Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study
Identifieur interne : 000150 ( Pmc/Curation ); précédent : 000149; suivant : 000151Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study
Auteurs : Bram. P. Prins [Pays-Bas, Royaume-Uni] ; Ali Abbasi [Pays-Bas, Royaume-Uni] ; Anson Wong [Canada] ; Ahmad Vaez [Pays-Bas, Iran] ; Ilja Nolte [Pays-Bas] ; Nora Franceschini [États-Unis] ; Philip E. Stuart [États-Unis] ; Javier Guterriez Achury [Pays-Bas] ; Vanisha Mistry [Royaume-Uni] ; Jonathan P. Bradfield [États-Unis] ; Ana M. Valdes [Royaume-Uni] ; Jose Bras [Royaume-Uni] ; Aleksey Shatunov [Royaume-Uni] ; Chen Lu [États-Unis] ; Buhm Han [États-Unis] ; Soumya Raychaudhuri [États-Unis, Royaume-Uni] ; Steve Bevan [Royaume-Uni] ; Maureen D. Mayes [États-Unis] ; Lam C. Tsoi [États-Unis] ; Evangelos Evangelou [Grèce, Royaume-Uni] ; Rajan P. Nair [États-Unis] ; Struan F. A. Grant [États-Unis] ; Constantin Polychronakos [Canada] ; Timothy R. D. Radstake [Pays-Bas] ; David A. Van Heel [Royaume-Uni] ; Melanie L. Dunstan [Royaume-Uni] ; Nicholas W. Wood [Royaume-Uni] ; Ammar Al-Chalabi [Royaume-Uni, États-Unis] ; Abbas Dehghan [Pays-Bas] ; Hakon Hakonarson [États-Unis] ; Hugh S. Markus [Royaume-Uni] ; James T. Elder [États-Unis] ; Jo Knight [Canada] ; Dan E. Arking [États-Unis] ; Timothy D. Spector [Royaume-Uni] ; Bobby P. C. Koeleman [Pays-Bas] ; Cornelia M. Van Duijn [Pays-Bas] ; Javier Martin [Espagne] ; Andrew P. Morris [Royaume-Uni] ; Rinse K. Weersma [Pays-Bas] ; Cisca Wijmenga [Pays-Bas] ; Patricia B. Munroe [Royaume-Uni] ; John R. B. Perry [Royaume-Uni] ; Jennie G. Pouget [Canada] ; Yalda Jamshidi [Royaume-Uni] ; Harold Snieder [Pays-Bas] ; Behrooz Z. Alizadeh [Pays-Bas]Source :
- PLoS Medicine [ 1549-1277 ] ; 2016.
Abstract
C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.
We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRS
The strengths (
Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed
Url:
DOI: 10.1371/journal.pmed.1001976
PubMed: 27327646
PubMed Central: 4915710
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<affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom</addr-line>
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<affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands</addr-line>
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<author><name sortKey="Wong, Anson" sort="Wong, Anson" uniqKey="Wong A" first="Anson" last="Wong">Anson Wong</name>
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<affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran</addr-line>
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<author><name sortKey="Franceschini, Nora" sort="Franceschini, Nora" uniqKey="Franceschini N" first="Nora" last="Franceschini">Nora Franceschini</name>
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<author><name sortKey="Stuart, Philip E" sort="Stuart, Philip E" uniqKey="Stuart P" first="Philip E." last="Stuart">Philip E. Stuart</name>
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<author><name sortKey="Guterriez Achury, Javier" sort="Guterriez Achury, Javier" uniqKey="Guterriez Achury J" first="Javier" last="Guterriez Achury">Javier Guterriez Achury</name>
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<author><name sortKey="Mistry, Vanisha" sort="Mistry, Vanisha" uniqKey="Mistry V" first="Vanisha" last="Mistry">Vanisha Mistry</name>
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<author><name sortKey="Bradfield, Jonathan P" sort="Bradfield, Jonathan P" uniqKey="Bradfield J" first="Jonathan P." last="Bradfield">Jonathan P. Bradfield</name>
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<author><name sortKey="Valdes, Ana M" sort="Valdes, Ana M" uniqKey="Valdes A" first="Ana M." last="Valdes">Ana M. Valdes</name>
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<author><name sortKey="Bras, Jose" sort="Bras, Jose" uniqKey="Bras J" first="Jose" last="Bras">Jose Bras</name>
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<author><name sortKey="Shatunov, Aleksey" sort="Shatunov, Aleksey" uniqKey="Shatunov A" first="Aleksey" last="Shatunov">Aleksey Shatunov</name>
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</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London</wicri:regionArea>
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<author><name sortKey="Lu, Chen" sort="Lu, Chen" uniqKey="Lu C" first="Chen" last="Lu">Chen Lu</name>
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<wicri:regionArea>Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts</wicri:regionArea>
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<author><name sortKey="Han, Buhm" sort="Han, Buhm" uniqKey="Han B" first="Buhm" last="Han">Buhm Han</name>
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<author><name sortKey="Raychaudhuri, Soumya" sort="Raychaudhuri, Soumya" uniqKey="Raychaudhuri S" first="Soumya" last="Raychaudhuri">Soumya Raychaudhuri</name>
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<wicri:regionArea>Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="aff032"><addr-line>Division of Rheumatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America</addr-line>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Rheumatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="aff033"><addr-line>Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America</addr-line>
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<wicri:regionArea>Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="aff034"><addr-line>Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Faculty of Medical and Human Sciences, University of Manchester, Manchester</wicri:regionArea>
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<author><name sortKey="Bevan, Steve" sort="Bevan, Steve" uniqKey="Bevan S" first="Steve" last="Bevan">Steve Bevan</name>
<affiliation wicri:level="1"><nlm:aff id="aff017"><addr-line>Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge</wicri:regionArea>
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<author><name sortKey="Mayes, Maureen D" sort="Mayes, Maureen D" uniqKey="Mayes M" first="Maureen D." last="Mayes">Maureen D. Mayes</name>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas</wicri:regionArea>
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</author>
<author><name sortKey="Tsoi, Lam C" sort="Tsoi, Lam C" uniqKey="Tsoi L" first="Lam C." last="Tsoi">Lam C. Tsoi</name>
<affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff035"><addr-line>Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biostatistics, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Evangelou, Evangelos" sort="Evangelou, Evangelos" uniqKey="Evangelou E" first="Evangelos" last="Evangelou">Evangelos Evangelou</name>
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</nlm:aff>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff036"><addr-line>Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nair, Rajan P" sort="Nair, Rajan P" uniqKey="Nair R" first="Rajan P." last="Nair">Rajan P. Nair</name>
<affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Grant, Struan F A" sort="Grant, Struan F A" uniqKey="Grant S" first="Struan F. A." last="Grant">Struan F. A. Grant</name>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff037"><addr-line>Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Polychronakos, Constantin" sort="Polychronakos, Constantin" uniqKey="Polychronakos C" first="Constantin" last="Polychronakos">Constantin Polychronakos</name>
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</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Endocrine Genetics Research Institute, McGill University Health Center, Montreal, Quebec</wicri:regionArea>
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</author>
<author><name sortKey="Radstake, Timothy R D" sort="Radstake, Timothy R D" uniqKey="Radstake T" first="Timothy R. D." last="Radstake">Timothy R. D. Radstake</name>
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</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Rheumatology & Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Heel, David A" sort="Van Heel, David A" uniqKey="Van Heel D" first="David A." last="Van Heel">David A. Van Heel</name>
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</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Dunstan, Melanie L" sort="Dunstan, Melanie L" uniqKey="Dunstan M" first="Melanie L." last="Dunstan">Melanie L. Dunstan</name>
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</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff</wicri:regionArea>
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<author><name sortKey="Wood, Nicholas W" sort="Wood, Nicholas W" uniqKey="Wood N" first="Nicholas W." last="Wood">Nicholas W. Wood</name>
<affiliation wicri:level="1"><nlm:aff id="aff023"><addr-line>Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Molecular Neuroscience, UCL Institute of Neurology, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Al Chalabi, Ammar" sort="Al Chalabi, Ammar" uniqKey="Al Chalabi A" first="Ammar" last="Al-Chalabi">Ammar Al-Chalabi</name>
<affiliation wicri:level="1"><nlm:aff id="aff016"><addr-line>Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff040"><addr-line>Complex Disease Genetics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Complex Disease Genetics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York</wicri:regionArea>
</affiliation>
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<author><name sortKey="Dehghan, Abbas" sort="Dehghan, Abbas" uniqKey="Dehghan A" first="Abbas" last="Dehghan">Abbas Dehghan</name>
<affiliation wicri:level="1"><nlm:aff id="aff041"><addr-line>Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hakonarson, Hakon" sort="Hakonarson, Hakon" uniqKey="Hakonarson H" first="Hakon" last="Hakonarson">Hakon Hakonarson</name>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff037"><addr-line>Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Markus, Hugh S" sort="Markus, Hugh S" uniqKey="Markus H" first="Hugh S." last="Markus">Hugh S. Markus</name>
<affiliation wicri:level="1"><nlm:aff id="aff017"><addr-line>Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Elder, James T" sort="Elder, James T" uniqKey="Elder J" first="James T." last="Elder">James T. Elder</name>
<affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Knight, Jo" sort="Knight, Jo" uniqKey="Knight J" first="Jo" last="Knight">Jo Knight</name>
<affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Institute of Medical Sciences, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff042"><addr-line>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff043"><addr-line>Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Psychiatry, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff044"><addr-line>Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Arking, Dan E" sort="Arking, Dan E" uniqKey="Arking D" first="Dan E." last="Arking">Dan E. Arking</name>
<affiliation wicri:level="1"><nlm:aff id="aff024"><addr-line>McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Spector, Timothy D" sort="Spector, Timothy D" uniqKey="Spector T" first="Timothy D." last="Spector">Timothy D. Spector</name>
<affiliation wicri:level="1"><nlm:aff id="aff045"><addr-line>Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Twin Research and Genetic Epidemiology, King’s College London, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Koeleman, Bobby P C" sort="Koeleman, Bobby P C" uniqKey="Koeleman B" first="Bobby P. C." last="Koeleman">Bobby P. C. Koeleman</name>
<affiliation wicri:level="1"><nlm:aff id="aff046"><addr-line>Complex Genetic Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Complex Genetic Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Duijn, Cornelia M" sort="Van Duijn, Cornelia M" uniqKey="Van Duijn C" first="Cornelia M." last="Van Duijn">Cornelia M. Van Duijn</name>
<affiliation wicri:level="1"><nlm:aff id="aff041"><addr-line>Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Martin, Javier" sort="Martin, Javier" uniqKey="Martin J" first="Javier" last="Martin">Javier Martin</name>
<affiliation wicri:level="1"><nlm:aff id="aff019"><addr-line>Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain</addr-line>
</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Granada</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Morris, Andrew P" sort="Morris, Andrew P" uniqKey="Morris A" first="Andrew P." last="Morris">Andrew P. Morris</name>
<affiliation wicri:level="1"><nlm:aff id="aff021"><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff047"><addr-line>Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Biostatistics, University of Liverpool, Liverpool</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Weersma, Rinse K" sort="Weersma, Rinse K" uniqKey="Weersma R" first="Rinse K." last="Weersma">Rinse K. Weersma</name>
<affiliation wicri:level="1"><nlm:aff id="aff048"><addr-line>Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Wijmenga, Cisca" sort="Wijmenga, Cisca" uniqKey="Wijmenga C" first="Cisca" last="Wijmenga">Cisca Wijmenga</name>
<affiliation wicri:level="1"><nlm:aff id="aff010"><addr-line>Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Munroe, Patricia B" sort="Munroe, Patricia B" uniqKey="Munroe P" first="Patricia B." last="Munroe">Patricia B. Munroe</name>
<affiliation wicri:level="1"><nlm:aff id="aff027"><addr-line>NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Queen Mary University of London, London</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff049"><addr-line>Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Perry, John R B" sort="Perry, John R B" uniqKey="Perry J" first="John R. B." last="Perry">John R. B. Perry</name>
<affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pouget, Jennie G" sort="Pouget, Jennie G" uniqKey="Pouget J" first="Jennie G." last="Pouget">Jennie G. Pouget</name>
<affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Institute of Medical Sciences, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff042"><addr-line>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff043"><addr-line>Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Psychiatry, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Jamshidi, Yalda" sort="Jamshidi, Yalda" uniqKey="Jamshidi Y" first="Yalda" last="Jamshidi">Yalda Jamshidi</name>
<affiliation wicri:level="1"><nlm:aff id="aff050"><addr-line>Cardiogenetics Lab, Cardiovascular and Cell Sciences Institute, St George’s Hospital Medical School, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Cardiogenetics Lab, Cardiovascular and Cell Sciences Institute, St George’s Hospital Medical School, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Snieder, Harold" sort="Snieder, Harold" uniqKey="Snieder H" first="Harold" last="Snieder">Harold Snieder</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Alizadeh, Behrooz Z" sort="Alizadeh, Behrooz Z" uniqKey="Alizadeh B" first="Behrooz Z." last="Alizadeh">Behrooz Z. Alizadeh</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff048"><addr-line>Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study</title>
<author><name sortKey="Prins, Bram P" sort="Prins, Bram P" uniqKey="Prins B" first="Bram. P." last="Prins">Bram. P. Prins</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Abbasi, Ali" sort="Abbasi, Ali" uniqKey="Abbasi A" first="Ali" last="Abbasi">Ali Abbasi</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Wong, Anson" sort="Wong, Anson" uniqKey="Wong A" first="Anson" last="Wong">Anson Wong</name>
<affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Institute of Medical Sciences, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Faculty of Medicine, University of Ottawa, Ottawa, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Vaez, Ahmad" sort="Vaez, Ahmad" uniqKey="Vaez A" first="Ahmad" last="Vaez">Ahmad Vaez</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran</addr-line>
</nlm:aff>
<country xml:lang="fr">Iran</country>
<wicri:regionArea>School of Medicine, Isfahan University of Medical Sciences, Isfahan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nolte, Ilja" sort="Nolte, Ilja" uniqKey="Nolte I" first="Ilja" last="Nolte">Ilja Nolte</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Franceschini, Nora" sort="Franceschini, Nora" uniqKey="Franceschini N" first="Nora" last="Franceschini">Nora Franceschini</name>
<affiliation wicri:level="1"><nlm:aff id="aff008"><addr-line>Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Stuart, Philip E" sort="Stuart, Philip E" uniqKey="Stuart P" first="Philip E." last="Stuart">Philip E. Stuart</name>
<affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Guterriez Achury, Javier" sort="Guterriez Achury, Javier" uniqKey="Guterriez Achury J" first="Javier" last="Guterriez Achury">Javier Guterriez Achury</name>
<affiliation wicri:level="1"><nlm:aff id="aff010"><addr-line>Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mistry, Vanisha" sort="Mistry, Vanisha" uniqKey="Mistry V" first="Vanisha" last="Mistry">Vanisha Mistry</name>
<affiliation wicri:level="1"><nlm:aff id="aff011"><addr-line>Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bradfield, Jonathan P" sort="Bradfield, Jonathan P" uniqKey="Bradfield J" first="Jonathan P." last="Bradfield">Jonathan P. Bradfield</name>
<affiliation wicri:level="1"><nlm:aff id="aff013"><addr-line>Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Valdes, Ana M" sort="Valdes, Ana M" uniqKey="Valdes A" first="Ana M." last="Valdes">Ana M. Valdes</name>
<affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Department of Academic Rheumatology, University of Nottingham, Nottingham, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Academic Rheumatology, University of Nottingham, Nottingham</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bras, Jose" sort="Bras, Jose" uniqKey="Bras J" first="Jose" last="Bras">Jose Bras</name>
<affiliation wicri:level="1"><nlm:aff id="aff015"><addr-line>Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Molecular Neuroscience, Institute of Neurology, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Shatunov, Aleksey" sort="Shatunov, Aleksey" uniqKey="Shatunov A" first="Aleksey" last="Shatunov">Aleksey Shatunov</name>
<affiliation wicri:level="1"><nlm:aff id="aff016"><addr-line>Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lu, Chen" sort="Lu, Chen" uniqKey="Lu C" first="Chen" last="Lu">Chen Lu</name>
<affiliation wicri:level="1"><nlm:aff id="aff029"><addr-line>Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Han, Buhm" sort="Han, Buhm" uniqKey="Han B" first="Buhm" last="Han">Buhm Han</name>
<affiliation wicri:level="1"><nlm:aff id="aff030"><addr-line>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Raychaudhuri, Soumya" sort="Raychaudhuri, Soumya" uniqKey="Raychaudhuri S" first="Soumya" last="Raychaudhuri">Soumya Raychaudhuri</name>
<affiliation wicri:level="1"><nlm:aff id="aff030"><addr-line>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff031"><addr-line>Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff032"><addr-line>Division of Rheumatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Rheumatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff033"><addr-line>Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff034"><addr-line>Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Faculty of Medical and Human Sciences, University of Manchester, Manchester</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bevan, Steve" sort="Bevan, Steve" uniqKey="Bevan S" first="Steve" last="Bevan">Steve Bevan</name>
<affiliation wicri:level="1"><nlm:aff id="aff017"><addr-line>Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mayes, Maureen D" sort="Mayes, Maureen D" uniqKey="Mayes M" first="Maureen D." last="Mayes">Maureen D. Mayes</name>
<affiliation wicri:level="1"><nlm:aff id="aff018"><addr-line>Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tsoi, Lam C" sort="Tsoi, Lam C" uniqKey="Tsoi L" first="Lam C." last="Tsoi">Lam C. Tsoi</name>
<affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff035"><addr-line>Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biostatistics, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Evangelou, Evangelos" sort="Evangelou, Evangelos" uniqKey="Evangelou E" first="Evangelos" last="Evangelou">Evangelos Evangelou</name>
<affiliation wicri:level="1"><nlm:aff id="aff020"><addr-line>Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece</addr-line>
</nlm:aff>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff036"><addr-line>Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nair, Rajan P" sort="Nair, Rajan P" uniqKey="Nair R" first="Rajan P." last="Nair">Rajan P. Nair</name>
<affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Grant, Struan F A" sort="Grant, Struan F A" uniqKey="Grant S" first="Struan F. A." last="Grant">Struan F. A. Grant</name>
<affiliation wicri:level="1"><nlm:aff id="aff013"><addr-line>Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff037"><addr-line>Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Polychronakos, Constantin" sort="Polychronakos, Constantin" uniqKey="Polychronakos C" first="Constantin" last="Polychronakos">Constantin Polychronakos</name>
<affiliation wicri:level="1"><nlm:aff id="aff038"><addr-line>Endocrine Genetics Research Institute, McGill University Health Center, Montreal, Quebec, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Endocrine Genetics Research Institute, McGill University Health Center, Montreal, Quebec</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Radstake, Timothy R D" sort="Radstake, Timothy R D" uniqKey="Radstake T" first="Timothy R. D." last="Radstake">Timothy R. D. Radstake</name>
<affiliation wicri:level="1"><nlm:aff id="aff039"><addr-line>Department of Rheumatology & Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Rheumatology & Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Heel, David A" sort="Van Heel, David A" uniqKey="Van Heel D" first="David A." last="Van Heel">David A. Van Heel</name>
<affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Dunstan, Melanie L" sort="Dunstan, Melanie L" uniqKey="Dunstan M" first="Melanie L." last="Dunstan">Melanie L. Dunstan</name>
<affiliation wicri:level="1"><nlm:aff id="aff026"><addr-line>Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Wood, Nicholas W" sort="Wood, Nicholas W" uniqKey="Wood N" first="Nicholas W." last="Wood">Nicholas W. Wood</name>
<affiliation wicri:level="1"><nlm:aff id="aff023"><addr-line>Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Molecular Neuroscience, UCL Institute of Neurology, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Al Chalabi, Ammar" sort="Al Chalabi, Ammar" uniqKey="Al Chalabi A" first="Ammar" last="Al-Chalabi">Ammar Al-Chalabi</name>
<affiliation wicri:level="1"><nlm:aff id="aff016"><addr-line>Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff040"><addr-line>Complex Disease Genetics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Complex Disease Genetics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Dehghan, Abbas" sort="Dehghan, Abbas" uniqKey="Dehghan A" first="Abbas" last="Dehghan">Abbas Dehghan</name>
<affiliation wicri:level="1"><nlm:aff id="aff041"><addr-line>Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hakonarson, Hakon" sort="Hakonarson, Hakon" uniqKey="Hakonarson H" first="Hakon" last="Hakonarson">Hakon Hakonarson</name>
<affiliation wicri:level="1"><nlm:aff id="aff013"><addr-line>Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff037"><addr-line>Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Markus, Hugh S" sort="Markus, Hugh S" uniqKey="Markus H" first="Hugh S." last="Markus">Hugh S. Markus</name>
<affiliation wicri:level="1"><nlm:aff id="aff017"><addr-line>Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Elder, James T" sort="Elder, James T" uniqKey="Elder J" first="James T." last="Elder">James T. Elder</name>
<affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Knight, Jo" sort="Knight, Jo" uniqKey="Knight J" first="Jo" last="Knight">Jo Knight</name>
<affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Institute of Medical Sciences, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff042"><addr-line>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff043"><addr-line>Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Psychiatry, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff044"><addr-line>Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Arking, Dan E" sort="Arking, Dan E" uniqKey="Arking D" first="Dan E." last="Arking">Dan E. Arking</name>
<affiliation wicri:level="1"><nlm:aff id="aff024"><addr-line>McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Spector, Timothy D" sort="Spector, Timothy D" uniqKey="Spector T" first="Timothy D." last="Spector">Timothy D. Spector</name>
<affiliation wicri:level="1"><nlm:aff id="aff045"><addr-line>Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Twin Research and Genetic Epidemiology, King’s College London, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Koeleman, Bobby P C" sort="Koeleman, Bobby P C" uniqKey="Koeleman B" first="Bobby P. C." last="Koeleman">Bobby P. C. Koeleman</name>
<affiliation wicri:level="1"><nlm:aff id="aff046"><addr-line>Complex Genetic Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Complex Genetic Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Duijn, Cornelia M" sort="Van Duijn, Cornelia M" uniqKey="Van Duijn C" first="Cornelia M." last="Van Duijn">Cornelia M. Van Duijn</name>
<affiliation wicri:level="1"><nlm:aff id="aff041"><addr-line>Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Martin, Javier" sort="Martin, Javier" uniqKey="Martin J" first="Javier" last="Martin">Javier Martin</name>
<affiliation wicri:level="1"><nlm:aff id="aff019"><addr-line>Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain</addr-line>
</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Granada</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Morris, Andrew P" sort="Morris, Andrew P" uniqKey="Morris A" first="Andrew P." last="Morris">Andrew P. Morris</name>
<affiliation wicri:level="1"><nlm:aff id="aff021"><addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff047"><addr-line>Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Biostatistics, University of Liverpool, Liverpool</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Weersma, Rinse K" sort="Weersma, Rinse K" uniqKey="Weersma R" first="Rinse K." last="Weersma">Rinse K. Weersma</name>
<affiliation wicri:level="1"><nlm:aff id="aff048"><addr-line>Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Wijmenga, Cisca" sort="Wijmenga, Cisca" uniqKey="Wijmenga C" first="Cisca" last="Wijmenga">Cisca Wijmenga</name>
<affiliation wicri:level="1"><nlm:aff id="aff010"><addr-line>Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Munroe, Patricia B" sort="Munroe, Patricia B" uniqKey="Munroe P" first="Patricia B." last="Munroe">Patricia B. Munroe</name>
<affiliation wicri:level="1"><nlm:aff id="aff027"><addr-line>NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Queen Mary University of London, London</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff049"><addr-line>Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Perry, John R B" sort="Perry, John R B" uniqKey="Perry J" first="John R. B." last="Perry">John R. B. Perry</name>
<affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pouget, Jennie G" sort="Pouget, Jennie G" uniqKey="Pouget J" first="Jennie G." last="Pouget">Jennie G. Pouget</name>
<affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Institute of Medical Sciences, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff042"><addr-line>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff043"><addr-line>Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Psychiatry, University of Toronto, Toronto, Ontario</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Jamshidi, Yalda" sort="Jamshidi, Yalda" uniqKey="Jamshidi Y" first="Yalda" last="Jamshidi">Yalda Jamshidi</name>
<affiliation wicri:level="1"><nlm:aff id="aff050"><addr-line>Cardiogenetics Lab, Cardiovascular and Cell Sciences Institute, St George’s Hospital Medical School, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Cardiogenetics Lab, Cardiovascular and Cell Sciences Institute, St George’s Hospital Medical School, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Snieder, Harold" sort="Snieder, Harold" uniqKey="Snieder H" first="Harold" last="Snieder">Harold Snieder</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Alizadeh, Behrooz Z" sort="Alizadeh, Behrooz Z" uniqKey="Alizadeh B" first="Behrooz Z." last="Alizadeh">Behrooz Z. Alizadeh</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff048"><addr-line>Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">PLoS Medicine</title>
<idno type="ISSN">1549-1277</idno>
<idno type="eISSN">1549-1676</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
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<profileDesc><textClass></textClass>
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</teiHeader>
<front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Background</title>
<p>C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.</p>
</sec>
<sec id="sec002"><title>Methods and Findings</title>
<p>We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRS<sub><italic>CRP</italic>
</sub>
), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRS<sub><italic>GWAS</italic>
</sub>
). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed <italic>p-</italic>
value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed.</p>
<p>The strengths (<italic>F</italic>
-statistics) of the IVs were 31.92–3,761.29 and 82.32–9,403.21 for GRS<sub><italic>CRP</italic>
</sub>
and GRS<sub><italic>GWAS</italic>
</sub>
, respectively. CRP GRS<sub><italic>GWAS</italic>
</sub>
showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79–0.94]; <italic>p <</italic>
0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94–0.98]; <italic>p <</italic>
1.72 × 10<sup>−6</sup>
). Further, we found that a standardized CRP polygenic risk score (CRP<sub><italic>PRS</italic>
</sub>
) at <italic>p-</italic>
value thresholds of 1 × 10<sup>−4</sup>
, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRP<sub><italic>PRS</italic>
</sub>
(built of SNPs with <italic>p</italic>
< 1 × 10<sup>−4</sup>
) showed a statistically significant (<italic>p <</italic>
2.45 × 10<sup>−4</sup>
) protective effect with an OR of 0.97 (95% CI 0.95–0.99). The CRP GRS<sub><italic>GWAS</italic>
</sub>
showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84–0.94]; <italic>p</italic>
< 2.4 × 10<sup>−5</sup>
) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74–0.98]; <italic>p <</italic>
0.03), Crohn disease (OR 0.81 [95% CI 0.70–0.94]; <italic>p <</italic>
0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00–1.84]; <italic>p <</italic>
0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01–1.36]; <italic>p <</italic>
0.04), and bipolar disorder (OR 1.21 [95% CI 1.05–1.40]; <italic>p <</italic>
0.007) and with an increase of 0.72 (95% CI 0.11–1.34; <italic>p <</italic>
0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06–0.84; <italic>p <</italic>
0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m<sup>2</sup>
(95% CI 0.003–0.02; <italic>p <</italic>
0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004–0.02; <italic>p <</italic>
0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008–0.05; <italic>p <</italic>
0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at <italic>p</italic>
< 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses.</p>
</sec>
<sec id="sec003"><title>Conclusions</title>
<p>Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed <italic>p <</italic>
0.05 using either GRS<sub><italic>CRP</italic>
</sub>
or GRS<sub><italic>GWAS</italic>
</sub>
—with persistence after correction for heterogeneity—for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes.</p>
</sec>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Med</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Med</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosmed</journal-id>
<journal-title-group><journal-title>PLoS Medicine</journal-title>
</journal-title-group>
<issn pub-type="ppub">1549-1277</issn>
<issn pub-type="epub">1549-1676</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, CA USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27327646</article-id>
<article-id pub-id-type="pmc">4915710</article-id>
<article-id pub-id-type="doi">10.1371/journal.pmed.1001976</article-id>
<article-id pub-id-type="publisher-id">PMEDICINE-D-15-01844</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Mental Health and Psychiatry</subject>
<subj-group><subject>Schizophrenia</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Genetics</subject>
<subj-group><subject>Genetics of Disease</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Computational Biology</subject>
<subj-group><subject>Genome Analysis</subject>
<subj-group><subject>Genome-Wide Association Studies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Genetics</subject>
<subj-group><subject>Genomics</subject>
<subj-group><subject>Genome Analysis</subject>
<subj-group><subject>Genome-Wide Association Studies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Genetics</subject>
<subj-group><subject>Human Genetics</subject>
<subj-group><subject>Genome-Wide Association Studies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Vascular Medicine</subject>
<subj-group><subject>Blood Pressure</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Mental Health and Psychiatry</subject>
<subj-group><subject>Mood Disorders</subject>
<subj-group><subject>Bipolar Disorder</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Rheumatology</subject>
<subj-group><subject>Arthritis</subject>
<subj-group><subject>Osteoarthritis</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Social Sciences</subject>
<subj-group><subject>Sociology</subject>
<subj-group><subject>Consortia</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Anatomy</subject>
<subj-group><subject>Musculoskeletal System</subject>
<subj-group><subject>Limbs (Anatomy)</subject>
<subj-group><subject>Legs</subject>
<subj-group><subject>Knees</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Anatomy</subject>
<subj-group><subject>Musculoskeletal System</subject>
<subj-group><subject>Limbs (Anatomy)</subject>
<subj-group><subject>Legs</subject>
<subj-group><subject>Knees</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study</article-title>
<alt-title alt-title-type="running-head">Mendelian Randomization of CRP in 32 Somatic and Psychiatric Outcomes</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Prins</surname>
<given-names>Bram. P.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-6452-4765</contrib-id>
<name><surname>Abbasi</surname>
<given-names>Ali</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
<xref ref-type="aff" rid="aff004"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-7269-9429</contrib-id>
<name><surname>Wong</surname>
<given-names>Anson</given-names>
</name>
<xref ref-type="aff" rid="aff005"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff006"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Vaez</surname>
<given-names>Ahmad</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff007"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nolte</surname>
<given-names>Ilja</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Franceschini</surname>
<given-names>Nora</given-names>
</name>
<xref ref-type="aff" rid="aff008"><sup>8</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-9546-6529</contrib-id>
<name><surname>Stuart</surname>
<given-names>Philip E.</given-names>
</name>
<xref ref-type="aff" rid="aff009"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Guterriez Achury</surname>
<given-names>Javier</given-names>
</name>
<xref ref-type="aff" rid="aff010"><sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mistry</surname>
<given-names>Vanisha</given-names>
</name>
<xref ref-type="aff" rid="aff011"><sup>11</sup>
</xref>
<xref ref-type="aff" rid="aff012"><sup>12</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bradfield</surname>
<given-names>Jonathan P.</given-names>
</name>
<xref ref-type="aff" rid="aff013"><sup>13</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Valdes</surname>
<given-names>Ana M.</given-names>
</name>
<xref ref-type="aff" rid="aff014"><sup>14</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bras</surname>
<given-names>Jose</given-names>
</name>
<xref ref-type="aff" rid="aff015"><sup>15</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shatunov</surname>
<given-names>Aleksey</given-names>
</name>
<xref ref-type="aff" rid="aff016"><sup>16</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>PAGE Consortium</collab>
<xref ref-type="aff" rid="aff009"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>International Stroke Genetics Consortium</collab>
<xref ref-type="aff" rid="aff017"><sup>17</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>Systemic Sclerosis consortium</collab>
<xref ref-type="aff" rid="aff018"><sup>18</sup>
</xref>
<xref ref-type="aff" rid="aff019"><sup>19</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>Treat OA consortium</collab>
<xref ref-type="aff" rid="aff020"><sup>20</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>DIAGRAM Consortium</collab>
<xref ref-type="aff" rid="aff021"><sup>21</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>CARDIoGRAMplusC4D Consortium</collab>
<xref ref-type="aff" rid="aff022"><sup>22</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>ALS consortium</collab>
<xref ref-type="aff" rid="aff016"><sup>16</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>International Parkinson’s Disease Genomics Consortium</collab>
<xref ref-type="aff" rid="aff023"><sup>23</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium</collab>
<xref ref-type="aff" rid="aff024"><sup>24</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>CKDGen consortium</collab>
<xref ref-type="aff" rid="aff025"><sup>25</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>GERAD1 Consortium</collab>
<xref ref-type="aff" rid="aff026"><sup>26</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>International Consortium for Blood Pressure</collab>
<xref ref-type="aff" rid="aff027"><sup>27</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>Schizophrenia Working Group of the Psychiatric Genomics Consortium</collab>
<xref ref-type="aff" rid="aff028"><sup>28</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>Inflammation Working Group of the CHARGE Consortium</collab>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lu</surname>
<given-names>Chen</given-names>
</name>
<xref ref-type="aff" rid="aff029"><sup>29</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Han</surname>
<given-names>Buhm</given-names>
</name>
<xref ref-type="aff" rid="aff030"><sup>30</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Raychaudhuri</surname>
<given-names>Soumya</given-names>
</name>
<xref ref-type="aff" rid="aff030"><sup>30</sup>
</xref>
<xref ref-type="aff" rid="aff031"><sup>31</sup>
</xref>
<xref ref-type="aff" rid="aff032"><sup>32</sup>
</xref>
<xref ref-type="aff" rid="aff033"><sup>33</sup>
</xref>
<xref ref-type="aff" rid="aff034"><sup>34</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bevan</surname>
<given-names>Steve</given-names>
</name>
<xref ref-type="aff" rid="aff017"><sup>17</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mayes</surname>
<given-names>Maureen D.</given-names>
</name>
<xref ref-type="aff" rid="aff018"><sup>18</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tsoi</surname>
<given-names>Lam C.</given-names>
</name>
<xref ref-type="aff" rid="aff009"><sup>9</sup>
</xref>
<xref ref-type="aff" rid="aff035"><sup>35</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Evangelou</surname>
<given-names>Evangelos</given-names>
</name>
<xref ref-type="aff" rid="aff020"><sup>20</sup>
</xref>
<xref ref-type="aff" rid="aff036"><sup>36</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nair</surname>
<given-names>Rajan P.</given-names>
</name>
<xref ref-type="aff" rid="aff009"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Grant</surname>
<given-names>Struan F. A.</given-names>
</name>
<xref ref-type="aff" rid="aff013"><sup>13</sup>
</xref>
<xref ref-type="aff" rid="aff037"><sup>37</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Polychronakos</surname>
<given-names>Constantin</given-names>
</name>
<xref ref-type="aff" rid="aff038"><sup>38</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Radstake</surname>
<given-names>Timothy R. D.</given-names>
</name>
<xref ref-type="aff" rid="aff039"><sup>39</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van Heel</surname>
<given-names>David A.</given-names>
</name>
<xref ref-type="aff" rid="aff012"><sup>12</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-3817-2142</contrib-id>
<name><surname>Dunstan</surname>
<given-names>Melanie L.</given-names>
</name>
<xref ref-type="aff" rid="aff026"><sup>26</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wood</surname>
<given-names>Nicholas W.</given-names>
</name>
<xref ref-type="aff" rid="aff023"><sup>23</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Al-Chalabi</surname>
<given-names>Ammar</given-names>
</name>
<xref ref-type="aff" rid="aff016"><sup>16</sup>
</xref>
<xref ref-type="aff" rid="aff040"><sup>40</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dehghan</surname>
<given-names>Abbas</given-names>
</name>
<xref ref-type="aff" rid="aff041"><sup>41</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hakonarson</surname>
<given-names>Hakon</given-names>
</name>
<xref ref-type="aff" rid="aff013"><sup>13</sup>
</xref>
<xref ref-type="aff" rid="aff037"><sup>37</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Markus</surname>
<given-names>Hugh S.</given-names>
</name>
<xref ref-type="aff" rid="aff017"><sup>17</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Elder</surname>
<given-names>James T.</given-names>
</name>
<xref ref-type="aff" rid="aff009"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Knight</surname>
<given-names>Jo</given-names>
</name>
<xref ref-type="aff" rid="aff005"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff042"><sup>42</sup>
</xref>
<xref ref-type="aff" rid="aff043"><sup>43</sup>
</xref>
<xref ref-type="aff" rid="aff044"><sup>44</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Arking</surname>
<given-names>Dan E.</given-names>
</name>
<xref ref-type="aff" rid="aff024"><sup>24</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Spector</surname>
<given-names>Timothy D.</given-names>
</name>
<xref ref-type="aff" rid="aff045"><sup>45</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Koeleman</surname>
<given-names>Bobby P. C.</given-names>
</name>
<xref ref-type="aff" rid="aff046"><sup>46</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van Duijn</surname>
<given-names>Cornelia M.</given-names>
</name>
<xref ref-type="aff" rid="aff041"><sup>41</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Martin</surname>
<given-names>Javier</given-names>
</name>
<xref ref-type="aff" rid="aff019"><sup>19</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Morris</surname>
<given-names>Andrew P.</given-names>
</name>
<xref ref-type="aff" rid="aff021"><sup>21</sup>
</xref>
<xref ref-type="aff" rid="aff047"><sup>47</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Weersma</surname>
<given-names>Rinse K.</given-names>
</name>
<xref ref-type="aff" rid="aff048"><sup>48</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wijmenga</surname>
<given-names>Cisca</given-names>
</name>
<xref ref-type="aff" rid="aff010"><sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Munroe</surname>
<given-names>Patricia B.</given-names>
</name>
<xref ref-type="aff" rid="aff027"><sup>27</sup>
</xref>
<xref ref-type="aff" rid="aff049"><sup>49</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Perry</surname>
<given-names>John R. B.</given-names>
</name>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pouget</surname>
<given-names>Jennie G.</given-names>
</name>
<xref ref-type="aff" rid="aff005"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff042"><sup>42</sup>
</xref>
<xref ref-type="aff" rid="aff043"><sup>43</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jamshidi</surname>
<given-names>Yalda</given-names>
</name>
<xref ref-type="aff" rid="aff050"><sup>50</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Snieder</surname>
<given-names>Harold</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alizadeh</surname>
<given-names>Behrooz Z.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff048"><sup>48</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
</contrib-group>
<aff id="aff001"><label>1</label>
<addr-line>Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands</addr-line>
</aff>
<aff id="aff002"><label>2</label>
<addr-line>Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom</addr-line>
</aff>
<aff id="aff003"><label>3</label>
<addr-line>MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom</addr-line>
</aff>
<aff id="aff004"><label>4</label>
<addr-line>Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands</addr-line>
</aff>
<aff id="aff005"><label>5</label>
<addr-line>Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada</addr-line>
</aff>
<aff id="aff006"><label>6</label>
<addr-line>Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada</addr-line>
</aff>
<aff id="aff007"><label>7</label>
<addr-line>School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran</addr-line>
</aff>
<aff id="aff008"><label>8</label>
<addr-line>Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America</addr-line>
</aff>
<aff id="aff009"><label>9</label>
<addr-line>Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</aff>
<aff id="aff010"><label>10</label>
<addr-line>Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands</addr-line>
</aff>
<aff id="aff011"><label>11</label>
<addr-line>Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom</addr-line>
</aff>
<aff id="aff012"><label>12</label>
<addr-line>Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom</addr-line>
</aff>
<aff id="aff013"><label>13</label>
<addr-line>Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, United States of America</addr-line>
</aff>
<aff id="aff014"><label>14</label>
<addr-line>Department of Academic Rheumatology, University of Nottingham, Nottingham, United Kingdom</addr-line>
</aff>
<aff id="aff015"><label>15</label>
<addr-line>Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom</addr-line>
</aff>
<aff id="aff016"><label>16</label>
<addr-line>Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom</addr-line>
</aff>
<aff id="aff017"><label>17</label>
<addr-line>Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom</addr-line>
</aff>
<aff id="aff018"><label>18</label>
<addr-line>Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, United States of America</addr-line>
</aff>
<aff id="aff019"><label>19</label>
<addr-line>Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain</addr-line>
</aff>
<aff id="aff020"><label>20</label>
<addr-line>Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece</addr-line>
</aff>
<aff id="aff021"><label>21</label>
<addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line>
</aff>
<aff id="aff022"><label>22</label>
<addr-line>Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany</addr-line>
</aff>
<aff id="aff023"><label>23</label>
<addr-line>Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom</addr-line>
</aff>
<aff id="aff024"><label>24</label>
<addr-line>McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America</addr-line>
</aff>
<aff id="aff025"><label>25</label>
<addr-line>NHLBI’s Framingham Heart Study, Center for Population Studies and Harvard Medical School, Framingham, Massachusetts, United States of America</addr-line>
</aff>
<aff id="aff026"><label>26</label>
<addr-line>Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom</addr-line>
</aff>
<aff id="aff027"><label>27</label>
<addr-line>NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom</addr-line>
</aff>
<aff id="aff028"><label>28</label>
<addr-line>MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, United Kingdom</addr-line>
</aff>
<aff id="aff029"><label>29</label>
<addr-line>Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America</addr-line>
</aff>
<aff id="aff030"><label>30</label>
<addr-line>Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America</addr-line>
</aff>
<aff id="aff031"><label>31</label>
<addr-line>Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America</addr-line>
</aff>
<aff id="aff032"><label>32</label>
<addr-line>Division of Rheumatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America</addr-line>
</aff>
<aff id="aff033"><label>33</label>
<addr-line>Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America</addr-line>
</aff>
<aff id="aff034"><label>34</label>
<addr-line>Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom</addr-line>
</aff>
<aff id="aff035"><label>35</label>
<addr-line>Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</aff>
<aff id="aff036"><label>36</label>
<addr-line>Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom</addr-line>
</aff>
<aff id="aff037"><label>37</label>
<addr-line>Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America</addr-line>
</aff>
<aff id="aff038"><label>38</label>
<addr-line>Endocrine Genetics Research Institute, McGill University Health Center, Montreal, Quebec, Canada</addr-line>
</aff>
<aff id="aff039"><label>39</label>
<addr-line>Department of Rheumatology & Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands</addr-line>
</aff>
<aff id="aff040"><label>40</label>
<addr-line>Complex Disease Genetics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America</addr-line>
</aff>
<aff id="aff041"><label>41</label>
<addr-line>Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam, the Netherlands</addr-line>
</aff>
<aff id="aff042"><label>42</label>
<addr-line>Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada</addr-line>
</aff>
<aff id="aff043"><label>43</label>
<addr-line>Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada</addr-line>
</aff>
<aff id="aff044"><label>44</label>
<addr-line>Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada</addr-line>
</aff>
<aff id="aff045"><label>45</label>
<addr-line>Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom</addr-line>
</aff>
<aff id="aff046"><label>46</label>
<addr-line>Complex Genetic Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands</addr-line>
</aff>
<aff id="aff047"><label>47</label>
<addr-line>Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom</addr-line>
</aff>
<aff id="aff048"><label>48</label>
<addr-line>Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands</addr-line>
</aff>
<aff id="aff049"><label>49</label>
<addr-line>Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom</addr-line>
</aff>
<aff id="aff050"><label>50</label>
<addr-line>Cardiogenetics Lab, Cardiovascular and Cell Sciences Institute, St George’s Hospital Medical School, London, United Kingdom</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Hay</surname>
<given-names>Phillipa J.</given-names>
</name>
<role>Academic Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>Western Sydney University, AUSTRALIA</addr-line>
</aff>
<author-notes><fn fn-type="conflict" id="coi001"><p>The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: BPP AA HS BZA CVD. Performed the experiments: NF JGA VM PES JPB AMV JB AS. Analyzed the data: BPP AA AV AM IN NF JGA VM PES JPB AMV JB AS AD BH SR SB MDM LT EE RPN SG CP TR DVH MD JN NW DA AAC BK HH HM JE TS CVD JM APM RW JP CW PM JGP YJ HS BZA JK. Contributed reagents/materials/analysis tools: CL AAC AD JK CVD. Wrote the first draft of the manuscript: BPP AA BZA. Contributed to the writing of the manuscript: BPP AA AV AW JGA VM PES AMV DEA BK TS JM RW JP JGP YJ HS BZA JK. Agree with the manuscript’s results and conclusions: BZA BPP AA AW AV IN NF PES JGA VM JPB AMV JB AS CL BH SR SB MDM LT EE RPN SG CP TR DVH MD NW AAC AD HH HM JE JK DA TS BK CVD JM APM RW CW PM JP JGP YJ HS. All authors have read, and confirm that they meet, ICMJE criteria for authorship.</p>
</fn>
<corresp id="cor001">* E-mail: <email>bram.prins@sanger.ac.uk</email>
(BPP); <email>b.z.alizadeh@umcg.nl</email>
(BZA)</corresp>
</author-notes>
<pub-date pub-type="epub"><day>21</day>
<month>6</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="collection"><month>6</month>
<year>2016</year>
</pub-date>
<volume>13</volume>
<issue>6</issue>
<elocation-id>e1001976</elocation-id>
<history><date date-type="received"><day>21</day>
<month>6</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>3</day>
<month>2</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>© 2016 Prins et al</copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>Prins et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>
, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="pmed.1001976.pdf"></self-uri>
<abstract><sec id="sec001"><title>Background</title>
<p>C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.</p>
</sec>
<sec id="sec002"><title>Methods and Findings</title>
<p>We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRS<sub><italic>CRP</italic>
</sub>
), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRS<sub><italic>GWAS</italic>
</sub>
). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed <italic>p-</italic>
value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed.</p>
<p>The strengths (<italic>F</italic>
-statistics) of the IVs were 31.92–3,761.29 and 82.32–9,403.21 for GRS<sub><italic>CRP</italic>
</sub>
and GRS<sub><italic>GWAS</italic>
</sub>
, respectively. CRP GRS<sub><italic>GWAS</italic>
</sub>
showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79–0.94]; <italic>p <</italic>
0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94–0.98]; <italic>p <</italic>
1.72 × 10<sup>−6</sup>
). Further, we found that a standardized CRP polygenic risk score (CRP<sub><italic>PRS</italic>
</sub>
) at <italic>p-</italic>
value thresholds of 1 × 10<sup>−4</sup>
, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRP<sub><italic>PRS</italic>
</sub>
(built of SNPs with <italic>p</italic>
< 1 × 10<sup>−4</sup>
) showed a statistically significant (<italic>p <</italic>
2.45 × 10<sup>−4</sup>
) protective effect with an OR of 0.97 (95% CI 0.95–0.99). The CRP GRS<sub><italic>GWAS</italic>
</sub>
showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84–0.94]; <italic>p</italic>
< 2.4 × 10<sup>−5</sup>
) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74–0.98]; <italic>p <</italic>
0.03), Crohn disease (OR 0.81 [95% CI 0.70–0.94]; <italic>p <</italic>
0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00–1.84]; <italic>p <</italic>
0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01–1.36]; <italic>p <</italic>
0.04), and bipolar disorder (OR 1.21 [95% CI 1.05–1.40]; <italic>p <</italic>
0.007) and with an increase of 0.72 (95% CI 0.11–1.34; <italic>p <</italic>
0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06–0.84; <italic>p <</italic>
0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m<sup>2</sup>
(95% CI 0.003–0.02; <italic>p <</italic>
0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004–0.02; <italic>p <</italic>
0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008–0.05; <italic>p <</italic>
0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at <italic>p</italic>
< 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses.</p>
</sec>
<sec id="sec003"><title>Conclusions</title>
<p>Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed <italic>p <</italic>
0.05 using either GRS<sub><italic>CRP</italic>
</sub>
or GRS<sub><italic>GWAS</italic>
</sub>
—with persistence after correction for heterogeneity—for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes.</p>
</sec>
</abstract>
<abstract abstract-type="toc"><p>Using genetic instruments, Behrooz Z. Alizadeh and colleagues examine the hypothesis that increased CRP levels play a causal role in common somatic and psychiatric conditions.</p>
</abstract>
<abstract abstract-type="editors-summary"><title>Editors' Summary</title>
<sec id="sec004"><title>Background</title>
<p>Inflammation is an important part of the human immune response, the network of cells and molecules that protects the body from attack by pathogens (infectious organisms) and from harmful substances and foreign particles (for example, splinters). When human cells are attacked by pathogens or injured by trauma or chemicals, molecules called inflammatory mediators induce fluid leakage from the blood vessels into the damaged tissue and attract “phagocytes” (a type of immune cell) to the site of infection or injury to “eat” the germs and dead or damaged cells. The end result is inflammation, which is characterized by swelling, redness, heat, and pain. The inflammatory response, although unpleasant, limits the damage caused by foreign invaders or chemicals by preventing further contact with body tissues. Sometimes, however, inflammation can be harmful. Persistent dysregulation of the inflammatory response is implicated in numerous somatic disorders (diseases that affect the body, such as cardiovascular disease) and neuropsychiatric disorders (mental disorders attributable to diseases of the nervous system, such as schizophrenia).</p>
</sec>
<sec id="sec005"><title>Why Was This Study Done?</title>
<p>Observational studies suggest that increased blood levels of C-reactive protein (CRP, an inflammatory protein) are associated with certain somatic and neuropsychiatric disorders. But observational studies cannot prove that changes in CRP levels actually cause any of these disorders. It could be that the individuals who develop a specific disease and who have a high CRP level also share another unknown characteristic that is actually responsible for disease development (confounding). Alternatively, it could be that the disease itself increases CRP levels (reverse causation). It is important to know whether CRP is causally involved in the development of specific diseases because it might then be possible to prevent or treat these diseases using drugs that control CRP levels. Here, the researchers undertake a Mendelian randomization study to determine whether CRP has a causal relationship with 32 common complex somatic and neuropsychiatric outcomes. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if CRP levels actually cause a specific somatic or neuropsychiatric disease, genetic variants that affect CRP levels should be associated with an altered risk for that disease.</p>
</sec>
<sec id="sec006"><title>What Did the Researchers Do and Find?</title>
<p>The researchers used data collected by several consortia involved in large genome-wide association studies (studies that ask whether specific genetic changes across the whole human genome, or blueprint, are associated with specific diseases) to look for associations between 32 somatic and neuropsychiatric outcomes and two genetic risk scores (GRSs) for CRP level. GRS<sub><italic>CRP</italic>
</sub>
consisted of four single nucleotide polymorphisms (SNPs; a type of genetic variant) in the gene encoding CRP; GRS<sub><italic>GWAS</italic>
</sub>
consisted of 18 SNPs that were associated with CRP level in a genome-wide association study. The researchers report that a genetically increased CRP level was significantly associated with a reduced risk of schizophrenia (a significant association is one unlikely to have arisen by chance). In addition, they found a nominally significant association (an association that needs to be confirmed) between genetically increased CRP levels and an increased risk of knee osteoarthritis, raised diastolic and systolic blood pressure, and bipolar disorder. Notably, there was no evidence for an effect of genetically increased CRP levels on any of the other 27 outcomes studied.</p>
</sec>
<sec id="sec007"><title>What Do These Findings Mean?</title>
<p>These findings suggest that genetically raised levels of CRP are causally associated with protection against schizophrenia, an unexpected finding given other recent studies that suggest that raised CRP levels and brain inflammation predispose individuals to schizophrenia. The findings also provide preliminary evidence that genetically raised levels of CRP may be causally associated with an increased risk of raised blood pressure, knee arthritis, and bipolar disorder. The lack of any association between genetically raised levels of CRP and the other outcomes studied suggests, however, that many previously identified disease-associated rises in CRP levels might be a response to the disease process rather than a cause of these diseases. Like all Mendelian randomization studies, the reliability of these findings depends on the validity of several assumptions made by the researchers and on the ability of the GRSs used in the study to explain variations in CRP level. Importantly, however, these findings suggest that interventions designed to lower CRP level are unlikely to decrease the risk of people developing the majority of common complex somatic and neuropsychiatric outcomes.</p>
</sec>
<sec id="sec008"><title>Additional Information</title>
<p>This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1371/journal.pmed.1001976">http://dx.doi.org/10.1371/journal.pmed.1001976</ext-link>
.</p>
<list list-type="bullet"><list-item><p>Wikipedia has pages on <ext-link ext-link-type="uri" xlink:href="https://en.wikipedia.org/wiki/Inflammation">inflammation</ext-link>
, <ext-link ext-link-type="uri" xlink:href="https://en.wikipedia.org/wiki/C-reactive_protein">C-reactive protein</ext-link>
, and <ext-link ext-link-type="uri" xlink:href="http://en.wikipedia.org/wiki/Mendelian_randomization">Mendelian randomization</ext-link>
(note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)</p>
</list-item>
<list-item><p>The MedlinePlus encyclopedia has a page on <ext-link ext-link-type="uri" xlink:href="https://www.nlm.nih.gov/medlineplus/ency/article/003356.htm">C-reactive protein</ext-link>
(in English and Spanish)</p>
</list-item>
<list-item><p>The American Heart Association provides a short article on <ext-link ext-link-type="uri" xlink:href="http://www.heart.org/HEARTORG/Conditions/More/MyHeartandStrokeNews/Inflammation-and-Heart-Disease_UCM_432150_Article.jsp#.VlSwQV60dTZ">inflammation and heart disease</ext-link>
</p>
</list-item>
<list-item><p>A UK National Health Service “Behind the Headlines” article explains a recent study that found <ext-link ext-link-type="uri" xlink:href="http://www.nhs.uk/news/2015/10October/Pages/Could-anti-inflammatory-drugs-prevent-schizophrenia.aspx">an association between immune activity in the brain and schizophrenia</ext-link>
</p>
</list-item>
</list>
</sec>
</abstract>
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<funding-statement>Please refer to file S1 Financial Disclosure for full information with regard to funding and financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
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<counts><fig-count count="4"></fig-count>
<table-count count="4"></table-count>
<page-count count="29"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>All our data which have been used for this study may be found in S1 Data file.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>All our data which have been used for this study may be found in S1 Data file.</p>
</notes>
</front>
</pmc>
</record>
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