroslau" sort="Compta, Yaroslau" uniqKey="Compta Y" first="Yaroslau" last="Compta">Yaroslau Compta</name><affiliation><nlm:aff id="aff23">Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff24">Parkinson's Disease & Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clínic/University of Barcelona/IDIBAPS, Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Revesz, Tamas" sort="Revesz, Tamas" uniqKey="Revesz T" first="Tamas" last="Revesz">Tamas Revesz</name><affiliation><nlm:aff id="aff23">Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</nlm:aff></affiliation></author><author><name sortKey="Lees, Andrew" sort="Lees, Andrew" uniqKey="Lees A" first="Andrew" last="Lees">Andrew Lees</name><affiliation><nlm:aff id="aff23">Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</nlm:aff></affiliation></author><author><name sortKey="Cairns, Nigel J" sort="Cairns, Nigel J" uniqKey="Cairns N" first="Nigel J." last="Cairns">Nigel J. Cairns</name><affiliation><nlm:aff id="aff25">Department of Neurology, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA</nlm:aff></affiliation></author><author><name sortKey="Halliday, Glenda M" sort="Halliday, Glenda M" uniqKey="Halliday G" first="Glenda M." last="Halliday">Glenda M. Halliday</name><affiliation><nlm:aff id="aff26">Neuroscience Research Australia, Sydney, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff27">School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia</nlm:aff></affiliation></author><author><name sortKey="Mann, David" sort="Mann, David" uniqKey="Mann D" first="David" last="Mann">David Mann</name><affiliation><nlm:aff id="aff28">Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK</nlm:aff></affiliation></author><author><name sortKey="Pickering Brown, Stuart" sort="Pickering Brown, Stuart" uniqKey="Pickering Brown S" first="Stuart" last="Pickering-Brown">Stuart Pickering-Brown</name><affiliation><nlm:aff id="aff28">Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK</nlm:aff></affiliation></author><author><name sortKey="Powell, John" sort="Powell, John" uniqKey="Powell J" first="John" last="Powell">John Powell</name><affiliation><nlm:aff id="aff29">Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Lunnon, Katie" sort="Lunnon, Katie" uniqKey="Lunnon K" first="Katie" last="Lunnon">Katie Lunnon</name><affiliation><nlm:aff id="aff30">Institute of Clinical and Biomedical Science, University of Exeter Medical School, University of Exeter, Exeter, UK</nlm:aff></affiliation></author><author><name sortKey="Lupton, Michelle K" sort="Lupton, Michelle K" uniqKey="Lupton M" first="Michelle K." last="Lupton">Michelle K. Lupton</name><affiliation><nlm:aff id="aff29">Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Dickson, Dennis" sort="Dickson, Dennis" uniqKey="Dickson D" first="Dennis" last="Dickson">Dennis Dickson</name><affiliation><nlm:aff id="aff19">Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</nlm:aff></affiliation></author><author><name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name><affiliation><nlm:aff id="aff31">Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</nlm:aff></affiliation></author><author><name sortKey="Singleton, Andrew" sort="Singleton, Andrew" uniqKey="Singleton A" first="Andrew" last="Singleton">Andrew Singleton</name><affiliation><nlm:aff id="aff4">Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA</nlm:aff></affiliation></author><author><name sortKey="Bras, Jose" sort="Bras, Jose" uniqKey="Bras J" first="Jose" last="Bras">Jose Bras</name><affiliation><nlm:aff id="aff1">Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK</nlm:aff></affiliation></author></analytic><series><title level="j">Neurobiology of Aging</title><idno type="ISSN">0197-4580</idno><idno type="eISSN">1558-1497</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the <italic>APOE</italic> locus, DLB is equally correlated to AD and PD.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bras, J" uniqKey="Bras J">J. Bras</name></author><author><name sortKey="Guerreiro, R" uniqKey="Guerreiro R">R. Guerreiro</name></author><author><name sortKey="Darwent, L" uniqKey="Darwent L">L. Darwent</name></author><author><name sortKey="Parkkinen, L" uniqKey="Parkkinen L">L. Parkkinen</name></author><author><name sortKey="Ansorge, O" uniqKey="Ansorge O">O. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Neurobiol Aging</journal-id><journal-id journal-id-type="iso-abbrev">Neurobiol. 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contrib-type="author"><name><surname>Lees</surname><given-names>Andrew</given-names></name><xref rid="aff23" ref-type="aff">w</xref></contrib><contrib contrib-type="author"><name><surname>Cairns</surname><given-names>Nigel J.</given-names></name><xref rid="aff25" ref-type="aff">y</xref></contrib><contrib contrib-type="author"><name><surname>Halliday</surname><given-names>Glenda M.</given-names></name><xref rid="aff26" ref-type="aff">z</xref><xref rid="aff27" ref-type="aff">aa</xref></contrib><contrib contrib-type="author"><name><surname>Mann</surname><given-names>David</given-names></name><xref rid="aff28" ref-type="aff">bb</xref></contrib><contrib contrib-type="author"><name><surname>Pickering-Brown</surname><given-names>Stuart</given-names></name><xref rid="aff28" ref-type="aff">bb</xref></contrib><contrib contrib-type="author"><name><surname>Powell</surname><given-names>John</given-names></name><xref rid="aff29" ref-type="aff">cc</xref></contrib><contrib contrib-type="author"><name><surname>Lunnon</surname><given-names>Katie</given-names></name><xref rid="aff30" ref-type="aff">dd</xref></contrib><contrib contrib-type="author"><name><surname>Lupton</surname><given-names>Michelle K.</given-names></name><xref rid="aff29" ref-type="aff">cc</xref></contrib><contrib contrib-type="author"><collab>International Parkinson's Disease Genomics Consortium (IPDGC)</collab><xref rid="fn1" ref-type="fn">1</xref></contrib><contrib contrib-type="author"><name><surname>Dickson</surname><given-names>Dennis</given-names></name><xref rid="aff19" ref-type="aff">s</xref></contrib><contrib contrib-type="author"><name><surname>Hardy</surname><given-names>John</given-names></name><xref rid="aff31" ref-type="aff">ee</xref></contrib><contrib contrib-type="author"><name><surname>Singleton</surname><given-names>Andrew</given-names></name><xref rid="aff4" ref-type="aff">d</xref></contrib><contrib contrib-type="author"><name><surname>Bras</surname><given-names>Jose</given-names></name><email>j.bras@ucl.ac.uk</email><xref rid="aff1" ref-type="aff">a</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>a</label>Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK</aff><aff id="aff2"><label>b</label>MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK</aff><aff id="aff3"><label>c</label>Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK</aff><aff id="aff4"><label>d</label>Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA</aff><aff id="aff5"><label>e</label>German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</aff><aff id="aff6"><label>f</label>Taub Institute for Alzheimer Disease and the Aging Brain, Columbia University, New York, NY, USA</aff><aff id="aff7"><label>g</label>Department of Pathology and Cell Biology, Columbia University, New York, NY, USA</aff><aff id="aff8"><label>h</label>Department of Neurology, Columbia University, New York, NY, USA</aff><aff id="aff9"><label>i</label>Department Of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands</aff><aff id="aff10"><label>j</label>Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada</aff><aff id="aff11"><label>k</label>Cambridge Institute for Medical Research, and Cambridge National Institute of Health Research Biomedical Research Unit in Dementia, University of Cambridge, Cambridge, UK</aff><aff id="aff12"><label>l</label>Clinical Memory Research Unit, Institute of Clinical Sciences Malmö, Lund University, Lund, Sweden</aff><aff id="aff13"><label>m</label>Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden</aff><aff id="aff14"><label>n</label>Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, (CIMA), University of Navarra, Pamplona, Spain</aff><aff id="aff15"><label>o</label>CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain</aff><aff id="aff16"><label>p</label>Memory and Movement Disorders Units, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain</aff><aff id="aff17"><label>q</label>Departments of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA</aff><aff id="aff18"><label>r</label>Department of Neurology, Mayo Clinic, Jacksonville, FL, USA</aff><aff id="aff19"><label>s</label>Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</aff><aff id="aff20"><label>t</label>Translation Cell Sciences—Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK</aff><aff id="aff21"><label>u</label>Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, Center of Neurology, University of Tuebingen, and DZNE, German Center for Neurodegenerative Diseases, Tuebingen, Germany</aff><aff id="aff22"><label>v</label>MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Department of Clinical Neuroscience, King's College London, London, UK</aff><aff id="aff23"><label>w</label>Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</aff><aff id="aff24"><label>x</label>Parkinson's Disease & Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clínic/University of Barcelona/IDIBAPS, Barcelona, Spain</aff><aff id="aff25"><label>y</label>Department of Neurology, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA</aff><aff id="aff26"><label>z</label>Neuroscience Research Australia, Sydney, Australia</aff><aff id="aff27"><label>aa</label>School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia</aff><aff id="aff28"><label>bb</label>Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK</aff><aff id="aff29"><label>cc</label>Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK</aff><aff id="aff30"><label>dd</label>Institute of Clinical and Biomedical Science, University of Exeter Medical School, University of Exeter, Exeter, UK</aff><aff id="aff31"><label>ee</label>Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author at: Department of Molecular Neuroscience, Institute of Neurology, University College of London, 8-11 Queen Square, DRC, Box 16, London, WC1N 3AR, UK. Tel.: +44 203 448 3936.Department of Molecular NeuroscienceInstitute of NeurologyUniversity College of London8-11 Queen SquareDRCBox 16LondonWC1N 3ARUK <email>j.bras@ucl.ac.uk</email></corresp><fn id="fn1"><label>1</label><p id="ntpara0010">A complete list of the IPDGC members is listed in the <xref rid="appsec1" ref-type="sec">Supplementary Material</xref>.</p></fn><fn id="fn2"><label>2</label><p id="ntpara0015">Equally contributing authors.</p></fn></author-notes><pub-date pub-type="pmc-release"><day>1</day><month>2</month><year>2016</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><month>2</month><year>2016</year></pub-date><volume>38</volume><fpage>214.e7</fpage><lpage>214.e10</lpage><history><date date-type="received"><day>13</day><month>10</month><year>2015</year></date><date date-type="rev-recd"><day>27</day><month>10</month><year>2015</year></date><date date-type="accepted"><day>28</day><month>10</month><year>2015</year></date></history><permissions><copyright-statement>© 2016 The Authors</copyright-statement><copyright-year>2016</copyright-year><license license-type="CC BY" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</license-p></license></permissions><abstract><p>The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the <italic>APOE</italic> locus, DLB is equally correlated to AD and PD.</p></abstract><kwd-group><title>Keywords</title><kwd>Dementia with Lewy bodies</kwd><kwd>Alzheimer's disease</kwd><kwd>Parkinson's disease</kwd><kwd>Genetic correlation</kwd></kwd-group></article-meta></front><body><sec id="sec1"><label>1</label><title>Introduction</title><p>As we move toward an era where precision medicine becomes a reality, being able to confidently differentiate between closely related diseases is fast becoming a key priority. This is even more relevant when therapeutic approaches from one disease have negative effects when used in patients from another, as is the case in dementia with Lewy bodies (DLB) where neuropsychiatric and dysautonomic features can be worsened by dopaminergic agents used in Parkinson's disease (PD; <xref rid="bib12" ref-type="bibr">Zweig and Galvin, 2014</xref>).</p><p>DLB is probably one of the most underserved common disorders and much of this stems from the fact that it is a disease for which a clinical diagnosis is a particularly difficult one to make as DLB can be misdiagnosed as Alzheimer's disease (AD) when starting with cognitive impairment or as PD when presenting with parkinsonism, and in turn PD can be easily mistaken as DLB if parkinsonism is overlooked. There are numerous shared aspects between DLB and the other more common neurodegenerative diseases PD and AD. This is not only true at the clinical level (particularly in the case of DLB and PD, to the point that an artificial and arbitrary “one-year-rule” in terms of the timing between parkinsonism and dementia has been needed to delineate them), but also, to some extent, at the pathological level, where Lewy bodies are a common characteristic of both DLB and PD, and beta-amyloid plaques and tau-positive neurofibrillary tangles, hallmarks of AD, often coexist in DLB and PD brains leading to the suggestion of a synergism between these pathologies (<xref rid="bib2" ref-type="bibr">Compta et al., 2011</xref>, <xref rid="bib5" ref-type="bibr">McKeith et al., 2005</xref>).</p><p>It is key that we have a better understanding of the molecular mechanisms occurring in DLB, not only because this is pivotal information for novel therapies to be developed for this disease, but also because it will help us gain a better understanding of PD, particularly when associating dementia, and AD.</p><p>We have recently performed a large-scale genetic analysis in DLB that showed similarities in common genetic risk between this disease, PD, and AD (<xref rid="bib1" ref-type="bibr">Bras et al., 2014</xref>) using NeuroX, a genome-wide genotyping array (<xref rid="bib9" ref-type="bibr">Nalls et al., 2015</xref>). To better understand and quantify these similarities we have now estimated the proportion of variance explained by all single nucleotide polymorphisms of the DLB cohort, and of independent AD and PD cohorts of similar size. We then performed a bivariate restricted maximum likelihood analysis of the genetic relationship matrix, to quantify the genetic covariance between pairs of diseases.</p></sec><sec id="sec2"><label>2</label><title>Methods</title><p>Details of the DLB cohort have been published previously (<xref rid="bib1" ref-type="bibr">Bras et al., 2014</xref>). We used a cohort of 804 European PD cases and a cohort of 959 clinically diagnosed European AD cases, as well as 2806 European and North-American controls, genotyped on Illumina's NeuroX. The PD samples are a UK-only subset of the previously published PD and control dataset (<xref rid="bib10" ref-type="bibr">Nalls et al., 2014</xref>). The AD cases were diagnosed as either definite or probable AD according to National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's disease and Related Disorders Association (<xref rid="bib6" ref-type="bibr">McKhann et al., 1984</xref>), and the Consortium to Establish a Registry for Alzheimer's disease guidelines (<xref rid="bib7" ref-type="bibr">Mirra et al., 1991</xref>). All samples used in this study were received with informed consents approved by the local Ethics Committees (<xref rid="tbl1" ref-type="table">Table 1</xref>).</p><p>Following standard raw data quality control procedures, which included removing variants with GenTrain scores (a metric to assess genotyping quality) lower than 0.9 and samples with call rate lower than 90% (meaning that samples that had less than 90% of the markers genotyped were excluded), we removed markers that had a genotyping rate of >10% and a minor allele frequency of <3%. To generate covariates for the analysis, multidimensional scaling was used to quantify genetic distances between members of the entire cohort.</p><p>After estimating the genetic relationship matrix between pairs of individuals, we performed a bivariate restricted maximum likelihood analysis on that matrix, as implemented in the software genome-wide complex trait analysis (<xref rid="bib4" ref-type="bibr">Lee et al., 2012</xref>, <xref rid="bib11" ref-type="bibr">Yang et al., 2010</xref>) using the first 2 principal components from multidimensional scaling.</p><p>For each comparison the control population was randomized and 1403 controls were assigned to each disease. The analysis between DLB and AD was then repeated excluding markers in the <italic>APOE</italic> region.</p></sec><sec id="sec3"><label>3</label><title>Results</title><p>When using the entire array content, after quality control procedures, the estimates for the proportion of variance explained by all single nucleotide polymorphisms for DLB was 0.31 (SE ± 0.03), for AD was 0.6 (SE ± 0.05), and for PD was 0.28 (SE ± 0.05). When excluding the <italic>APOE</italic> region, the estimates were 0.22 (SE ± 0.03), 0.42 (SE ± 0.05), and 0.28 (SE ± 0.05), for DLB, AD, and PD. The decrease seen in DLB and AD reflect the strong and robust association of the <italic>APOE</italic> locus in these diseases.</p><p>When comparing pairs of diseases for genetic correlation (i.e., estimating the additive genetic effect i.e., shared between pairs of traits), the highest score was obtained for the AD/DLB pair (0.578, SE ± 0.075). The comparison between PD or DLB yielded a correlation score of 0.362 (SE ± 0.107). Both scores were highly significant with <italic>p</italic>-values of 1.1 × 10<sup>−12</sup> and 7.1 × 10<sup>−4</sup>, respectively. As a control experiment, we compared AD/PD and obtained a significantly lower score 0.08 (SE ± 0.101) (<italic>p</italic>-value = 0.006, with the most conservative estimate provided by the cocor.dep.groups.overlap function from the cocor package in R, a test of significance for the difference between 2 correlations based on dependent groups with 1 variable in common), that does not deviate from the null hypothesis of no correlation (<italic>p</italic>-value = 0.39).</p><p>Given the strong effect from <italic>APOE</italic> in AD and DLB, we have performed the same analysis excluding this locus in these 2 cohorts and obtained a correlation score for AD/DLB_NO_APOE (0.332 ± 0.106) that is not statistically different from the PD/DLB correlation (0.362 ± 0.107) (<italic>p</italic>-value = 0.761, using the same test as mentioned previously). The AD/DLB_NO_APOE correlation is still highly significant 1.8 × 10<sup>−3</sup> (<xref rid="tbl2" ref-type="table">Table 2</xref>).</p></sec><sec id="sec4"><label>4</label><title>Discussion</title><p>We have previously described that DLB shares genetic risk determinants with both PD and AD. Here we quantify that overlap by showing that these diseases are, in fact, correlated from a purely genetic perspective.</p><p>The DLB cohort is the largest reported so far and a majority of these cases are neuropathologically confirmed (85%), which greatly increases the diagnostic accuracy (<xref rid="bib1" ref-type="bibr">Bras et al., 2014</xref>). The numbers of PD and AD cases in this study are small, particularly when in comparison with other published datasets. We should note, however, that the fact that we fully replicate the phenotypic variance associated with all types of PD from large meta-analysis studies (<xref rid="bib3" ref-type="bibr">Keller et al., 2012</xref>), suggests these cohorts are representative, and not substantially underpowered for this type of analysis. In addition, our data shows no genetic correlation between PD and AD (correlation = 0.08, SE ± 0.101, <italic>p</italic>-value = 0.39 when correlation is fixed at 0), a result that replicates previous independent findings (<xref rid="bib8" ref-type="bibr">Moskvina et al., 2013</xref>).</p><p>It should be noted that although being a genome-wide array, NeuroX is not a completely unbiased genotyping platform. A proportion of the variants assayed in this array were included because they were known to be involved in these diseases. Because of this, some of these values may be inflated, however, for the purposes of determining genetic correlation, and comparing between pairs of diseases, this should have no discernible effect.</p><p>That DLB seems to share approximately the same amount of genetic risk determinants with PD and AD fits with our understanding of this disease, given the clinical and neuropathological overlap. Although not assessed in this work, it would be interesting to test if these correlations reflect quantitative pathology (e.g., would excluding DLB cases with prominent AD-related pathology reduce the correlation score between DLB and AD).</p></sec><sec id="sec5"><label>5</label><title>Conclusions</title><p>This is the first study to look at genetic correlation between DLB, PD, and AD. Despite using small cohorts, we show that these data replicate previously published results. We also show that DLB shares approximately the same amount of genetic determinants with PD as it does with AD, when the <italic>APOE</italic> locus is excluded. These results show us that, from a mechanistic standpoint, DLB is a different, but highly related disease to both AD and PD. They further emphasize the need for more studies in DLB—this is a greatly underappreciated disease and these data strongly support this fact. Fully dissecting the genetic architecture of DLB will allow us to gain a better understanding of not just one but all 3 diseases. In addition, these data also show that we should gradually move from the current model of binary diagnosis to a more quantitative one.</p></sec><sec id="sec6"><title>Disclosure statement</title><p>The authors have no conflicts of interest to disclose.</p></sec></body><back><ref-list><title>References</title><ref id="bib1"><element-citation publication-type="journal" id="sref1"><person-group person-group-type="author"><name><surname>Bras</surname><given-names>J.</given-names></name><name><surname>Guerreiro</surname><given-names>R.</given-names></name><name><surname>Darwent</surname><given-names>L.</given-names></name><name><surname>Parkkinen</surname><given-names>L.</given-names></name><name><surname>Ansorge</surname><given-names>O.</given-names></name><name><surname>Escott-Price</surname><given-names>V.</given-names></name><name><surname>Hernandez</surname><given-names>D.G.</given-names></name><name><surname>Nalls</surname><given-names>M.A.</given-names></name><name><surname>Clark</surname><given-names>L.N.</given-names></name><name><surname>Honig</surname><given-names>L.S.</given-names></name><name><surname>Marder</surname><given-names>K.</given-names></name><name><surname>Van Der Flier</surname><given-names>W.M.</given-names></name><name><surname>Lemstra</surname><given-names>A.</given-names></name><name><surname>Scheltens</surname><given-names>P.</given-names></name><name><surname>Rogaeva</surname><given-names>E.</given-names></name><name><surname>St George-Hyslop</surname><given-names>P.</given-names></name><name><surname>Londos</surname><given-names>E.</given-names></name><name><surname>Zetterberg</surname><given-names>H.</given-names></name><name><surname>Ortega-Cubero</surname><given-names>S.</given-names></name><name><surname>Pastor</surname><given-names>P.</given-names></name><name><surname>Ferman</surname><given-names>T.J.</given-names></name><name><surname>Graff-Radford</surname><given-names>N.R.</given-names></name><name><surname>Ross</surname><given-names>O.A.</given-names></name><name><surname>Barber</surname><given-names>I.</given-names></name><name><surname>Braae</surname><given-names>A.</given-names></name><name><surname>Brown</surname><given-names>K.</given-names></name><name><surname>Morgan</surname><given-names>K.</given-names></name><name><surname>Maetzler</surname><given-names>W.</given-names></name><name><surname>Berg</surname><given-names>D.</given-names></name><name><surname>Troakes</surname><given-names>C.</given-names></name><name><surname>Al-Sarraj</surname><given-names>S.</given-names></name><name><surname>Lashley</surname><given-names>T.</given-names></name><name><surname>Compta</surname><given-names>Y.</given-names></name><name><surname>Revesz</surname><given-names>T.</given-names></name><name><surname>Lees</surname><given-names>A.</given-names></name><name><surname>Cairns</surname><given-names>N.</given-names></name><name><surname>Halliday</surname><given-names>G.M.</given-names></name><name><surname>Mann</surname><given-names>D.</given-names></name><name><surname>Pickering-Brown</surname><given-names>S.</given-names></name><name><surname>Dickson</surname><given-names>D.W.</given-names></name><name><surname>Singleton</surname><given-names>A.</given-names></name><name><surname>Hardy</surname><given-names>J.</given-names></name></person-group><article-title>Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies</article-title><source>Hum. 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Ther.</source><volume>6</volume><year>2014</year><fpage>21</fpage><pub-id pub-id-type="pmid">25031635</pub-id></element-citation></ref></ref-list><sec id="appsec1" sec-type="supplementary-material"><label>Appendix A</label><title>Supplementary data</title><p><supplementary-material content-type="local-data" id="ec1"><caption><title>Supplementary Material</title></caption><media xlink:href="mmc1.docx"></media></supplementary-material></p></sec><ack id="ack0010"><title>Acknowledgements</title><p>Rita Guerreiro and Jose Bras are supported by Research Fellowships from the Alzheimer's Society. This work was supported in part by a Parkinson's UK Innovation Award (K-1204) in collaboration with the Lewy Body Society and by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium whose members are from the UCL Institute of Neurology, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee and by an anonymous Foundation. The authors would like to acknowledge Elena Lorenzo for her technical assistance. This study was supported in part by grants from the <funding-source id="gs1">Spanish Ministry of Science and Innovation</funding-source> SAF2006-10126 (2006–2009) and SAF2010-22329-C02-01 (2011–2013) and SAF2013-47939-R (2013–2015) to Pau Pastor and by the UTE project FIMA to Pau Pastor. They acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK, and the NIHR Oxford Biomedical Research Centre. The sample collection and database of the Amsterdam Dementia Cohort was funded by Stichting Dioraphte and Stichting VUMC fonds. Glenda M. Halliday is a Senior Principal Research Fellow of the National Health and Medical Research Council of Australia. For the neuropathologically confirmed samples from Australia, brain tissue was received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia, the University of New South Wales, and the National Health and Medical Research Council of Australia. This study was also partially funded by the <funding-source id="gs2">Wellcome Trust</funding-source>, <funding-source id="gs3">Medical Research Council</funding-source>, <funding-source id="gs4">Canadian Institutes of Health Research</funding-source>, <funding-source id="gs5">Ontario Research Fund</funding-source>. The Nottingham Genetics Group is supported by ARUK and The Big Lottery Fund. The effort from Columbia University was supported by the <funding-source id="gs6">Taub Institute</funding-source>, the <funding-source id="gs7">Panasci Fund</funding-source>, the <funding-source id="gs8">Parkinson's Disease Foundation</funding-source>, and <funding-source id="gs9">NIH</funding-source> grants NS060113 (Lorraine Clark), P50AG008702 (P.I. Scott Small), P50NS038370 (P.I. R. Burke), and UL1TR000040 (P.I. H. Ginsberg). Owen A. Ross is supported by the Michael J. Fox Foundation, NINDS R01# NS078086. The Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187) and is supported by the Mangurian Foundation for Lewy body research. This work has received support from <funding-source id="gs10">The Queen Square Brain Bank</funding-source> at the UCL Institute of Neurology. Some of the tissue samples studies were provided by the MRC London Neurodegenerative Diseases Brain Bank and the Brains for Dementia Research project (funded by Alzheimer's Society and ARUK). This research was supported in part by the <funding-source id="gs11">NIHR UCLH Biomedical Research Centre</funding-source>, the Queen Square Dementia Biomedical Research Unit, the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit and Biomedical Research Centre at South London and <funding-source id="gs13">Maudsley NHS Foundation Trust</funding-source> and <funding-source id="gs14">King's College Hospital</funding-source>, London. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project AG000951-12. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust and the Medical Research Council.</p></ack><fn-group><fn id="appsec2" fn-type="supplementary-material"><label>Appendix A</label><p>Supplementary data associated with this article can be found, in the online version, at <ext-link ext-link-type="doi" xlink:href="10.1016/j.neurobiolaging.2015.10.028" id="intref0010">http://dx.doi.org/10.1016/j.neurobiolaging.2015.10.028</ext-link>.</p></fn></fn-group></back><floats-group><table-wrap id="tbl1" position="float"><label>Table 1</label><caption><p>Samples included in the study</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Trait</th><th>Total cases</th><th>Pathologically confirmed cases</th></tr></thead><tbody><tr><td>DLB</td><td align="char">788</td><td align="char">667</td></tr><tr><td>AD</td><td align="char">959</td><td align="char">113</td></tr><tr><td>PD</td><td align="char">804</td><td align="char">0</td></tr></tbody></table><table-wrap-foot><fn><p>Key: AD, Alzheimer's disease; DLB, dementia with Lewy bodies; PD, Parkinson's disease.</p></fn></table-wrap-foot></table-wrap><table-wrap id="tbl2" position="float"><label>Table 2</label><caption><p>Genetic correlation scores between pairs of diseases</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Trait1</th><th>Trait2</th><th>Genetic correlation</th><th>SE</th><th><italic>p</italic>-value</th></tr></thead><tbody><tr><td>AD</td><td>DLB</td><td align="char">0.578</td><td align="char">0.075</td><td align="char">1.1 × 10<sup>−12</sup></td></tr><tr><td>PD</td><td>DLB</td><td align="char">0.362</td><td align="char">0.107</td><td align="char">7.1 × 10<sup>−4</sup></td></tr><tr><td>AD</td><td>PD</td><td align="char">0.08</td><td align="char">0.101</td><td>0.39</td></tr><tr><td>AD</td><td>DLB_NO_APOE</td><td align="char">0.332</td><td align="char">0.106</td><td align="char">1.8 × 10<sup>−3</sup></td></tr></tbody></table><table-wrap-foot><fn><p>Key: AD, Alzheimer's disease; DLB, dementia with Lewy bodies; PD, Parkinson's disease; SE, standard error.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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