Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

doi:10.1038/ng.3552

. 2016 Jun;48(6):624-33.

doi: 10.1038/ng.3552. Epub 2016 Apr 18.

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Aysu Okbay^{1

2

3}, Bart M L Baselmans^{4

5}, Jan-Emmanuel De Neve⁶, Patrick Turley⁷, Michel G Nivard⁴, Mark Alan Fontana⁸, S Fleur W Meddens^{3

9

10}, Richard Karlsson Linnér^{3

9

10}, Cornelius A Rietveld^{1

2

3}, Jaime Derringer¹¹, Jacob Gratten¹², James J Lee¹³, Jimmy Z Liu¹⁴, Ronald de Vlaming^{1

2

3}, Tarunveer S Ahluwalia^{15

16

17}, Jadwiga Buchwald¹⁸, Alana Cavadino^{19

20}, Alexis C Frazier-Wood²¹, Nicholas A Furlotte²², Victoria Garfield²³, Marie Henrike Geisel²⁴, Juan R Gonzalez^{25

26

27}, Saskia Haitjema²⁸, Robert Karlsson²⁹, Sander W van der Laan²⁸, Karl-Heinz Ladwig³⁰, Jari Lahti^{31

32

33}, Sven J van der Lee², Penelope A Lind³⁴, Tian Liu^{35

36}, Lindsay Matteson¹³, Evelin Mihailov³⁷, Michael B Miller¹³, Camelia C Minica⁴, Ilja M Nolte³⁸, Dennis Mook-Kanamori^{39

40

41}, Peter J van der Most³⁸, Christopher Oldmeadow^{42

43}, Yong Qian⁴⁴, Olli Raitakari^{45

46}, Rajesh Rawal⁴⁷, Anu Realo^{48

49}, Rico Rueedi^{50

51}, Börge Schmidt²⁴, Albert V Smith^{52

53}, Evie Stergiakouli⁵⁴, Toshiko Tanaka⁵⁵, Kent Taylor⁵⁶, Gudmar Thorleifsson, Juho Wedenoja¹⁸, Juergen Wellmann⁵⁷, Harm-Jan Westra^{58

59}, Sara M Willems², Wei Zhao⁶⁰; LifeLines Cohort Study; Najaf Amin², Andrew Bakshi¹², Sven Bergmann, Gyda Bjornsdottir, Patricia A Boyle⁶¹, Samantha Cherney⁶², Simon R Cox^{63

64}, Gail Davies^{63

64}, Oliver S P Davis⁵⁴, Jun Ding⁴⁴, Nese Direk², Peter Eibich^{65

66}, Rebecca T Emeny^{67

68}, Ghazaleh Fatemifar⁶⁹, Jessica D Faul⁷⁰, Luigi Ferrucci⁵⁵, Andreas J Forstner^{71

72}, Christian Gieger⁴⁷, Richa Gupta¹⁸, Tamara B Harris⁷³, Juliette M Harris⁷⁴, Elizabeth G Holliday^{42

43}, Jouke-Jan Hottenga^{4

5}, Philip L De Jager^{75

76

77}, Marika A Kaakinen^{78

79}, Eero Kajantie^{80

81}, Ville Karhunen⁷⁹, Ivana Kolcic⁸², Meena Kumari⁸³, Lenore J Launer⁸⁴, Lude Franke⁸⁵, Ruifang Li-Gao³⁹, David C Liewald, Marisa Koini⁸⁶, Anu Loukola¹⁸, Pedro Marques-Vidal⁸⁷, Grant W Montgomery⁸⁸, Miriam A Mosing⁸⁹, Lavinia Paternoster⁵⁴, Alison Pattie⁶⁴, Katja E Petrovic⁸⁶, Laura Pulkki-Råback^{31

33}, Lydia Quaye⁷⁴, Katri Räikkönen³¹, Igor Rudan⁹⁰, Rodney J Scott^{43

91}, Jennifer A Smith⁶⁰, Angelina R Sutin^{55

92}, Maciej Trzaskowski^{12

82}, Anna E Vinkhuyzen¹², Lei Yu⁹³, Delilah Zabaneh⁸², John R Attia^{42

43}, David A Bennett⁹³, Klaus Berger⁵⁷, Lars Bertram^{94

95}, Dorret I Boomsma^{4

5

96}, Harold Snieder³⁸, Shun-Chiao Chang⁹⁷, Francesco Cucca⁹⁸, Ian J Deary^{63

64}, Cornelia M van Duijn², Johan G Eriksson^{99

100

101}, Ute Bültmann¹⁰², Eco J C de Geus^{4

5

96}, Patrick J F Groenen^{3

103}, Vilmundur Gudnason^{52

53}, Torben Hansen¹⁶, Catharine A Hartman¹⁰⁴, Claire M A Haworth⁵⁴, Caroline Hayward¹⁰⁵, Andrew C Heath¹⁰⁶, David A Hinds²², Elina Hyppönen^{20

107

108}, William G Iacono¹³, Marjo-Riitta Järvelin^{78

109

110

111}, Karl-Heinz Jöckel²⁴, Jaakko Kaprio^{18

112

113}, Sharon L R Kardia⁶⁰, Liisa Keltikangas-Järvinen³¹, Peter Kraft¹¹⁴, Laura D Kubzansky¹¹⁵, Terho Lehtimäki^{116

117}, Patrik K E Magnusson²⁹, Nicholas G Martin¹¹⁸, Matt McGue¹³, Andres Metspalu^{37

119}, Melinda Mills¹²⁰, Renée de Mutsert³⁹, Albertine J Oldehinkel¹⁰³, Gerard Pasterkamp^{28

121}, Nancy L Pedersen²⁹, Robert Plomin¹²², Ozren Polasek⁸², Christine Power^{20

108}, Stephen S Rich¹²³, Frits R Rosendaal³⁹, Hester M den Ruijter²⁸, David Schlessinger⁴⁴, Helena Schmidt^{86

124}, Rauli Svento¹²⁵, Reinhold Schmidt⁸⁶, Behrooz Z Alizadeh^{38

126}, Thorkild I A Sørensen^{16

54

127}, Tim D Spector⁷⁴, John M Starr, Kari Stefansson, Andrew Steptoe²³, Antonio Terracciano^{55

92}, Unnur Thorsteinsdottir, A Roy Thurik^{1

3

128

129}, Nicholas J Timpson⁵⁴, Henning Tiemeier^{2

130

131}, André G Uitterlinden^{2

3

132}, Peter Vollenweider⁸⁷, Gert G Wagner^{35

65

133}, David R Weir⁷⁰, Jian Yang^{12

134}, Dalton C Conley¹³⁵, George Davey Smith⁵⁴, Albert Hofman^{2

136}, Magnus Johannesson¹³⁷, David I Laibson⁷, Sarah E Medland³⁴, Michelle N Meyer^{138

139}, Joseph K Pickrell^{14

140}, Tõnu Esko³⁷, Robert F Krueger¹³, Jonathan P Beauchamp⁷, Philipp D Koellinger^{3

9

10}, Daniel J Benjamin⁸, Meike Bartels^{4

5

96}, David Cesarini^{141

142}

Affiliations

¹ Department of Applied Economics, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, the Netherlands.
² Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
³ Erasmus University Rotterdam Institute for Behavior and Biology, Rotterdam, the Netherlands.
⁴ Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
⁵ EMGO+ Institute for Health and Care Research, Amsterdam, the Netherlands.
⁶ Saïd Business School, University of Oxford, Oxford, UK.
⁷ Department of Economics, Harvard University, Cambridge, Massachusetts, USA.
⁸ Center for Economic and Social Research, University of Southern California, Los Angeles, California, USA.
⁹ Department of Complex Trait Genetics, Vrije Universiteit, Center for Neurogenomics and Cognitive Research, Amsterdam, the Netherlands.
¹⁰ Amsterdam Business School, University of Amsterdam, Amsterdam, the Netherlands.
¹¹ Department of Psychology, University of Illinois, Champaign, Illinois, USA.
¹² Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
¹³ Department of Psychology, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA.
¹⁴ New York Genome Center, New York, New York, USA.
¹⁵ COPSAC (Copenhagen Prospective Studies on Asthma in Childhood), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁶ Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.
¹⁷ Steno Diabetes Center, Gentofte, Denmark.
¹⁸ Department of Public Health, University of Helsinki, Helsinki, Finland.
¹⁹ Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.
²⁰ South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
²¹ USDA-ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA.
²² 23andMe, Inc., Mountain View, California, USA.
²³ Department of Epidemiology and Public Health, University College London, London, UK.
²⁴ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany.
²⁵ Centre for Research in Environmental Epidemiology, Institute for Global Health, Barcelona, Spain.
²⁶ Universitat Pompeu Fabra, Barcelona, Spain.
²⁷ CIBER Epidemiología y Salud Pública, Barcelona, Spain.
²⁸ Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
²⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³⁰ Department of Psychosomatic Medicine and Psychotherapy, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
³¹ Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
³² Folkhälsan Research Centre, Helsingfors, Finland.
³³ Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
³⁴ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³⁵ Max Planck Institute for Human Development, Berlin, Germany.
³⁶ Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics, Berlin, Germany.
³⁷ Estonian Genome Center, University of Tartu, Tartu, Estonia.
³⁸ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
³⁹ Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
⁴⁰ Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
⁴¹ BESC, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
⁴² Public Health Stream, Hunter Medical Research Institute, New Lambton, New South Wales, Australia.
⁴³ Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia.
⁴⁴ Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA.
⁴⁵ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁴⁶ Department of Clinical Physiology, Turku University Hospital, Turku, Finland.
⁴⁷ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁴⁸ Department of Psychology, University of Tartu, Tartu, Estonia.
⁴⁹ Department of Psychology, University of Warwick, Coventry, UK.
⁵⁰ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
⁵¹ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁵² Icelandic Heart Association, Kopavogur, Iceland.
⁵³ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁵⁴ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁵⁵ National Institute on Aging, US National Institutes of Health, Baltimore, Maryland, USA.
⁵⁶ Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA, Torrence, California, USA.
⁵⁷ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
⁵⁸ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁵⁹ Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁶⁰ Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA.
⁶¹ Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, USA.
⁶² RAND Corporation, Santa Monica, California, USA.
⁶³ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
⁶⁴ Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁶⁵ German Socio-Economic Panel Study, DIW Berlin, Berlin, Germany.
⁶⁶ Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁶⁷ Institute of Epidemiology II, Mental Health Research Unit, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁶⁸ Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
⁶⁹ Farr Institute of Health Informatics, University College London, London, UK.
⁷⁰ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan, USA.
⁷¹ Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁷² Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
⁷³ Laboratory of Epidemiology, Demography, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
⁷⁴ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
⁷⁵ Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁷⁶ Harvard Medical School, Boston, Massachusetts, USA.
⁷⁷ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
⁷⁸ Department of Genomics of Common Disease, Imperial College London, London, UK.
⁷⁹ Center for Life Course Health Research, University of Oulu and Oulu University Hospital, Oulu, Finland.
⁸⁰ Department of Pediatrics, University of Helsinki, Helsinki, Finland.
⁸¹ National Institute for Health and Welfare, Helsinki, Finland.
⁸² Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia.
⁸³ Institute for Social and Economic Research, University of Essex, Wivenhoe Park, UK.
⁸⁴ Neuroepidemiology Section, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
⁸⁵ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁸⁶ Department of Neurology, General Hospital and Medical University Graz, Graz, Austria.
⁸⁷ Department of Internal Medicine, Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
⁸⁸ Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁸⁹ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁹⁰ Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
⁹¹ Information-Based Medicine Stream, Hunter Medical Research Institute, New Lambton, New South Wales, Australia.
⁹² Department of Behavioral Sciences and Social Medicine, Florida State University College of Medicine, Tallahassee, Florida, USA.
⁹³ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
⁹⁴ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institute of Neurogenetics and Institute of Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
⁹⁵ Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
⁹⁶ Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
⁹⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁹⁸ Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, Cittadella Universitarià di Monserrato, Monserrato, Italy.
⁹⁹ Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
¹⁰⁰ Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
¹⁰¹ Unit of General Practice, University Central Hospital, Helsinki, Finland.
¹⁰² Department of Health Sciences, Community and Occupational Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁰³ Econometric Institute, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, the Netherlands.
¹⁰⁴ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁰⁵ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
¹⁰⁶ Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁰⁷ Centre for Population Health Research, School of Health Sciences and Sansom Institute, University of South Australia, Adelaide, South Australia, Australia.
¹⁰⁸ Population, Policy and Practice, UCL Institute of Child Health, London, UK.
¹⁰⁹ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
¹¹⁰ Biocenter Oulu, University of Oulu, Oulu, Finland.
¹¹¹ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
¹¹² Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
¹¹³ Department for Health, THL (National Institute for Health and Welfare), Helsinki, Finland.
¹¹⁴ Department of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
¹¹⁵ Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
¹¹⁶ Fimlab Laboratories, Tampere, Finland.
¹¹⁷ Department of Clinical Chemistry, University of Tampere, School of Medicine, Tampere, Finland.
¹¹⁸ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹¹⁹ Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
¹²⁰ Department of Sociology, University of Oxford, Oxford, UK.
¹²¹ Laboratory of Clinical Chemistry and Hematology, Division of Laboratories and Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands.
¹²² Social, Genetic and Developmental Psychiatry Centre, King's College London, De Crespigny Park, UK.
¹²³ Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.
¹²⁴ Research Unit for Genetic Epidemiology, Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, General Hospital and Medical University Graz, Graz, Austria.
¹²⁵ Department of Economics, Oulu Business School, Oulu, Finland.
¹²⁶ Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹²⁷ Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, Capital Region, Frederiksberg, Denmark.
¹²⁸ Montpellier Business School, Montpellier, France.
¹²⁹ Panteia, Zoetermeer, the Netherlands.
¹³⁰ Department of Psychiatry, Erasmus Medical Center, Rotterdam, the Netherlands.
¹³¹ Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, the Netherlands.
¹³² Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
¹³³ School of Economics and Management, Berlin University of Technology, Berlin, Germany.
¹³⁴ University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
¹³⁵ Department of Sociology, Princeton University, Princeton, New Jersey, USA.
¹³⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
¹³⁷ Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
¹³⁸ Department of Bioethics, Clarkson University, Schenectady, New York, USA.
¹³⁹ Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴⁰ Department of Biological Sciences, Columbia University, New York, New York, USA.
¹⁴¹ Department of Economics, New York University, New York, New York, USA.
¹⁴² Research Institute for Industrial Economics, Stockholm, Sweden.

PMID: 27089181
PMCID: PMC4884152
DOI: 10.1038/ng.3552

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Aysu Okbay et al. Nat Genet. 2016 Jun.

. 2016 Jun;48(6):624-33.

doi: 10.1038/ng.3552. Epub 2016 Apr 18.

Authors

Affiliations

¹ Department of Applied Economics, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, the Netherlands.
² Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
³ Erasmus University Rotterdam Institute for Behavior and Biology, Rotterdam, the Netherlands.
⁴ Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
⁵ EMGO+ Institute for Health and Care Research, Amsterdam, the Netherlands.
⁶ Saïd Business School, University of Oxford, Oxford, UK.
⁷ Department of Economics, Harvard University, Cambridge, Massachusetts, USA.
⁸ Center for Economic and Social Research, University of Southern California, Los Angeles, California, USA.
⁹ Department of Complex Trait Genetics, Vrije Universiteit, Center for Neurogenomics and Cognitive Research, Amsterdam, the Netherlands.
¹⁰ Amsterdam Business School, University of Amsterdam, Amsterdam, the Netherlands.
¹¹ Department of Psychology, University of Illinois, Champaign, Illinois, USA.
¹² Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
¹³ Department of Psychology, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA.
¹⁴ New York Genome Center, New York, New York, USA.
¹⁵ COPSAC (Copenhagen Prospective Studies on Asthma in Childhood), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁶ Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.
¹⁷ Steno Diabetes Center, Gentofte, Denmark.
¹⁸ Department of Public Health, University of Helsinki, Helsinki, Finland.
¹⁹ Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.
²⁰ South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
²¹ USDA-ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA.
²² 23andMe, Inc., Mountain View, California, USA.
²³ Department of Epidemiology and Public Health, University College London, London, UK.
²⁴ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany.
²⁵ Centre for Research in Environmental Epidemiology, Institute for Global Health, Barcelona, Spain.
²⁶ Universitat Pompeu Fabra, Barcelona, Spain.
²⁷ CIBER Epidemiología y Salud Pública, Barcelona, Spain.
²⁸ Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
²⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³⁰ Department of Psychosomatic Medicine and Psychotherapy, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
³¹ Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
³² Folkhälsan Research Centre, Helsingfors, Finland.
³³ Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
³⁴ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³⁵ Max Planck Institute for Human Development, Berlin, Germany.
³⁶ Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics, Berlin, Germany.
³⁷ Estonian Genome Center, University of Tartu, Tartu, Estonia.
³⁸ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
³⁹ Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
⁴⁰ Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
⁴¹ BESC, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
⁴² Public Health Stream, Hunter Medical Research Institute, New Lambton, New South Wales, Australia.
⁴³ Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia.
⁴⁴ Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA.
⁴⁵ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁴⁶ Department of Clinical Physiology, Turku University Hospital, Turku, Finland.
⁴⁷ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁴⁸ Department of Psychology, University of Tartu, Tartu, Estonia.
⁴⁹ Department of Psychology, University of Warwick, Coventry, UK.
⁵⁰ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
⁵¹ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁵² Icelandic Heart Association, Kopavogur, Iceland.
⁵³ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁵⁴ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁵⁵ National Institute on Aging, US National Institutes of Health, Baltimore, Maryland, USA.
⁵⁶ Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA, Torrence, California, USA.
⁵⁷ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
⁵⁸ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁵⁹ Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁶⁰ Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA.
⁶¹ Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, USA.
⁶² RAND Corporation, Santa Monica, California, USA.
⁶³ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
⁶⁴ Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁶⁵ German Socio-Economic Panel Study, DIW Berlin, Berlin, Germany.
⁶⁶ Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁶⁷ Institute of Epidemiology II, Mental Health Research Unit, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁶⁸ Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
⁶⁹ Farr Institute of Health Informatics, University College London, London, UK.
⁷⁰ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan, USA.
⁷¹ Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁷² Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
⁷³ Laboratory of Epidemiology, Demography, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
⁷⁴ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
⁷⁵ Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁷⁶ Harvard Medical School, Boston, Massachusetts, USA.
⁷⁷ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
⁷⁸ Department of Genomics of Common Disease, Imperial College London, London, UK.
⁷⁹ Center for Life Course Health Research, University of Oulu and Oulu University Hospital, Oulu, Finland.
⁸⁰ Department of Pediatrics, University of Helsinki, Helsinki, Finland.
⁸¹ National Institute for Health and Welfare, Helsinki, Finland.
⁸² Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia.
⁸³ Institute for Social and Economic Research, University of Essex, Wivenhoe Park, UK.
⁸⁴ Neuroepidemiology Section, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
⁸⁵ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁸⁶ Department of Neurology, General Hospital and Medical University Graz, Graz, Austria.
⁸⁷ Department of Internal Medicine, Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
⁸⁸ Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁸⁹ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁹⁰ Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
⁹¹ Information-Based Medicine Stream, Hunter Medical Research Institute, New Lambton, New South Wales, Australia.
⁹² Department of Behavioral Sciences and Social Medicine, Florida State University College of Medicine, Tallahassee, Florida, USA.
⁹³ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
⁹⁴ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institute of Neurogenetics and Institute of Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
⁹⁵ Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
⁹⁶ Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
⁹⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁹⁸ Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, Cittadella Universitarià di Monserrato, Monserrato, Italy.
⁹⁹ Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
¹⁰⁰ Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
¹⁰¹ Unit of General Practice, University Central Hospital, Helsinki, Finland.
¹⁰² Department of Health Sciences, Community and Occupational Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁰³ Econometric Institute, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, the Netherlands.
¹⁰⁴ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁰⁵ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
¹⁰⁶ Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁰⁷ Centre for Population Health Research, School of Health Sciences and Sansom Institute, University of South Australia, Adelaide, South Australia, Australia.
¹⁰⁸ Population, Policy and Practice, UCL Institute of Child Health, London, UK.
¹⁰⁹ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
¹¹⁰ Biocenter Oulu, University of Oulu, Oulu, Finland.
¹¹¹ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
¹¹² Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
¹¹³ Department for Health, THL (National Institute for Health and Welfare), Helsinki, Finland.
¹¹⁴ Department of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
¹¹⁵ Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
¹¹⁶ Fimlab Laboratories, Tampere, Finland.
¹¹⁷ Department of Clinical Chemistry, University of Tampere, School of Medicine, Tampere, Finland.
¹¹⁸ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹¹⁹ Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
¹²⁰ Department of Sociology, University of Oxford, Oxford, UK.
¹²¹ Laboratory of Clinical Chemistry and Hematology, Division of Laboratories and Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands.
¹²² Social, Genetic and Developmental Psychiatry Centre, King's College London, De Crespigny Park, UK.
¹²³ Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.
¹²⁴ Research Unit for Genetic Epidemiology, Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, General Hospital and Medical University Graz, Graz, Austria.
¹²⁵ Department of Economics, Oulu Business School, Oulu, Finland.
¹²⁶ Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹²⁷ Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, Capital Region, Frederiksberg, Denmark.
¹²⁸ Montpellier Business School, Montpellier, France.
¹²⁹ Panteia, Zoetermeer, the Netherlands.
¹³⁰ Department of Psychiatry, Erasmus Medical Center, Rotterdam, the Netherlands.
¹³¹ Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, the Netherlands.
¹³² Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
¹³³ School of Economics and Management, Berlin University of Technology, Berlin, Germany.
¹³⁴ University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
¹³⁵ Department of Sociology, Princeton University, Princeton, New Jersey, USA.
¹³⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
¹³⁷ Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
¹³⁸ Department of Bioethics, Clarkson University, Schenectady, New York, USA.
¹³⁹ Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴⁰ Department of Biological Sciences, Columbia University, New York, New York, USA.
¹⁴¹ Department of Economics, New York University, New York, New York, USA.
¹⁴² Research Institute for Industrial Economics, Stockholm, Sweden.

PMID: 27089181
PMCID: PMC4884152
DOI: 10.1038/ng.3552

Erratum in

Corrigendum: Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses.
Okbay A, Baselmans BM, Neve JE, Turley P, Nivard MG, Fontana MA, Meddens SF, Linnér RK, Rietveld CA, Derringer J, Gratten J, Lee JJ, Liu JZ, de Vlaming R, Ahluwalia TS, Buchwald J, Cavadino A, Frazier-Wood AC, Furlotte NA, Garfield V, Geisel MH, Gonzalez JR, Haitjema S, Karlsson R, van der Laan SW, Ladwig KH, Lahti J, van der Lee SJ, Lind PA, Liu T, Matteson L, Mihailov E, Miller MB, Minica CC, Nolte IM, Mook-Kanamori D, van der Most PJ, Oldmeadow C, Qian Y, Raitakari O, Rawal R, Realo A, Rueedi R, Schmidt B, Smith AV, Stergiakouli E, Tanaka T, Taylor K, Thorleifsson G, Wedenoja J, Wellmann J, Westra HJ, Willems SM, Zhao W; LifeLines Cohort Study; Amin N, Bakshi A, Bergmann S, Bjornsdottir G, Boyle PA, Cherney S, Cox SR, Davies G, Davis OS, Ding J, Direk N, Eibich P, Emeny RT, Fatemifar G, Faul JD, Ferrucci L, Forstner AJ, Gieger C, Gupta R, Harris TB, Harris JM, Holliday EG, Hottenga JJ, Jager PL, Kaakinen MA, Kajantie E, Karhunen V, Kolcic I, Kumari M, Launer LJ, Franke L, Li-Gao R, Liewald DC, Koini M, Loukola A, Marques-Vidal P, Montgomery GW, Mosing MA, Paternoster L, Pattie A, Petrovic KE, Pulkki-Råback L, Quaye L, Räikkönen K, Rudan I, Scott RJ, Smith JA, Sutin AR, Trzaskow… See abstract for full author list ➔ Okbay A, et al. Nat Genet. 2016 Jul 27;48(8):970. doi: 10.1038/ng0816-970c. Nat Genet. 2016. PMID: 27463399 No abstract available.
Corrigendum: Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses.
Okbay A, Baselmans BM, De Neve JE, Turley P, Nivard MG, Fontana MA, Meddens SF, Linnér RK, Rietveld CA, Derringer J, Gratten J, Lee JJ, Liu JZ, de Vlaming R, Ahluwalia TS, Buchwald J, Cavadino A, Frazier-Wood AC, Furlotte NA, Garfield V, Geisel MH, Gonzalez JR, Haitjema S, Karlsson R, van der Laan SW, Ladwig KH, Lahti J, van der Lee SJ, Lind PA, Liu T, Matteson L, Mihailov E, Miller MB, Minica CC, Nolte IM, Mook-Kanamori D, van der Most PJ, Oldmeadow C, Qian Y, Raitakari O, Rawal R, Realo A, Rueedi R, Schmidt B, Smith AV, Stergiakouli E, Tanaka T, Taylor K, Thorleifsson G, Wedenoja J, Wellmann J, Westra HJ, Willems SM, Zhao W; LifeLines Cohort Study; Amin N, Bakshi A, Bergmann S, Bjornsdottir G, Boyle PA, Cherney S, Cox SR, Davies G, Davis OS, Ding J, Direk N, Eibich P, Emeny RT, Fatemifar G, Faul JD, Ferrucci L, Forstner AJ, Gieger C, Gupta R, Harris TB, Harris JM, Holliday EG, Hottenga JJ, De Jager PL, Kaakinen MA, Kajantie E, Karhunen V, Kolcic I, Kumari M, Launer LJ, Franke L, Li-Gao R, Liewald DC, Koini M, Loukola A, Marques-Vidal P, Montgomery GW, Mosing MA, Paternoster L, Pattie A, Petrovic KE, Pulkki-Råback L, Quaye L, Räikkönen K, Rudan I, Scott RJ, Smith JA, Sutin AR, Tr… See abstract for full author list ➔ Okbay A, et al. Nat Genet. 2016 Nov 29;48(12):1591. doi: 10.1038/ng1216-1587b. Nat Genet. 2016. PMID: 27898078 Free PMC article. No abstract available.

Abstract

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

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Conflict of interest statement

Competing Financial Interests: The authors declare no competing financial interests.

Figures

**Fig. 1. Manhattan plots of GWAS results**
**(a)** Subjective well-being (N = 298,420), **(b)** Depressive symptoms (N = 180,866), **(c)** Neuroticism (N = 170,911). The x-axis is chromosomal position, and the y-axis is the significance on a −log₁₀ scale. The upper dashed line marks the threshold for genome-wide significance (p = 5×10 ); the lower line marks the threshold for nominal significance (p = 10 ). Each approximately independent genome-wide significant association (“lead SNP”) is marked by ×. Each lead SNP is the lowest p-value SNP within the locus, as defined by our clumping algorithm (Supplementary Note).

**Fig. 2. Genetic correlations with bars representing 95% confidence intervals**
The correlations are estimated using bivariate LD Score (LDSC) regression. (a) Genetic correlations between subjective well-being, depressive symptoms, and neuroticism (“our three phenotypes”), as well as between our three phenotypes and height. (b) Genetic correlations between our three phenotypes and selected neuropsychiatric phenotypes. (c) Genetic correlations between our three phenotypes and selected physical health phenotypes. In (b) and (c), we report the negative of the estimated correlation with depressive symptoms and neuroticism (but not subjective well-being).

**Fig. 3. Quasi-replication and lookup of lead SNPs**
In quasi-replication analyses, we examined whether (a) lead SNPs identified in the subjective well-being meta-analyses are associated with depressive symptoms or neuroticism, (b) lead SNPs identified in the analyses of depressive symptoms are associated with subjective well-being, and (c) lead SNPs identified in the analyses of neuroticism are associated with subjective well-being. The quasi-replication sample is always restricted to non-overlapping cohorts. In a separate lookup exercise, we examined whether lead SNPs for depressive symptoms and neuroticism are associated with depression in an independent sample of 23andMe customers (N = 368,890). The results from this lookup are depicted as green crosses in (b) and (c). Bars represent 95% CIs (not adjusted for multiple testing). For interpretational ease, we choose the reference allele so that positive coefficients imply that the estimated effect is in the predicted direction. Listed below each lead SNP is the nearest gene.

**Fig. 4. Results from selected biological analyses**
(a) Estimates of the expected increase in the phenotypic variance accounted for by a SNP due to the SNP’s being in a given category (*τ_c*), divided by the LD Score heritability of the phenotype (h²). Each estimate of *τ_c* comes from a separate stratified LD Score regression, controlling for the 52 functional annotation categories in the “baseline model.” The bars represent 95% CIs (not adjusted for multiple testing). To benchmark the estimates, we compare them to those obtained from a recent study of height. (b) Inversion polymorphism on chromosome 8 and the 7 genes for which the inversion is a significant *cis*-eQTL at FDR < 0.05. The upper half of the figure shows the Manhattan plot for neuroticism for the inversion and surrounding regions. The bottom half shows the squared correlation between the SNPs and the principal component that captures the inversion. The inlay plots the relationship, for each SNP in the inversion region, between the SNP’s significance and its squared correlation with the principal component that captures the inversion.

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References

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1. Weiss A, Bates TC, Luciano M. Happiness is a personal(ity) thing: The genetics of personality and well-being in a representative sample. Psychol Sci. 2008;19:205–210. - PubMed
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[1] Kendler KS, Myers J. The genetic and environmental relationship between major depression and the five-factor model of personality. Psychol Med. 2009;40:801. - PubMed

[2] Kendler KS, Myers J. The genetic and environmental relationship between major depression and the five-factor model of personality. Psychol Med. 2009;40:801. - PubMed

[3] Weiss A, Bates TC, Luciano M. Happiness is a personal(ity) thing: The genetics of personality and well-being in a representative sample. Psychol Sci. 2008;19:205–210. - PubMed

[4] Weiss A, Bates TC, Luciano M. Happiness is a personal(ity) thing: The genetics of personality and well-being in a representative sample. Psychol Sci. 2008;19:205–210. - PubMed

[5] Bartels M, Cacioppo JT, van Beijsterveldt TCEM, Boomsma DI. Exploring the association between well-being and psychopathology in adolescents. Behav Genet. 2013;43:177–190. - PMC - PubMed

[6] Bartels M, Cacioppo JT, van Beijsterveldt TCEM, Boomsma DI. Exploring the association between well-being and psychopathology in adolescents. Behav Genet. 2013;43:177–190. - PMC - PubMed

[7] de Moor MHM, et al. Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with Major Depressive Disorder. JAMA Psychiatry. 2015;72:642–650. - PMC - PubMed

[8] de Moor MHM, et al. Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with Major Depressive Disorder. JAMA Psychiatry. 2015;72:642–650. - PMC - PubMed

[9] Hyman S. Mental health: Depression needs large human-genetics studies. Nature. 2014;515:189–191. - PubMed

[10] Hyman S. Mental health: Depression needs large human-genetics studies. Nature. 2014;515:189–191. - PubMed

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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

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