Abstract
Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 170-182 |
| Number of pages | 13 |
| Journal | Behavior Genetics |
| Volume | 46 |
| Issue number | 2 |
| DOIs | |
| State | Published - Mar 1 2016 |
Keywords
- Common genetic variants
- Imputation
- Personality
- Phenotype harmonization
- Polygenic risk
ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Genetics
- Genetics(clinical)
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In: Behavior Genetics, Vol. 46, No. 2, 01.03.2016, p. 170-182.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Meta-analysis of Genome-Wide Association Studies for Extraversion
T2 - Findings from the Genetics of Personality Consortium
AU - van den Berg, Stéphanie M.
AU - de Moor, Marleen H.M.
AU - Verweij, Karin J.H.
AU - Krueger, Robert F.
AU - Luciano, Michelle
AU - Arias Vasquez, Alejandro
AU - Matteson, Lindsay K.
AU - Derringer, Jaime
AU - Esko, Tõnu
AU - Amin, Najaf
AU - Gordon, Scott D.
AU - Hansell, Narelle K.
AU - Hart, Amy B.
AU - Seppälä, Ilkka
AU - Huffman, Jennifer E.
AU - Konte, Bettina
AU - Lahti, Jari
AU - Lee, Minyoung
AU - Miller, Mike
AU - Nutile, Teresa
AU - Tanaka, Toshiko
AU - Teumer, Alexander
AU - Viktorin, Alexander
AU - Wedenoja, Juho
AU - Abdellaoui, Abdel
AU - Abecasis, Goncalo R.
AU - Adkins, Daniel E.
AU - Agrawal, Arpana
AU - Allik, Jüri
AU - Appel, Katja
AU - Bigdeli, Timothy B.
AU - Busonero, Fabio
AU - Campbell, Harry
AU - Costa, Paul T.
AU - Smith, George Davey
AU - Davies, Gail
AU - de Wit, Harriet
AU - Ding, Jun
AU - Engelhardt, Barbara E.
AU - Eriksson, Johan G.
AU - Fedko, Iryna O.
AU - Ferrucci, Luigi
AU - Franke, Barbara
AU - Giegling, Ina
AU - Grucza, Richard
AU - Hartmann, Annette M.
AU - Heath, Andrew C.
AU - Heinonen, Kati
AU - Henders, Anjali K.
AU - Homuth, Georg
AU - Hottenga, Jouke Jan
AU - Iacono, William G.
AU - Janzing, Joost
AU - Jokela, Markus
AU - Karlsson, Robert
AU - Kemp, John P.
AU - Kirkpatrick, Matthew G.
AU - Latvala, Antti
AU - Lehtimäki, Terho
AU - Liewald, David C.
AU - Madden, Pamela A.F.
AU - Magri, Chiara
AU - Magnusson, Patrik K.E.
AU - Marten, Jonathan
AU - Maschio, Andrea
AU - Mbarek, Hamdi
AU - Medland, Sarah E.
AU - Mihailov, Evelin
AU - Milaneschi, Yuri
AU - Montgomery, Grant W.
AU - Nauck, Matthias
AU - Nivard, Michel G.
AU - Ouwens, Klaasjan G.
AU - Palotie, Aarno
AU - Pettersson, Erik
AU - Polasek, Ozren
AU - Qian, Yong
AU - Pulkki-Råback, Laura
AU - Raitakari, Olli T.
AU - Realo, Anu
AU - Rose, Richard J.
AU - Ruggiero, Daniela
AU - Schmidt, Carsten O.
AU - Slutske, Wendy S.
AU - Sorice, Rossella
AU - Starr, John M.
AU - St Pourcain, Beate
AU - Sutin, Angelina R.
AU - Timpson, Nicholas J.
AU - Trochet, Holly
AU - Vermeulen, Sita
AU - Vuoksimaa, Eero
AU - Widen, Elisabeth
AU - Wouda, Jasper
AU - Wright, Margaret J.
AU - Zgaga, Lina
AU - Generation Scotland, Scotland
AU - Porteous, David
AU - Minelli, Alessandra
AU - Palmer, Abraham A.
AU - Rujescu, Dan
AU - Ciullo, Marina
AU - Hayward, Caroline
AU - Rudan, Igor
AU - Metspalu, Andres
AU - Kaprio, Jaakko
AU - Deary, Ian J.
AU - Räikkönen, Katri
AU - Wilson, James F.
AU - Keltikangas-Järvinen, Liisa
AU - Bierut, Laura J.
AU - Hettema, John M.
AU - Grabe, Hans J.
AU - Penninx, Brenda W.J.H.
AU - van Duijn, Cornelia M.
AU - Evans, David M.
AU - Schlessinger, David
AU - Pedersen, Nancy L.
AU - Terracciano, Antonio
AU - McGue, Matt
AU - Martin, Nicholas G.
AU - Boomsma, Dorret I.
N1 - Funding Information: SAGE – COGA/CONGEND Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401) and the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract “High throughput genotyping for studying the genetic contributions to human disease”(HHSN268200782096C). The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut, includes ten different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B. Porjesz); Washington University in St. Louis (L. Bierut, A. Goate, J. Rice, K. Bucholz); University of California at San Diego (M. Schuckit); Rutgers University (J. Tischfield); Texas Biomedical Research Institute (L. Almasy), Howard University (R. Taylor) and Virginia Commonwealth University (D. Dick). Other COGA collaborators include: L. Bauer (University of Connecticut); D. Koller, S. O’Connor, L. Wetherill, X. Xuei (Indiana University); Grace Chan (University of Iowa); S. Kang, N. Manz, M. Rangaswamy (SUNY Downstate); J. Rohrbaugh, J-C Wang (Washington University in St. Louis); A. Brooks (Rutgers University); and F. Aliev (Virginia Commonwealth University). A. Parsian and M. Reilly are the NIAAA Staff Collaborators. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). The Collaborative Genetic Study of Nicotine Dependence (COGEND) project is a collaborative research group and part of the NIDA Genetics Consortium. Subject collection was supported by NIH Grant P01 CA089392 (L.J. Bierut) from the National Cancer Institute. Phenotypic and genotypic data are stored in the NIDA Center for Genetic Studies (NCGS) at http://zork.wustl.edu/ under NIDA Contract HHSN271200477451C (J. Tischfield and J. Rice). Jaime Derringer was supported by NIH T32 MH016880. Funding Information: EGCUT AM and TE received support from FP7 Grants (201413 ENGAGE, 212111 BBMRI, ECOGENE (No. 205419, EBC)) and OpenGENE. AM and TE also received targeted financing from Estonian Government SF0180142s08 and by EU via the European Regional Development Fund, in the frame of Centre of Excellence in Genomics. The genotyping of the Estonian Genome Project samples were performed in Estonian Biocentre Genotyping Core Facility, AM and TE thank Mari Nelis and Viljo Soo for their contributions. AR and JA were supported by a grant from the Estonian Ministry of Science and Education (SF0180029s08). Funding Information: BLSA We acknowledge support from the Intramural Research Program of the NIH, National Institute on Aging. We thank Robert McCrae. Funding Information: LBC1921 & LBC1936 For the Lothian Birth Cohorts, we thank Paul Redmond for database management; Alan Gow, Michelle Taylor, Janie Corley, Caroline Brett and Caroline Cameron for data collection and data entry; nurses and staff at the Wellcome Trust Clinical Research Facility, where blood extraction and genotyping was performed; staff at the Lothian Health Board, and the staff at the SCRE Centre, University of Glasgow. The research was supported by a program grant from Research Into Ageing. The research continues with program grants from Age UK (The Disconnected Mind). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. IJD, DJP and colleagues receive support from Wellcome Trust Strategic Award 104036/Z/14/Z. Funding Information: SHIP SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grants No. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG. This work was also funded by the German Research Foundation (DFG: GR 1912/5-1). Funding Information: HBCS We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. Funding Information: SardiNIA We acknowledge support from the Intramural Research Program of the NIH, National Institute on Aging. Funding was provided by the National Institute on Aging, NIH Contract No. NO1-AG-1-2109 to the SardiNIA (‘ProgeNIA’) team. Funding Information: ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. Funding Information: CHICAGO This work was supported by NIH Grants, DA007255 (ABH), HG006265 (to BEE), DA02812 (to HdW), and DA021336 and DA024845 (to AAP). BEE was also funded through the Bioinformatics Research Development Fund, supported by Kathryn and George Gould. We wish to thank Andrew D. Skol for providing advice about genotype calling. Funding Information: GS:SHFHS GS:SFHS is funded by the Scottish Executive Health Department, Chief Scientist Office, Grant Number CZD/16/6. Exome array genotyping for GS:SFHS was funded by the Medical Research Council UK and performed at the Wellcome Trust Clinical Research Facility Genetics Core at Western General Hospital, Edinburgh, UK. We would like to acknowledge the invaluable contributions of the families who took part in the GS:SFHS, the general practitioners and Scottish School of Primary Care for their help in recruiting them, and the whole GS:SFHS team, which includes academic researchers, IT staff, laboratory technicians, statisticians and research managers. Funding Information: YFS The Young Finns Study has been financially supported by the Academy of Finland (Grants 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), 41071 (Skidi), and 265869 (Mind)), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (Grant 9N035 for Dr. Lehtimäki), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation (for Dr. Lehtimäki). The expert technical assistance in statistical analysis by Irina Lisinen, Mika Helminen, and Ville Aalto is gratefully acknowledged. Funding Information: We would like to thank all participating subjects. Analyses were carried out on the Genetic Cluster Computer ( http://www.geneticcluster.org ), which is financially supported by the Netherlands Organization for Scientific Research (NWO 480-05-003). Funding Information: STR The STR was supported by grants from the Ministry for Higher Education, the Swedish Research Council (M-2005-1112 and 2009-2298), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), NIH Grant DK U01-066134, The Swedish Foundation for Strategic Research (SSF; ICA08-0047), the Swedish Heart–Lung Foundation, the Royal Swedish Academy of Science, and ENGAGE (within the European Union Seventh Framework Programme, HEALTH-F4-2007-201413). Funding Information: ALSPAC We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council (Grant 74882), the Wellcome Trust (Grant 076467) and the University of Bristol provide core support for ALSPAC. We thank 23andMe for funding the genotyping of the ALSPAC children’s sample. This publication is the work of the authors, and they will serve as guarantors for the contents of this paper. Funding Information: ERF The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP Grant Number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013)/Grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme “Quality of Life and Management of the Living Resources” of 5th Framework Programme (no. QLG2-CT-2002-01254). The ERF study was further supported by ENGAGE consortium and CMSB. High-throughput analysis of the ERF data was supported by joint grant from Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). ERF was further supported by the ZonMw Grant (Project 91111025). We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. Funding Information: Research reported in this publication was supported by the National Institutes of Health under award numbers R37DA005147, R01AA009367, R01AA011886, R01DA013240, R01MH066140, and U01DA024417. Funding Information: CILENTO We acknowledge Dr Maria Enza Amendola for the test administration and thank the personnel working in the organization of the study in the villages. MC received funding support from the Italian Ministry of Universities (FIRB - RBNE08NKH7, INTEROMICS Flaghip Project), the Assessorato Ricerca Regione Campania, the Fondazione con il SUD (2011-PDR-13), and the Fondazione Banco di Napoli. Funding Information: BRESCIA We acknowledge support from the Italian Ministry of Health (RC and RF2007 Conv. 42) and Regione Lombardia (ID: 17387 SAL-13). We thank Ilaria Gandin for imputation analysis support. Funding Information: Finnish Twin Cohort (FTC) We acknowledge support from the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant Numbers: 213506, 129680), the Academy of Finland (Grants 100499, 205585, 118555 and 141054 to JK, Grant 257075 to EV), Global Research Awards for Nicotine Dependence (GRAND), ENGAGE (European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, Grant Agreement Number 201413), DA12854 to P A F Madden, and AA-12502, AA-00145, and AA-09203 to RJRose, AA15416 and K02AA018755 to DM Dick. Funding Information: CROATIA-Korcula The CROATIA-Korcula study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research Grants to I.R. (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the people of Korcula. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. Funding Information: We would like to thank all participating subjects. Analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org ), which is financially supported by the Netherlands Organization for Scientific Research (NWO 480-05-003). ALSPAC We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council (Grant 74882), the Wellcome Trust (Grant 076467) and the University of Bristol provide core support for ALSPAC. We thank 23andMe for funding the genotyping of the ALSPAC children's sample. This publication is the work of the authors, and they will serve as guarantors for the contents of this paper. BLSA We acknowledge support from the Intramural Research Program of the NIH, National Institute on Aging. We thank Robert McCrae. BRESCIA We acknowledge support from the Italian Ministry of Health (RC and RF2007 Conv. 42) and Regione Lombardia (ID: 17387 SAL-13). We thank Ilaria Gandin for imputation analysis support. CHICAGO This work was supported by NIH Grants, DA007255 (ABH), HG006265 (to BEE), DA02812 (to HdW), and DA021336 and DA024845 (to AAP). BEE was also funded through the Bioinformatics Research Development Fund, supported by Kathryn and George Gould. We wish to thank Andrew D. Skol for providing advice about genotype calling. CILENTO We acknowledge Dr Maria Enza Amendola for the test administration and thank the personnel working in the organization of the study in the villages. MC received funding support from the Italian Ministry of Universities (FIRB - RBNE08NKH7, INTEROMICS Flaghip Project), the Assessorato Ricerca Regione Campania, the Fondazione con il SUD (2011-PDR-13), and the Fondazione Banco di Napoli. SAGE â COGA/CONGEND Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401) and the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease"(HHSN268200782096C). The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut, includes ten different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B. Porjesz); Washington University in St. Louis (L. Bierut, A. Goate, J. Rice, K. Bucholz); University of California at San Diego (M. Schuckit); Rutgers University (J. Tischfield); Texas Biomedical Research Institute (L. Almasy), Howard University (R. Taylor) and Virginia Commonwealth University (D. Dick). Other COGA collaborators include: L. Bauer (University of Connecticut); D. Koller, S. O'Connor, L. Wetherill, X. Xuei (Indiana University); Grace Chan (University of Iowa); S. Kang, N. Manz, M. Rangaswamy (SUNY Downstate); J. Rohrbaugh, J-C Wang (Washington University in St. Louis); A. Brooks (Rutgers University); and F. Aliev (Virginia Commonwealth University). A. Parsian and M. Reilly are the NIAAA Staff Collaborators. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). The Collaborative Genetic Study of Nicotine Dependence (COGEND) project is a collaborative research group and part of the NIDA Genetics Consortium. Subject collection was supported by NIH Grant P01 CA089392 (L.J. Bierut) from the National Cancer Institute. Phenotypic and genotypic data are stored in the NIDA Center for Genetic Studies (NCGS) at http://zork.wustl.edu/ under NIDA Contract HHSN271200477451C (J. Tischfield and J. Rice). Jaime Derringer was supported by NIH T32 MH016880. EGCUT AM and TE received support from FP7 Grants (201413 ENGAGE, 212111 BBMRI, ECOGENE (No. 205419, EBC)) and OpenGENE. AM and TE also received targeted financing from Estonian Government SF0180142s08 and by EU via the European Regional Development Fund, in the frame of Centre of Excellence in Genomics. The genotyping of the Estonian Genome Project samples were performed in Estonian Biocentre Genotyping Core Facility, AM and TE thank Mari Nelis and Viljo Soo for their contributions. AR and JA were supported by a grant from the Estonian Ministry of Science and Education (SF0180029s08). ERF The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP Grant Number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/Grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002-01254). The ERF study was further supported by ENGAGE consortium and CMSB. High-throughput analysis of the ERF data was supported by joint grant from Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). ERF was further supported by the ZonMw Grant (Project 91111025). We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. Finnish Twin Cohort (FTC) We acknowledge support from the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant Numbers: 213506, 129680), the Academy of Finland (Grants 100499, 205585, 118555 and 141054 to JK, Grant 257075 to EV), Global Research Awards for Nicotine Dependence (GRAND), ENGAGE (European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, Grant Agreement Number 201413), DA12854 to P A F Madden, and AA-12502, AA-00145, and AA-09203 to RJRose, AA15416 and K02AA018755 to DM Dick. HBCS We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. CROATIA -Korcula The CROATIA-Korcula study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research Grants to I.R. (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the people of Korcula. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. LBC1921 & LBC1936 For the Lothian Birth Cohorts, we thank Paul Redmond for database management; Alan Gow, Michelle Taylor, Janie Corley, Caroline Brett and Caroline Cameron for data collection and data entry; nurses and staff at the Wellcome Trust Clinical Research Facility, where blood extraction and genotyping was performed; staff at the Lothian Health Board, and the staff at the SCRE Centre, University of Glasgow. The research was supported by a program grant from Research Into Ageing. The research continues with program grants from Age UK (The Disconnected Mind). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. IJD, DJP and colleagues receive support from Wellcome Trust Strategic Award 104036/Z/14/Z. MCTFR We would like to thank Rob Kirkpatrick for his help running analyses. Research reported in this publication was supported by the National Institutes of Health under award numbers R37DA005147, R01AA009367, R01AA011886, R01DA013240, R01MH066140, and U01DA024417. MGS Samples were collected under the following grants: NIMH Schizophrenia Genetics Initiative U01s: MH46276, MH46289, and MH46318; and Molecular Genetics of Schizophrenia Part 1 (MGS1) and Part 2 (MGS2) R01s: MH67257, MH59588, MH59571, MH59565, MH59587, MH60870, MH60879, MH59566, MH59586, and MH61675. Genotyping and analyses were funded under the MGS U01s: MH79469 and MH79470. NBS Principal investigators of the Nijmegen Biomedical Study are L.A.L.M. Kiemeney, M. den Heijer, A.L.M. Verbeek, D.W. Swinkels and B. Franke. NESDA The Netherlands Study of Depression and Anxiety (NESDA) were funded by the Netherlands Organization for Scientific Research (Geestkracht program Grant 10-000-1002); the Center for Medical Systems Biology (CMSB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam. Genotyping was funded by the US National Institute of Mental Health (RC2MH089951) as part of the American Recovery and Reinvestment Act of 2009. BP is financially supported by NWO-VIDI Grant No. 91811602. NTR We acknowledge financial support from the Netherlands Organization for Scientific Research (NWO): Grants 575-25-006, 480-04-004, 904-61-090; 904-61-193, 400-05-717 and Spinozapremie SPI 56-464-14192 and the European Research Council (ERC-230374). MHMdeM is supported by NWO VENI Grant No. 016-115-035. Genotyping was funded by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from Genetic Association Information Network and the NIMH (MH081802). Genotype data were obtained from dbGaP (http://www.ncbi.nlm.nih.gov/dbgap , accession number phs000020.v1.p1). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. PAGES none. QIMR Berghofer adolescents/adults We thank Marlene Grace and Ann Eldridge for sample collection; Megan Campbell, Lisa Bowdler, Steven Crooks and staff of the Molecular Epidemiology Laboratory for sample processing and preparation; Harry Beeby, David Smyth and Daniel Park for IT support. We acknowledge support from the Australian Research Council Grants A79600334, A79906588, A79801419, DP0212016, DP0343921, DP0664638, and DP1093900 (to NGM and MJW), Beyond Blue and the Borderline Personality Disorder Research Foundation (to NGM), NIH Grants DA12854 (to PAFM), AA07728, AA07580, AA11998, AA13320, AA13321 (to ACH) and MH66206 (to WSS); and grants from the Australian National Health and Medical Research Council; MLP is supported by DA019951. Genotyping was partly funded by the National Health and Medical Research Council (Medical Bioinformatics Genomics Proteomics Program, 389891) and the 5th Framework Programme (FP-5) GenomEUtwin Project (QLG2-CT-2002-01254). Further genotyping at the Center for Inherited Disease Research was supported by a grant to the late Richard Todd, M.D., Ph.D., former Principal Investigator of Grant AA13320. SEM and GWM are supported by the National Health and Medical Research Council Fellowship Scheme. Further, we gratefully acknowledge Dr Dale R Nyholt for his substantial involvement in the QC and preparation of the QIMR GWA data sets. Dr Nyholt also contributed 8 % of the GWAS for the QIMR adult cohort (NHMRC IDs 339462, 442981, 389938, 496739). SardiNIA We acknowledge support from the Intramural Research Program of the NIH, National Institute on Aging. Funding was provided by the National Institute on Aging, NIH Contract No. NO1-AG-1-2109 to the SardiNIA (âProgeNIA') team. SHIP SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grants No. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the âCenter of Knowledge Interchange' program of the Siemens AG. This work was also funded by the German Research Foundation (DFG: GR 1912/5-1). STR The STR was supported by grants from the Ministry for Higher Education, the Swedish Research Council (M-2005-1112 and 2009-2298), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), NIH Grant DK U01-066134, The Swedish Foundation for Strategic Research (SSF; ICA08-0047), the Swedish HeartâLung Foundation, the Royal Swedish Academy of Science, and ENGAGE (within the European Union Seventh Framework Programme, HEALTH-F4-2007-201413). CROATIA -Vis The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research Grants to I.R. (108-1080315-0302). We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. YFS The Young Finns Study has been financially supported by the Academy of Finland (Grants 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), 41071 (Skidi), and 265869 (Mind)), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (Grant 9N035 for Dr. Lehtimäki), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation (for Dr. Lehtimäki). The expert technical assistance in statistical analysis by Irina Lisinen, Mika Helminen, and Ville Aalto is gratefully acknowledged. GS:SHFHS GS:SFHS is funded by the Scottish Executive Health Department, Chief Scientist Office, Grant Number CZD/16/6. Exome array genotyping for GS:SFHS was funded by the Medical Research Council UK and performed at the Wellcome Trust Clinical Research Facility Genetics Core at Western General Hospital, Edinburgh, UK. We would like to acknowledge the invaluable contributions of the families who took part in the GS:SFHS, the general practitioners and Scottish School of Primary Care for their help in recruiting them, and the whole GS:SFHS team, which includes academic researchers, IT staff, laboratory technicians, statisticians and research managers. Funding Information: CROATIA-Vis The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research Grants to I.R. (108-1080315-0302). We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. Funding Information: QIMR Berghofer adolescents/adults We thank Marlene Grace and Ann Eldridge for sample collection; Megan Campbell, Lisa Bowdler, Steven Crooks and staff of the Molecular Epidemiology Laboratory for sample processing and preparation; Harry Beeby, David Smyth and Daniel Park for IT support. We acknowledge support from the Australian Research Council Grants A79600334, A79906588, A79801419, DP0212016, DP0343921, DP0664638, and DP1093900 (to NGM and MJW), Beyond Blue and the Borderline Personality Disorder Research Foundation (to NGM), NIH Grants DA12854 (to PAFM), AA07728, AA07580, AA11998, AA13320, AA13321 (to ACH) and MH66206 (to WSS); and grants from the Australian National Health and Medical Research Council; MLP is supported by DA019951. Genotyping was partly funded by the National Health and Medical Research Council (Medical Bioinformatics Genomics Proteomics Program, 389891) and the 5th Framework Programme (FP-5) GenomEUtwin Project (QLG2-CT-2002-01254). Further genotyping at the Center for Inherited Disease Research was supported by a grant to the late Richard Todd, M.D., Ph.D., former Principal Investigator of Grant AA13320. SEM and GWM are supported by the National Health and Medical Research Council Fellowship Scheme. Further, we gratefully acknowledge Dr Dale R Nyholt for his substantial involvement in the QC and preparation of the QIMR GWA data sets. Dr Nyholt also contributed 8 % of the GWAS for the QIMR adult cohort (NHMRC IDs 339462, 442981, 389938, 496739). Funding Information: NTR We acknowledge financial support from the Netherlands Organization for Scientific Research (NWO): Grants 575-25-006, 480-04-004, 904-61-090; 904-61-193, 400-05-717 and Spinozapremie SPI 56-464-14192 and the European Research Council (ERC-230374). MHMdeM is supported by NWO VENI Grant No. 016-115-035. Genotyping was funded by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from Genetic Association Information Network and the NIMH (MH081802). Genotype data were obtained from dbGaP ( http://www.ncbi.nlm.nih.gov/dbgap , accession number phs000020.v1.p1). Funding Information: NESDA The Netherlands Study of Depression and Anxiety (NESDA) were funded by the Netherlands Organization for Scientific Research (Geestkracht program Grant 10-000-1002); the Center for Medical Systems Biology (CMSB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University’s EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam. Genotyping was funded by the US National Institute of Mental Health (RC2MH089951) as part of the American Recovery and Reinvestment Act of 2009. BP is financially supported by NWO-VIDI Grant No. 91811602. Publisher Copyright: © 2015, The Author(s).
PY - 2016/3/1
Y1 - 2016/3/1
N2 - Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.
AB - Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.
KW - Common genetic variants
KW - Imputation
KW - Personality
KW - Phenotype harmonization
KW - Polygenic risk
UR - http://www.scopus.com/inward/record.url?scp=84957952518&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84957952518&partnerID=8YFLogxK
U2 - 10.1007/s10519-015-9735-5
DO - 10.1007/s10519-015-9735-5
M3 - Article
C2 - 26362575
AN - SCOPUS:84957952518
SN - 0001-8244
VL - 46
SP - 170
EP - 182
JO - Behavior Genetics
JF - Behavior Genetics
IS - 2
ER -