Genetic effects influencing risk for major depressive disorder in China and Europe

on behalf of the CONVERGE consortium and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

doi:10.1038/tp.2016.292

Genetic effects influencing risk for major depressive disorder in China and Europe

on behalf of the CONVERGE consortium and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (∼30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log₁₀ Bayes Factor = 8.08) but failed to replicate in an independent European sample (P = 0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

Original language	English
Article number	e1074
Journal	Translational psychiatry
Volume	7
Issue number	3
DOIs	https://doi.org/10.1038/tp.2016.292
State	Published - 2017

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10.1038/tp.2016.292

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@article{5aefd6a69b314d7f8eb70d795c89f772,

title = "Genetic effects influencing risk for major depressive disorder in China and Europe",

abstract = "Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (∼30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor = 8.08) but failed to replicate in an independent European sample (P = 0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.",

author = "{on behalf of the CONVERGE consortium and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and Bigdeli, {T. B.} and S. Ripke and Peterson, {R. E.} and M. Trzaskowski and Bacanu, {S. A.} and A. Abdellaoui and Andlauer, {T. F.M.} and Beekman, {A. T.F.} and K. Berger and Blackwood, {D. H.R.} and Boomsma, {D. I.} and G. Breen and Buttensch{\o}n, {H. N.} and Byrne, {E. M.} and S. Cichon and Clarke, {T. K.} and B. Couvy-Duchesne and N. Craddock and {De Geus}, {E. J.C.} and F. Degenhardt and Dunn, {E. C.} and Edwards, {A. C.} and Fanous, {A. H.} and Forstner, {A. J.} and J. Frank and M. Gill and Gordon, {S. D.} and Grabe, {H. J.} and Hamilton, {S. P.} and O. Hardiman and C. Hayward and Heath, {A. C.} and Henders, {A. K.} and S. Herms and Hickie, {I. B.} and P. Hoffmann and G. Homuth and Hottenga, {J. J.} and M. Ising and R. Jansen and S. Kloiber and Knowles, {J. A.} and M. Lang and Li, {Q. S.} and S. Lucae and MacIntyre, {D. J.} and Madden, {P. A.F.} and Martin, {N. G.} and McGrath, {P. J.} and P. McGuffin and McIntosh, {A. M.} and Medland, {S. E.} and D. Mehta and Middeldorp, {C. M.} and Y. Milaneschi and Montgomery, {G. W.} and O. Mors and B. M{\"u}ller-Myhsok and M. Nauck and Nyholt, {D. R.} and N{\"o}then, {M. M.} and Owen, {M. J.} and Penninx, {B. W.J.H.} and Pergadia, {M. L.} and Perlis, {R. H.} and Peyrot, {W. J.} and Porteous, {D. J.} and Potash, {J. B.} and Rice, {J. P.} and M. Rietschel and Riley, {B. P.} and M. Rivera and R. Schoevers and Schulze, {T. G.} and J. Shi and Shyn, {S. I.} and Smit, {J. H.} and Smoller, {J. W.} and F. Streit and J. Strohmaier and A. Teumer and J. Treutlein and {Van Der Auwera}, S. and {Van Grootheest}, G. and {Van Hemert}, {A. M.} and H. V{\"o}lzke and Webb, {B. T.} and Weissman, {M. M.} and J. Wellmann and G. Willemsen and Witt, {S. H.} and Levinson, {D. F.} and Lewis, {C. M.} and Wray, {N. R.} and J. Flint and Sullivan, {P. F.} and Kendler, {K. S.}",

note = "Funding Information: The CONVERGE study was funded by the Wellcome Trust (WT090532/Z/09/Z, WT083573/Z/07/Z, WT089269/Z/09/Z) and by NIH grant MH100549. All authors are part of the CONVERGE consortium (China, Oxford and VCU Experimental Research on Genetic Epidemiology) and gratefully acknowledge the support of all partners in hospitals across China. The PGC is supported by NIH grant U01 MH094421. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster. org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. We thank TH Pers for support for the DEPICT software. Generation Scotland (GS:SFHS) was supported by a Wellcome Trust Strategic Award 'Stratifying Resilience and Depression Longitudinally' (STRaDL; Reference 104036/Z/14/Z), and received core support from the Chief Scientist Office (CSO) of the Scottish Government Health Directorates (grant number CZD/16/6) and the Scottish Funding Council (HR03006). AMM is supported by a Scottish Funding Council Senior Clinical Fellowship and by the Dame Theresa and Mortimer Sackler Foundation. The Bonn/Manheim (BoMa) study was supported by the German Federal Ministry of Education and Research(BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to Markus M N{\"o}then and Sven Cichon, grant 01GS08147 to Marcella Rietschel), under the auspices of the National Genome Research Network plus (NGFNplus), and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders, grant BMBF01ZX1314G), under the auspices of the e:Med Programme. The GenRED GWAS project was supported by NIMH R01 Grants MH061686 (DF Levinson), MH059542 (WH Coryell), MH075131 (WB Lawson), MH059552 (JB Potash), MH059541 (WA Scheftner) and MH060912 (MM Weissman). We acknowledge the contributions of Dr George S Zubenko and Dr Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality-control analyses of the control data set were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression. We are grateful to Knowledge Networks (Menlo Park, CA, USA) for assistance in collecting the control data set. We express our profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. The RADIANT studies were funded by the following: a joint grant from the UK Medical Research Council and GlaxoSmithKline (G0701420); the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King's College London; and the UK Medical Research Council (G0000647). The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression (01ES0811). Genotyping was supported by the Bavarian Ministry of Commerce, and the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145). The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) contributed to GAIN-MDD and to MDD2000. This study was funded by the Netherlands Organization for Scientific Research (MagW/ ZonMW Grants 904-61-090, 985-10- 002, 904-61-193, 480-04-004, 400-05-717, 912-100- 20; Spinozapremie 56-464-14192; Geestkracht program Grant 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, VU University's EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, NBIC/BioAssist/ RK (2008.024); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Science Council (ERC, 230374). Genotyping was funded in part by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802). Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674 and 619667), the Australian Research Council (FT0991360 and FT0991022), the FP-5 GenomEUtwin Project (QLG2-CT- 2002-01254) and the US National Institutes of Health (AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854 and DA019951) and the Center for Inherited Disease Research (Baltimore, MD, USA). We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. Genotyping of STAR∗D was supported by an NIMH Grant MH072802 (SP Hamilton). STAR∗D was funded by the National Institute of Mental Health (contract N01MH90003) to the University of Texas Southwestern Medical Center at Dallas (AJ Rush, principal investigator). 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 as well as the Social Ministry of the Federal State of Mecklenburg- West Pomerania and the network 'Greifswald Approach to Individualized Medicine (GANI-MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data of SHIP 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 Cach{\'e} Campus program of the InterSystems GmbH. SHIP LEGEND was funded by the German Research Foundation (grant GR1912/5-1). The Harvard i2b2 project was supported by Award # U54LM008748 from the National Library of Medicine (to ISK) and R01MH086026 and R01MH085542 from the National Institute of Mental Health (to RHP and JWS, respectively). Funding Information: The CONVERGE study was funded by the Wellcome Trust (WT090532/Z/09/Z, WT083573/Z/07/Z, WT089269/Z/09/Z) and by NIH grant MH100549. All authors are part of the CONVERGE consortium (China, Oxford and VCU Experimental Research on Genetic Epidemiology) and gratefully acknowledge the support of all partners in hospitals across China. The PGC is supported by NIH grant U01 MH094421. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster. org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. We thank TH Pers for support for the DEPICT software. Generation Scotland (GS:SFHS) was supported by a Wellcome Trust Strategic Award 'Stratifying Resilience and Depression Longitudinally' (STRaDL; Reference 104036/Z/14/Z), and received core support from the Chief Scientist Office (CSO) of the Scottish Government Health Directorates (grant number CZD/16/6) and the Scottish Funding Council (HR03006). AMM is supported by a Scottish Funding Council Senior Clinical Fellowship and by the Dame Theresa and Mortimer Sackler Foundation. The Bonn/Manheim (BoMa) study was supported by the German Federal Ministry of Education and Research(BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to Markus M N{\"o}then and Sven Cichon, grant 01GS08147 to Marcella Rietschel), under the auspices of the National Genome Research Network plus (NGFNplus), and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders, grant BMBF01ZX1314G), under the auspices of the e:Med Programme. The GenRED GWAS project was supported by NIMH R01 Grants MH061686 (DF Levinson), MH059542 (WH Coryell), MH075131 (WB Lawson), MH059552 (JB Potash), MH059541 (WA Scheftner) and MH060912 (MM Weissman). We acknowledge the contributions of Dr George S Zubenko and Dr Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality-control analyses of the control data set were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression. We are grateful to Knowledge Networks (Menlo Park, CA, USA) for assistance in collecting the control data set. We express our profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. The RADIANT studies were funded by the following: a joint grant from the UK Medical Research Council and GlaxoSmithKline (G0701420); the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London; and the UK Medical Research Council (G0000647). The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression (01ES0811). Genotyping was supported by the Bavarian Ministry of Commerce, and the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145). The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) contributed to GAIN-MDD and to MDD2000. This study was funded by the Netherlands Organization for Scientific Research (MagW/ ZonMW Grants 904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program Grant 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, VU University{\textquoteright}s EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, NBIC/BioAssist/ RK (2008.024); the European Science Foundation (EU/QLRT-2001-01254); the European Community{\textquoteright}s Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Science Council (ERC, 230374). Genotyping was funded in part by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802). Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674 and 619667), the Australian Research Council (FT0991360 and FT0991022), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854 and DA019951) and the Center for Inherited Disease Research (Baltimore, MD, USA). We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. Genotyping of STAR*D was supported by an NIMH Grant MH072802 (SP Hamilton). STAR*D was funded by the National Institute of Mental Health (contract N01MH90003) to the University of Texas Southwestern Medical Center at Dallas (AJ Rush, principal investigator). 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 as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania and the network {\textquoteleft}Greifswald Approach to Individualized Medicine (GANI_MED){\textquoteright} funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data of SHIP 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 Cach{\'e} Campus program of the InterSystems GmbH. SHIP LEGEND was funded by the German Research Foundation (grant GR1912/5-1). The Harvard i2b2 project was supported by Award # U54LM008748 from the National Library of Medicine (to ISK) and R01MH086026 and R01MH085542 from the National Institute of Mental Health (to RHP and JWS, respectively). Funding Information: PFS is a scientific advisor to Pfizer. HJG reports receiving funding from the following: German Research Foundation; Federal Ministry of Education and Research Germany; speakers honoraria from, Eli Lilly and Servier. BM-M consulted for Affectis Pharmaceuticals. RP has received consulting fees from Proteus Biomedical, Concordant Rater Systems, Genomind and RID Ventures. The remaining author declare no conflict of interest. Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

doi = "10.1038/tp.2016.292",

language = "English",

volume = "7",

journal = "Translational Psychiatry",

issn = "2158-3188",

number = "3",

}

TY - JOUR

T1 - Genetic effects influencing risk for major depressive disorder in China and Europe

AU - on behalf of the CONVERGE consortium and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Bigdeli, T. B.

AU - Ripke, S.

AU - Peterson, R. E.

AU - Trzaskowski, M.

AU - Bacanu, S. A.

AU - Abdellaoui, A.

AU - Andlauer, T. F.M.

AU - Beekman, A. T.F.

AU - Berger, K.

AU - Blackwood, D. H.R.

AU - Boomsma, D. I.

AU - Breen, G.

AU - Buttenschøn, H. N.

AU - Byrne, E. M.

AU - Cichon, S.

AU - Clarke, T. K.

AU - Couvy-Duchesne, B.

AU - Craddock, N.

AU - De Geus, E. J.C.

AU - Degenhardt, F.

AU - Dunn, E. C.

AU - Edwards, A. C.

AU - Fanous, A. H.

AU - Forstner, A. J.

AU - Frank, J.

AU - Gill, M.

AU - Gordon, S. D.

AU - Grabe, H. J.

AU - Hamilton, S. P.

AU - Hardiman, O.

AU - Hayward, C.

AU - Heath, A. C.

AU - Henders, A. K.

AU - Herms, S.

AU - Hickie, I. B.

AU - Hoffmann, P.

AU - Homuth, G.

AU - Hottenga, J. J.

AU - Ising, M.

AU - Jansen, R.

AU - Kloiber, S.

AU - Knowles, J. A.

AU - Lang, M.

AU - Li, Q. S.

AU - Lucae, S.

AU - MacIntyre, D. J.

AU - Madden, P. A.F.

AU - Martin, N. G.

AU - McGrath, P. J.

AU - McGuffin, P.

AU - McIntosh, A. M.

AU - Medland, S. E.

AU - Mehta, D.

AU - Middeldorp, C. M.

AU - Milaneschi, Y.

AU - Montgomery, G. W.

AU - Mors, O.

AU - Müller-Myhsok, B.

AU - Nauck, M.

AU - Nyholt, D. R.

AU - Nöthen, M. M.

AU - Owen, M. J.

AU - Penninx, B. W.J.H.

AU - Pergadia, M. L.

AU - Perlis, R. H.

AU - Peyrot, W. J.

AU - Porteous, D. J.

AU - Potash, J. B.

AU - Rice, J. P.

AU - Rietschel, M.

AU - Riley, B. P.

AU - Rivera, M.

AU - Schoevers, R.

AU - Schulze, T. G.

AU - Shi, J.

AU - Shyn, S. I.

AU - Smit, J. H.

AU - Smoller, J. W.

AU - Streit, F.

AU - Strohmaier, J.

AU - Teumer, A.

AU - Treutlein, J.

AU - Van Der Auwera, S.

AU - Van Grootheest, G.

AU - Van Hemert, A. M.

AU - Völzke, H.

AU - Webb, B. T.

AU - Weissman, M. M.

AU - Wellmann, J.

AU - Willemsen, G.

AU - Witt, S. H.

AU - Levinson, D. F.

AU - Lewis, C. M.

AU - Wray, N. R.

AU - Flint, J.

AU - Sullivan, P. F.

AU - Kendler, K. S.

N1 - Funding Information: The CONVERGE study was funded by the Wellcome Trust (WT090532/Z/09/Z, WT083573/Z/07/Z, WT089269/Z/09/Z) and by NIH grant MH100549. All authors are part of the CONVERGE consortium (China, Oxford and VCU Experimental Research on Genetic Epidemiology) and gratefully acknowledge the support of all partners in hospitals across China. The PGC is supported by NIH grant U01 MH094421. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster. org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. We thank TH Pers for support for the DEPICT software. Generation Scotland (GS:SFHS) was supported by a Wellcome Trust Strategic Award 'Stratifying Resilience and Depression Longitudinally' (STRaDL; Reference 104036/Z/14/Z), and received core support from the Chief Scientist Office (CSO) of the Scottish Government Health Directorates (grant number CZD/16/6) and the Scottish Funding Council (HR03006). AMM is supported by a Scottish Funding Council Senior Clinical Fellowship and by the Dame Theresa and Mortimer Sackler Foundation. The Bonn/Manheim (BoMa) study was supported by the German Federal Ministry of Education and Research(BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to Markus M Nöthen and Sven Cichon, grant 01GS08147 to Marcella Rietschel), under the auspices of the National Genome Research Network plus (NGFNplus), and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders, grant BMBF01ZX1314G), under the auspices of the e:Med Programme. The GenRED GWAS project was supported by NIMH R01 Grants MH061686 (DF Levinson), MH059542 (WH Coryell), MH075131 (WB Lawson), MH059552 (JB Potash), MH059541 (WA Scheftner) and MH060912 (MM Weissman). We acknowledge the contributions of Dr George S Zubenko and Dr Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality-control analyses of the control data set were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression. We are grateful to Knowledge Networks (Menlo Park, CA, USA) for assistance in collecting the control data set. We express our profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. The RADIANT studies were funded by the following: a joint grant from the UK Medical Research Council and GlaxoSmithKline (G0701420); the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King's College London; and the UK Medical Research Council (G0000647). The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression (01ES0811). Genotyping was supported by the Bavarian Ministry of Commerce, and the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145). The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) contributed to GAIN-MDD and to MDD2000. This study was funded by the Netherlands Organization for Scientific Research (MagW/ ZonMW Grants 904-61-090, 985-10- 002, 904-61-193, 480-04-004, 400-05-717, 912-100- 20; Spinozapremie 56-464-14192; Geestkracht program Grant 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, VU University's EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, NBIC/BioAssist/ RK (2008.024); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Science Council (ERC, 230374). Genotyping was funded in part by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802). Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674 and 619667), the Australian Research Council (FT0991360 and FT0991022), the FP-5 GenomEUtwin Project (QLG2-CT- 2002-01254) and the US National Institutes of Health (AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854 and DA019951) and the Center for Inherited Disease Research (Baltimore, MD, USA). We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. Genotyping of STAR∗D was supported by an NIMH Grant MH072802 (SP Hamilton). STAR∗D was funded by the National Institute of Mental Health (contract N01MH90003) to the University of Texas Southwestern Medical Center at Dallas (AJ Rush, principal investigator). 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 as well as the Social Ministry of the Federal State of Mecklenburg- West Pomerania and the network 'Greifswald Approach to Individualized Medicine (GANI-MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data of SHIP 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 Caché Campus program of the InterSystems GmbH. SHIP LEGEND was funded by the German Research Foundation (grant GR1912/5-1). The Harvard i2b2 project was supported by Award # U54LM008748 from the National Library of Medicine (to ISK) and R01MH086026 and R01MH085542 from the National Institute of Mental Health (to RHP and JWS, respectively). Funding Information: The CONVERGE study was funded by the Wellcome Trust (WT090532/Z/09/Z, WT083573/Z/07/Z, WT089269/Z/09/Z) and by NIH grant MH100549. All authors are part of the CONVERGE consortium (China, Oxford and VCU Experimental Research on Genetic Epidemiology) and gratefully acknowledge the support of all partners in hospitals across China. The PGC is supported by NIH grant U01 MH094421. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster. org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. We thank TH Pers for support for the DEPICT software. Generation Scotland (GS:SFHS) was supported by a Wellcome Trust Strategic Award 'Stratifying Resilience and Depression Longitudinally' (STRaDL; Reference 104036/Z/14/Z), and received core support from the Chief Scientist Office (CSO) of the Scottish Government Health Directorates (grant number CZD/16/6) and the Scottish Funding Council (HR03006). AMM is supported by a Scottish Funding Council Senior Clinical Fellowship and by the Dame Theresa and Mortimer Sackler Foundation. The Bonn/Manheim (BoMa) study was supported by the German Federal Ministry of Education and Research(BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to Markus M Nöthen and Sven Cichon, grant 01GS08147 to Marcella Rietschel), under the auspices of the National Genome Research Network plus (NGFNplus), and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders, grant BMBF01ZX1314G), under the auspices of the e:Med Programme. The GenRED GWAS project was supported by NIMH R01 Grants MH061686 (DF Levinson), MH059542 (WH Coryell), MH075131 (WB Lawson), MH059552 (JB Potash), MH059541 (WA Scheftner) and MH060912 (MM Weissman). We acknowledge the contributions of Dr George S Zubenko and Dr Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality-control analyses of the control data set were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression. We are grateful to Knowledge Networks (Menlo Park, CA, USA) for assistance in collecting the control data set. We express our profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. The RADIANT studies were funded by the following: a joint grant from the UK Medical Research Council and GlaxoSmithKline (G0701420); the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King’s College London; and the UK Medical Research Council (G0000647). The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression (01ES0811). Genotyping was supported by the Bavarian Ministry of Commerce, and the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145). The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) contributed to GAIN-MDD and to MDD2000. This study was funded by the Netherlands Organization for Scientific Research (MagW/ ZonMW Grants 904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program Grant 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, VU University’s EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, NBIC/BioAssist/ RK (2008.024); the European Science Foundation (EU/QLRT-2001-01254); the European Community’s Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Science Council (ERC, 230374). Genotyping was funded in part by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802). Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674 and 619667), the Australian Research Council (FT0991360 and FT0991022), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854 and DA019951) and the Center for Inherited Disease Research (Baltimore, MD, USA). We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. Genotyping of STAR*D was supported by an NIMH Grant MH072802 (SP Hamilton). STAR*D was funded by the National Institute of Mental Health (contract N01MH90003) to the University of Texas Southwestern Medical Center at Dallas (AJ Rush, principal investigator). 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 as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data of SHIP 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 Caché Campus program of the InterSystems GmbH. SHIP LEGEND was funded by the German Research Foundation (grant GR1912/5-1). The Harvard i2b2 project was supported by Award # U54LM008748 from the National Library of Medicine (to ISK) and R01MH086026 and R01MH085542 from the National Institute of Mental Health (to RHP and JWS, respectively). Funding Information: PFS is a scientific advisor to Pfizer. HJG reports receiving funding from the following: German Research Foundation; Federal Ministry of Education and Research Germany; speakers honoraria from, Eli Lilly and Servier. BM-M consulted for Affectis Pharmaceuticals. RP has received consulting fees from Proteus Biomedical, Concordant Rater Systems, Genomind and RID Ventures. The remaining author declare no conflict of interest. Publisher Copyright: © The Author(s) 2017.

PY - 2017

Y1 - 2017

N2 - Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (∼30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor = 8.08) but failed to replicate in an independent European sample (P = 0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

AB - Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (∼30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor = 8.08) but failed to replicate in an independent European sample (P = 0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

UR - http://www.scopus.com/inward/record.url?scp=85020498216&partnerID=8YFLogxK

U2 - 10.1038/tp.2016.292

DO - 10.1038/tp.2016.292

M3 - Article

C2 - 28350396

AN - SCOPUS:85020498216

SN - 2158-3188

VL - 7

JO - Translational Psychiatry

JF - Translational Psychiatry

IS - 3

M1 - e1074

ER -

Genetic effects influencing risk for major depressive disorder in China and Europe

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