Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

doi:10.1016/j.biopsych.2019.06.031

Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Medicine

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

24 Citations (Scopus)

Abstract

Background: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. Methods: We fine-mapped the classical MHC (chr6: 29.6–33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10⁻⁶) and a candidate threshold (1.6 × 10⁻⁴). Results: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97–0.99). Conclusions: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

Original language	English
Pages (from-to)	419-430
Number of pages	12
Journal	Biological Psychiatry
Volume	87
Issue number	5
DOIs	https://doi.org/10.1016/j.biopsych.2019.06.031
Publication status	Published - Mar 1 2020

Bibliographical note

Funding Information:
GenPod/Newmeds : Funding support was provided by the Medical Research Council, UK (Grant No. G0200243 [principal investigators, G. Lewis and M. O'Donovan]), EU 6th framework, UK (Grant No. LSHB-CT-2003-503428 [principal investigator, R. Uher]), and EU Innovative Medicines Initiative Joint Undertaking, UK (Grant No. 15008 [principal investigator, G. Lewis]).

Funding Information:
Rotterdam Study : Funding support was provided by the Netherlands Organization of Scientific Research (NWO) Investments (Grant No. 175.010.2005.011 , 911-03-012 [principal investigator, A.G. Uitterlinden]). The Rotterdam Study is also funded by Erasmus Medical Center and Erasmus University .

Funding Information:
NTR : NTR is supported by the Netherlands Organization for Scientific Research (NOW) (Grant No. 480-15-001/674 )

Funding Information:
NESDA: The infrastructure for the NESDA study ( www.nesda.nl ) is funded through the Geestkracht program of the Netherlands Organization for Health Research and Development (ZonMw) (Grant No. 10-000-1002 ) and financial contributions by participating universities and mental health care organizations (Vrije Universiteit Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, and Rob Giel Onderzoekscentrum). Genotyping was supported by the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL) and National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health, Grand Opportunity Grnat Nos. 1RC2 MH089951 and 1RC2 MH089995 [principal investigator, BJWH Penninx]).

Funding Information:
We thank participants and scientists involved in making the UK Biobank resource available ( http://www.ukbiobank.ac.uk/ ). UK Biobank data used in this study were obtained under approved application 18177, which was supported by funding from the Medical Research Council (Grant No. MR/N015746/1 ).

Funding Information:
QIMR : We thank the twins and their families for their willing participation in our studies. Funding support was provided by the National Health and Medical Research Council, Australia (Grant Nos. 941177 , 971232 , 3399450 , and 443011 [principal investigator, N.G. Martin]) and National Institute on Alcohol Abuse and Alcoholism (Grant Nos. AA07535 , AA07728 , and AA10249 [principal investigator, A.C. Heath]).

Funding Information:
Harvard i2b2 : Funding support was provided by the National Institute of Mental Health (NIMH) (Grant Nos. R01 MH085542 and R01 MH086026 [principal investigators, J.W. Smoller and R.H. Perlis])

Funding Information:
We are deeply indebted to the investigators who comprise the PGC and to the hundreds of thousands of participants who have shared their life experiences with PGC investigators. The PGC has received major funding from the United States National Institute of Mental Health (Grant No. U01 MH109528-03 [principal investigator, P.F. Sullivan]), the United States National Institute of Drug Abuse (Grant No. U01 MH1095320 [principal investigator A. Agrawal]), the Netherlands Scientific Organization (Grant No. 480-05-003 [principal investigator, D. Posthuma]), and the Dutch Brain Foundation and the Vrije Universiteit Amsterdam (principal investigator, D. Posthuma).

Funding Information:
This work was supported by the UK Medical Research Council (Grant No. MR/N015746/1 Grant No. MR/N015746/1 , Ph.D. studentship [to KPG]) and partially funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King’s College London . The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.

Funding Information:
BOMA : Funding support was provided by Deutsche Forschungsgemeinschaft, Germany (Grant Nos. RI 908/11-1 , NO246/10-1 and Excellence Cluster ImmunoSensation [principal investigators, M. Rietschel and M.M. Nöthen]), the German Federal Ministry for Education and Research (BMBF) IntegraMent, Germany (Grant Nos. 01ZX1314A/01ZX1614A and 01ZX1314G/01ZX1614G [principal investigators, M.M. Nöthen, M. Rietschel, and S. Cichon]), and BMBF NGFNplus MooDS, Germany (Grant Nos. 01GS08144 and 01GS08147 [principal investigators, M.M. Nöthen, M. Rietschel, and S. Cichon]).

Funding Information:
Funding support for the Genome-Wide Association of Schizophrenia Study was provided by NIMH (Grant Nos. R01 MH67257 , R01 MH59588 , R01 MH59571 , R01 MH59565 , R01 MH59587 , R01 MH60870 , R01 MH59566 , R01 MH59586 , R01 MH61675 , R01 MH60879 , R01 MH81800 , U01 MH46276 , U01 MH46289 U01 MH46318 , U01 MH79469 , and U01 MH79470 ), and the genotyping of samples was provided through GAIN. The data sets used for the analyses described in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v3.p2. Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (principal investigator, Pablo V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, IL).

Funding Information:
EDINBURGH : Genotyping was conducted at the Genetics Core Laboratory at the Clinical Research Facility (University of Edinburgh). Funding support was provided by Wellcome Trust, UK (Grant No. 104036/Z/14/Z [principal investigator, A.M. McIntosh]).

Funding Information:
Statistical analyses were performed on the NL Genetic Cluster computer ( http://www.geneticcluster.org/ ) hosted by SURFsara, and the King's Health Partners High Performance Compute Cluster funded with capital equipment grants from the Guy's and St Thomas' Charity (Grant No. TR130505 ) and Maudsley Charity (Grant No. 980 ).

Funding Information:
PsyColaus : Funding support was provided by the Swiss National Science Foundation, Switzerland (Grant Nos. 3200B0-105993 , 3200B0-118308 , 33CSCO-122661 , 33CS30-139468 , and 33CS30-148401 [principal investigator, M. Preisig]). PsyCoLaus/CoLaus received additional support from research grants from GlaxoSmithKline and the Faculty of Biology and Medicine of Lausanne .

Funding Information:
CoFaMS – Adelaide : Funding support was provided by National Health and Medical Research Council, Australia (Grant No. APP1060524 [principal investigator, B.T. Baune]).

Funding Information:
STAR*D : The authors appreciate the efforts of the STAR*D investigator team for acquiring, compiling, and sharing the STAR*D clinical data set. Funding support was provided by NIMH (Grant No. R01 MH-072802 [principal investigator, S.P. Hamilton]).

Funding Information:
TwinGene : Thanks the Karolinska Institutet for infrastructural support of the Swedish Twin Registry . Funding support was provided by GenomeEUtwin, EU (Grant Nos. EU/QLRT-2001-01254 and QLG2-CT-2002-01254 [principal investigator, N. Pedersen]), the Heart and Lung foundation, Sweden (Grant No. 20070481 [principal investigator, P. Magnusson]), SSF, Sweden and Vetenskapsrådet, Sweden (Grant No. M-2005-1112 [principal investigator, U. de Faire]).

Funding Information:
MARS : This work was funded by the Max Planck Society , the Max Planck Excellence Foundation , the BMBF in the National Genome Research Network framework (NGFN2 and NGFN-Plus) (Grant No. FKZ 01GS0481 ), and by the BMBF Program (Grant No. FKZ 01ES0811 ). We acknowledge all study participants. We thank numerous people at Max Planck Institute, and all study sites in Germany and Switzerland who contributed to this project. Controls were from the Dortmund Health Study, which was supported NGFNplus MooDS by the German Migraine and Headache Society and by unrestricted grants to the University of Münster from Almirall , AstraZeneca , Berlin Chemie , Boehringer , Boots Health Care , Glaxo-Smith-Kline , Janssen Cilag , McNeil Pharma , MSD Sharp and Dohme , and Pfizer . Blood collection was funded by the Institute of Epidemiology and Social Medicine , University of Münster. Genotyping was supported by the BMBF (Grant No. 01ER0816 ).

Funding Information:
Danish Radiant : Funding support was provided by Højteknologifonden, Denmark (Grant No. 0001-2009-2 [principal investigators, T. Werge (controls) and O. Mors (cases)]) and Lundbeck Foundation, Denmark (Grant No. R24-A3242 [principal investigators, T. Werge (controls) and O. Mors (cases)])

Funding Information:
This work was supported by the UK Medical Research Council (Grant No. MR/N015746/1 Grant No. MR/N015746/1, Ph.D. studentship [to KPG]) and partially funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. We thank participants and scientists involved in making the UK Biobank resource available (http://www.ukbiobank.ac.uk/). UK Biobank data used in this study were obtained under approved application 18177, which was supported by funding from the Medical Research Council (Grant No. MR/N015746/1). We are deeply indebted to the investigators who comprise the PGC and to the hundreds of thousands of participants who have shared their life experiences with PGC investigators. The PGC has received major funding from the United States National Institute of Mental Health (Grant No. U01 MH109528-03 [principal investigator, P.F. Sullivan]), the United States National Institute of Drug Abuse (Grant No. U01 MH1095320 [principal investigator A. Agrawal]), the Netherlands Scientific Organization (Grant No. 480-05-003 [principal investigator, D. Posthuma]), and the Dutch Brain Foundation and the Vrije Universiteit Amsterdam (principal investigator, D. Posthuma). We thank contributors to the primary studies constituting the PGC-MDD sample in this article. BOMA: Funding support was provided by Deutsche Forschungsgemeinschaft, Germany (Grant Nos. RI 908/11-1, NO246/10-1 and Excellence Cluster ImmunoSensation [principal investigators, M. Rietschel and M.M. N?then]), the German Federal Ministry for Education and Research (BMBF) IntegraMent, Germany (Grant Nos. 01ZX1314A/01ZX1614A and 01ZX1314G/01ZX1614G [principal investigators, M.M. N?then, M. Rietschel, and S. Cichon]), and BMBF NGFNplus MooDS, Germany (Grant Nos. 01GS08144 and 01GS08147 [principal investigators, M.M. N?then, M. Rietschel, and S. Cichon]). CoFaMS ? Adelaide: Funding support was provided by National Health and Medical Research Council, Australia (Grant No. APP1060524 [principal investigator, B.T. Baune]). Danish Radiant: Funding support was provided by H?jteknologifonden, Denmark (Grant No. 0001-2009-2 [principal investigators, T. Werge (controls) and O. Mors (cases)]) and Lundbeck Foundation, Denmark (Grant No. R24-A3242 [principal investigators, T. Werge (controls) and O. Mors (cases)]), EDINBURGH: Genotyping was conducted at the Genetics Core Laboratory at the Clinical Research Facility (University of Edinburgh). Funding support was provided by Wellcome Trust, UK (Grant No. 104036/Z/14/Z [principal investigator, A.M. McIntosh]). GenPod/Newmeds: Funding support was provided by the Medical Research Council, UK (Grant No. G0200243 [principal investigators, G. Lewis and M. O'Donovan]), EU 6th framework, UK (Grant No. LSHB-CT-2003-503428 [principal investigator, R. Uher]), and EU Innovative Medicines Initiative Joint Undertaking, UK (Grant No. 15008 [principal investigator, G. Lewis]). GSK-MUNICH: We thank all participants in the GSK-Munich study. We thank numerous people at GSK and Max Planck Institute, BKH Augsburg, and Klinikum Ingolstadt in Germany who contributed to this project. Harvard i2b2: Funding support was provided by the National Institute of Mental Health (NIMH) (Grant Nos. R01 MH085542 and R01 MH086026 [principal investigators, J.W. Smoller and R.H. Perlis]), MARS: This work was funded by the Max Planck Society, the Max Planck Excellence Foundation, the BMBF in the National Genome Research Network framework (NGFN2 and NGFN-Plus) (Grant No. FKZ 01GS0481), and by the BMBF Program (Grant No. FKZ 01ES0811). We acknowledge all study participants. We thank numerous people at Max Planck Institute, and all study sites in Germany and Switzerland who contributed to this project. Controls were from the Dortmund Health Study, which was supported NGFNplus MooDS by the German Migraine and Headache Society and by unrestricted grants to the University of M?nster from Almirall, AstraZeneca, Berlin Chemie, Boehringer, Boots Health Care, Glaxo-Smith-Kline, Janssen Cilag, McNeil Pharma, MSD Sharp and Dohme, and Pfizer. Blood collection was funded by the Institute of Epidemiology and Social Medicine, University of M?nster. Genotyping was supported by the BMBF (Grant No. 01ER0816). NESDA: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organization for Health Research and Development (ZonMw) (Grant No. 10-000-1002) and financial contributions by participating universities and mental health care organizations (Vrije Universiteit Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, and Rob Giel Onderzoekscentrum). Genotyping was supported by the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL) and National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health, Grand Opportunity Grnat Nos. 1RC2 MH089951 and 1RC2 MH089995 [principal investigator, BJWH Penninx]). NTR: NTR is supported by the Netherlands Organization for Scientific Research (NOW) (Grant No. 480-15-001/674), BBMRI-NL: Funding support was provided by Biobanking and Biomolecular Resources Research Infrastructure (Grant Nos. 184.021.007 and BBMRI-NL2.0 184.033.111). Genotyping was supported by BBMRI-NL, the Avera Institute, Sioux Falls, SD, and National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health, Grand Opportunity Grant Nos. 1RC2 MH089951 and 1RC2 MH089995 [principal investigator, D.I. Boomsma]). PsyColaus: Funding support was provided by the Swiss National Science Foundation, Switzerland (Grant Nos. 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, and 33CS30-148401 [principal investigator, M. Preisig]). PsyCoLaus/CoLaus received additional support from research grants from GlaxoSmithKline and the Faculty of Biology and Medicine of Lausanne. QIMR: We thank the twins and their families for their willing participation in our studies. Funding support was provided by the National Health and Medical Research Council, Australia (Grant Nos. 941177, 971232, 3399450, and 443011 [principal investigator, N.G. Martin]) and National Institute on Alcohol Abuse and Alcoholism (Grant Nos. AA07535, AA07728, and AA10249 [principal investigator, A.C. Heath]). RADIANT: This report represents independent research funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding support was provided by the Medical Research Council, UK (Grant Nos. G0701420 and G0901245 [principal investigators, C. Lewis and G. Breen]) and NIMH, UK (Grant No. U01 MH109528 [principal investigator, G. Breen]). Rotterdam Study: Funding support was provided by the Netherlands Organization of Scientific Research (NWO) Investments (Grant No. 175.010.2005.011, 911-03-012 [principal investigator, A.G. Uitterlinden]). The Rotterdam Study is also funded by Erasmus Medical Center and Erasmus University. SHIP-LEGEND/TREND: SHIP is part of the Community Medicine Research net of the University of Greifswald, which is funded by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genotyping in SHIP was funded by Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. The SHIP-LEGEND/TREND Study is also funded by the German Research Foundation (Grant No. DFG: GR 1912/5-1 [principal investigator, H.J. Grabe]). Genotyping in SHIP-TREND-0 was supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012). STAR*D: The authors appreciate the efforts of the STAR*D investigator team for acquiring, compiling, and sharing the STAR*D clinical data set. Funding support was provided by NIMH (Grant No. R01 MH-072802 [principal investigator, S.P. Hamilton]). TwinGene: Thanks the Karolinska Institutet for infrastructural support of the Swedish Twin Registry. Funding support was provided by GenomeEUtwin, EU (Grant Nos. EU/QLRT-2001-01254 and QLG2-CT-2002-01254 [principal investigator, N. Pedersen]), the Heart and Lung foundation, Sweden (Grant No. 20070481 [principal investigator, P. Magnusson]), SSF, Sweden and Vetenskapsr?det, Sweden (Grant No. M-2005-1112 [principal investigator, U. de Faire]). Funding support for the Genome-Wide Association of Schizophrenia Study was provided by NIMH (Grant Nos. R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289 U01 MH46318, U01 MH79469, and U01 MH79470), and the genotyping of samples was provided through GAIN. The data sets used for the analyses described in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v3.p2. Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (principal investigator, Pablo V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, IL). Statistical analyses were performed on the NL Genetic Cluster computer (http://www.geneticcluster.org/) hosted by SURFsara, and the King's Health Partners High Performance Compute Cluster funded with capital equipment grants from the Guy's and St Thomas' Charity (Grant No. TR130505) and Maudsley Charity (Grant No. 980). JE is an employee of GlaxoSmithKline Pharmaceuticals. PFS is on the scientific advisory board for Pfizer and the advisory committee for Lundbeck. All other authors report no biomedical financial interests or potential conflicts of interest. Due to the highly sensitive nature of genetic information used in this study, supporting data cannot be made openly available. Researchers may apply to the Psychiatric Genomics Consortium (https://www.med.unc.edu/pgc/shared-methods/) and/or UK Biobank (https://www.ukbiobank.ac.uk/) to gain access to the supporting data. Naomi R. Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski 1, Enda M. Byrne1, Abdel Abdellaoui9, Mark J. Adams10, Esben Agerbo11,12,13, Tracy M. Air14, Till F.M. Andlauer15,16, Silviu-Alin Bacanu17, Marie B?kvad-Hansen13,18, Aartjan T.F. Beekman19, Tim B. Bigdeli17,20, Elisabeth B. Binder15,21, Julien Bryois22, Henriette N. Buttensch?n13,23,24, Jonas Bybjerg-Grauholm13,18, Na Cai25,26, Enrique Castelao27, Jane Hvarregaard Christensen8,13,24, Toni-Kim Clarke10, Jonathan R.I. Coleman28, Luc?a Colodro-Conde29, Baptiste Couvy-Duchesne2,30, Nick Craddock31, Gregory E. Crawford32,33, Gail Davies34, Ian J. Deary34, Franziska Degenhardt35, Eske M. Derks29, Nese Direk36,37, Conor V. Dolan9, Erin C. Dunn38,39,40, Thalia C. Eley28, Valentina Escott-Price41, Farnush Farhadi Hassan Kiadeh42, Hilary K. Finucane43,44, Jerome C. Foo45, Andreas J. Forstner35,46,47,48, Josef Frank45, H?l?na A. Gaspar28, Michael Gill49, Fernando S. Goes50, Scott D. Gordon29, Jakob Grove8,13,24,51, Lynsey S. Hall10,52, Christine S?holm Hansen13,18, Thomas F. Hansen53,54,55, Stefan Herms35,47, Ian B. Hickie56, Per Hoffmann35,47, Georg Homuth57, Carsten Horn58, Jouke-Jan Hottenga9, David M. Hougaard13,18, David M. Howard10,28, Marcus Ising59, Rick Jansen19, Ian Jones60, Lisa A. Jones61, Eric Jorgenson62, James A. Knowles63, Isaac S. Kohane64,65,66, Julia Kraft4, Warren W. Kretzschmar67, Zolt?n Kutalik68,69, Yihan Li67, Penelope A. Lind29, Donald J. MacIntyre70,71, Dean F. MacKinnon50, Robert M. Maier2, Wolfgang Maier72, Jonathan Marchini73, Hamdi Mbarek9, Patrick McGrath74, Peter McGuffin28, Sarah E. Medland29, Divya Mehta2,75, Christel M. Middeldorp9,76,77, Evelin Mihailov78, Yuri Milaneschi19, Lili Milani78, Francis M. Mondimore50, Grant W. Montgomery1, Sara Mostafavi79,80, Niamh Mullins28, Matthias Nauck81,82, Bernard Ng80, Michel G. Nivard9, Dale R. Nyholt83, Paul F. O'Reilly28, Hogni Oskarsson84, Michael J. Owen60, Jodie N. Painter29, Carsten B?cker Pedersen11,12,13, Marianne Gi?rtz Pedersen11,12,13, Roseann E. Peterson17,85, Erik Pettersson22, Wouter J. Peyrot19, Giorgio Pistis27, Danielle Posthuma86,87, Jorge A. Quiroz88, Per Qvist8,13,24, John P. Rice89, Brien P. Riley17, Margarita Rivera28,90, Saira Saeed Mirza36, Robert Schoevers91, Eva C. Schulte92,93, Ling Shen62, Jianxin Shi94, Stanley I. Shyn95, Engilbert Sigurdsson96, Grant C. B. Sinnamon97, Johannes H. Smit19, Daniel J. Smith98, Hreinn Stefansson99, Stacy Steinberg99, Fabian Streit45, Jana Strohmaier45, Katherine E. Tansey100, Henning Teismann101, Alexander Teumer102, Wesley Thompson13,54,103,104, Pippa A. Thomson105, Thorgeir E. Thorgeirsson99, Matthew Traylor106, Jens Treutlein45, Vassily Trubetskoy4, Andr?s G. Uitterlinden107, Daniel Umbricht108, Sandra Van der Auwera109, Albert M. van Hemert110, Alexander Viktorin22, Peter M. Visscher1,2, Yunpeng Wang13,54,104, Bradley T. Webb111, Shantel Marie Weinsheimer13,54, J?rgen Wellmann101, Gonneke Willemsen9, Stephanie H. Witt45, Yang Wu1, Hualin S. Xi112, Jian Yang2,113, Futao Zhang1, Volker Arolt114, Bernhard T. Baune115,116,117, Klaus Berger101, Dorret I. Boomsma9, Sven Cichon35,47,118,119, Udo Dannlowski114, EJC. de Geus9,120, J. Raymond DePaulo50, Enrico Domenici121, Katharina Domschke122,123, T?nu Esko5,78, Hans J. Grabe109, Steven P. Hamilton124, Caroline Hayward125, Andrew C. Heath89, Kenneth S. Kendler17, Stefan Kloiber59,126,127, Glyn Lewis128, Qingqin S. Li129, Susanne Lucae59, Pamela AF. Madden89, Patrik K. Magnusson22, Nicholas G. Martin29, Andrew M. McIntosh10,34, Andres Metspalu78,130, Ole Mors13,131, Preben Bo Mortensen11,12,13,24, Bertram M?ller-Myhsok15,132,133, Merete Nordentoft13,134, Markus M. N?then35, Michael C. O'Donovan60, Sara A. Paciga135, Nancy L. Pedersen22, Brenda W.J.H. Penninx19, Roy H. Perlis38,136, David J. Porteous105, James B. Potash137, Martin Preisig27, Marcella Rietschel45, Catherine Schaefer62, Thomas G. Schulze45,93,138,139,140, Jordan W. Smoller38,39,40, Kari Stefansson99,141, Henning Tiemeier36,142,143, Rudolf Uher144, Henry V?lzke102, Myrna M. Weissman74,145, Thomas Werge13,54,146, Cathryn M. Lewis28,147, Douglas F. Levinson148, Gerome Breen28,149, Anders D. B?rglum8,13,24, Patrick F. Sullivan22,150,151

Funding Information:
SHIP-LEGEND/TREND : SHIP is part of the Community Medicine Research net of the University of Greifswald, which is funded by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603 , 01ZZ0103 , and 01ZZ0403 ), the Ministry of Cultural Affairs , and the Social Ministry of the Federal State of Mecklenburg-West Pomerania . Genotyping in SHIP was funded by Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania . The SHIP-LEGEND/TREND Study is also funded by the German Research Foundation (Grant No. DFG: GR 1912/5-1 [principal investigator, H.J. Grabe]). Genotyping in SHIP-TREND-0 was supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012 ).

Funding Information:
RADIANT : This report represents independent research funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust , and King’s College London . The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding support was provided by the Medical Research Council, UK (Grant Nos. G0701420 and G0901245 [principal investigators, C. Lewis and G. Breen]) and NIMH, UK (Grant No. U01 MH109528 [principal investigator, G. Breen]).

Funding Information:
BBMRI-NL: Funding support was provided by Biobanking and Biomolecular Resources Research Infrastructure (Grant Nos. 184.021.007 and BBMRI-NL2.0 184.033.111 ). Genotyping was supported by BBMRI-NL , the Avera Institute , Sioux Falls , SD , and National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health, Grand Opportunity Grant Nos. 1RC2 MH089951 and 1RC2 MH089995 [principal investigator, D.I. Boomsma]).

Publisher Copyright:
© 2019 Society of Biological Psychiatry

ASJC Scopus Subject Areas

Biological Psychiatry

PubMed: MeSH publication types

Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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@article{a8a0ee37b4354098a010c40f05c2b405,

title = "Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression",

abstract = "Background: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. Methods: We fine-mapped the classical MHC (chr6: 29.6–33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10−6) and a candidate threshold (1.6 × 10−4). Results: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97–0.99). Conclusions: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.",

author = "{Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and Glanville, {Kylie P.} and Coleman, {Jonathan R.I.} and Hanscombe, {Ken B.} and Jack Euesden and Choi, {Shing Wan} and Purves, {Kirstin L.} and Gerome Breen and Air, {Tracy M.} and Andlauer, {Till F.M.} and Baune, {Bernhard T.} and Binder, {Elisabeth B.} and Blackwood, {Douglas H.R.} and Boomsma, {Dorret I.} and Buttensch{\o}n, {Henriette N.} and Luc{\'i}a Colodro-Conde and Udo Dannlowski and Nese Direk and Dunn, {Erin C.} and Forstner, {Andreas J.} and {de Geus}, {Eco J.C.} and Grabe, {Hans J.} and Hamilton, {Steven P.} and Ian Jones and Jones, {Lisa A.} and Knowles, {James A.} and Zolt{\'a}n Kutalik and Levinson, {Douglas F.} and Glyn Lewis and Lind, {Penelope A.} and Susanne Lucae and Magnusson, {Patrik K.} and Peter McGuffin and McIntosh, {Andrew M.} and Yuri Milaneschi and Ole Mors and Sara Mostafavi and Bertram M{\"u}ller-Myhsok and Pedersen, {Nancy L.} and Penninx, {Brenda W.J.H.} and Potash, {James B.} and Martin Preisig and Stephan Ripke and Jianxin Shi and Shyn, {Stanley I.} and Smoller, {Jordan W.} and Fabian Streit and Sullivan, {Patrick F.} and Henning Tiemeier and Rudolf Uher and {Van der Auwera}, Sandra",

note = "Funding Information: GenPod/Newmeds : Funding support was provided by the Medical Research Council, UK (Grant No. G0200243 [principal investigators, G. Lewis and M. O'Donovan]), EU 6th framework, UK (Grant No. LSHB-CT-2003-503428 [principal investigator, R. Uher]), and EU Innovative Medicines Initiative Joint Undertaking, UK (Grant No. 15008 [principal investigator, G. Lewis]). Funding Information: Rotterdam Study : Funding support was provided by the Netherlands Organization of Scientific Research (NWO) Investments (Grant No. 175.010.2005.011 , 911-03-012 [principal investigator, A.G. Uitterlinden]). The Rotterdam Study is also funded by Erasmus Medical Center and Erasmus University . Funding Information: NTR : NTR is supported by the Netherlands Organization for Scientific Research (NOW) (Grant No. 480-15-001/674 ) Funding Information: NESDA: The infrastructure for the NESDA study ( www.nesda.nl ) is funded through the Geestkracht program of the Netherlands Organization for Health Research and Development (ZonMw) (Grant No. 10-000-1002 ) and financial contributions by participating universities and mental health care organizations (Vrije Universiteit Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, and Rob Giel Onderzoekscentrum). Genotyping was supported by the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL) and National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health, Grand Opportunity Grnat Nos. 1RC2 MH089951 and 1RC2 MH089995 [principal investigator, BJWH Penninx]). Funding Information: We thank participants and scientists involved in making the UK Biobank resource available ( http://www.ukbiobank.ac.uk/ ). UK Biobank data used in this study were obtained under approved application 18177, which was supported by funding from the Medical Research Council (Grant No. MR/N015746/1 ). Funding Information: QIMR : We thank the twins and their families for their willing participation in our studies. Funding support was provided by the National Health and Medical Research Council, Australia (Grant Nos. 941177 , 971232 , 3399450 , and 443011 [principal investigator, N.G. Martin]) and National Institute on Alcohol Abuse and Alcoholism (Grant Nos. AA07535 , AA07728 , and AA10249 [principal investigator, A.C. Heath]). Funding Information: Harvard i2b2 : Funding support was provided by the National Institute of Mental Health (NIMH) (Grant Nos. R01 MH085542 and R01 MH086026 [principal investigators, J.W. Smoller and R.H. Perlis]) Funding Information: We are deeply indebted to the investigators who comprise the PGC and to the hundreds of thousands of participants who have shared their life experiences with PGC investigators. The PGC has received major funding from the United States National Institute of Mental Health (Grant No. U01 MH109528-03 [principal investigator, P.F. Sullivan]), the United States National Institute of Drug Abuse (Grant No. U01 MH1095320 [principal investigator A. Agrawal]), the Netherlands Scientific Organization (Grant No. 480-05-003 [principal investigator, D. Posthuma]), and the Dutch Brain Foundation and the Vrije Universiteit Amsterdam (principal investigator, D. Posthuma). Funding Information: This work was supported by the UK Medical Research Council (Grant No. MR/N015746/1 Grant No. MR/N015746/1 , Ph.D. studentship [to KPG]) and partially funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King{\textquoteright}s College London . The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Funding Information: BOMA : Funding support was provided by Deutsche Forschungsgemeinschaft, Germany (Grant Nos. RI 908/11-1 , NO246/10-1 and Excellence Cluster ImmunoSensation [principal investigators, M. Rietschel and M.M. N{\"o}then]), the German Federal Ministry for Education and Research (BMBF) IntegraMent, Germany (Grant Nos. 01ZX1314A/01ZX1614A and 01ZX1314G/01ZX1614G [principal investigators, M.M. N{\"o}then, M. Rietschel, and S. Cichon]), and BMBF NGFNplus MooDS, Germany (Grant Nos. 01GS08144 and 01GS08147 [principal investigators, M.M. N{\"o}then, M. Rietschel, and S. Cichon]). Funding Information: Funding support for the Genome-Wide Association of Schizophrenia Study was provided by NIMH (Grant Nos. R01 MH67257 , R01 MH59588 , R01 MH59571 , R01 MH59565 , R01 MH59587 , R01 MH60870 , R01 MH59566 , R01 MH59586 , R01 MH61675 , R01 MH60879 , R01 MH81800 , U01 MH46276 , U01 MH46289 U01 MH46318 , U01 MH79469 , and U01 MH79470 ), and the genotyping of samples was provided through GAIN. The data sets used for the analyses described in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v3.p2. Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (principal investigator, Pablo V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, IL). Funding Information: EDINBURGH : Genotyping was conducted at the Genetics Core Laboratory at the Clinical Research Facility (University of Edinburgh). Funding support was provided by Wellcome Trust, UK (Grant No. 104036/Z/14/Z [principal investigator, A.M. McIntosh]). Funding Information: Statistical analyses were performed on the NL Genetic Cluster computer ( http://www.geneticcluster.org/ ) hosted by SURFsara, and the King's Health Partners High Performance Compute Cluster funded with capital equipment grants from the Guy's and St Thomas' Charity (Grant No. TR130505 ) and Maudsley Charity (Grant No. 980 ). Funding Information: PsyColaus : Funding support was provided by the Swiss National Science Foundation, Switzerland (Grant Nos. 3200B0-105993 , 3200B0-118308 , 33CSCO-122661 , 33CS30-139468 , and 33CS30-148401 [principal investigator, M. Preisig]). PsyCoLaus/CoLaus received additional support from research grants from GlaxoSmithKline and the Faculty of Biology and Medicine of Lausanne . Funding Information: CoFaMS – Adelaide : Funding support was provided by National Health and Medical Research Council, Australia (Grant No. APP1060524 [principal investigator, B.T. Baune]). Funding Information: STAR*D : The authors appreciate the efforts of the STAR*D investigator team for acquiring, compiling, and sharing the STAR*D clinical data set. Funding support was provided by NIMH (Grant No. R01 MH-072802 [principal investigator, S.P. Hamilton]). Funding Information: TwinGene : Thanks the Karolinska Institutet for infrastructural support of the Swedish Twin Registry . Funding support was provided by GenomeEUtwin, EU (Grant Nos. EU/QLRT-2001-01254 and QLG2-CT-2002-01254 [principal investigator, N. Pedersen]), the Heart and Lung foundation, Sweden (Grant No. 20070481 [principal investigator, P. Magnusson]), SSF, Sweden and Vetenskapsr{\aa}det, Sweden (Grant No. M-2005-1112 [principal investigator, U. de Faire]). Funding Information: MARS : This work was funded by the Max Planck Society , the Max Planck Excellence Foundation , the BMBF in the National Genome Research Network framework (NGFN2 and NGFN-Plus) (Grant No. FKZ 01GS0481 ), and by the BMBF Program (Grant No. FKZ 01ES0811 ). We acknowledge all study participants. We thank numerous people at Max Planck Institute, and all study sites in Germany and Switzerland who contributed to this project. Controls were from the Dortmund Health Study, which was supported NGFNplus MooDS by the German Migraine and Headache Society and by unrestricted grants to the University of M{\"u}nster from Almirall , AstraZeneca , Berlin Chemie , Boehringer , Boots Health Care , Glaxo-Smith-Kline , Janssen Cilag , McNeil Pharma , MSD Sharp and Dohme , and Pfizer . Blood collection was funded by the Institute of Epidemiology and Social Medicine , University of M{\"u}nster. Genotyping was supported by the BMBF (Grant No. 01ER0816 ). Funding Information: Danish Radiant : Funding support was provided by H{\o}jteknologifonden, Denmark (Grant No. 0001-2009-2 [principal investigators, T. Werge (controls) and O. Mors (cases)]) and Lundbeck Foundation, Denmark (Grant No. R24-A3242 [principal investigators, T. Werge (controls) and O. Mors (cases)]) Funding Information: This work was supported by the UK Medical Research Council (Grant No. MR/N015746/1 Grant No. MR/N015746/1, Ph.D. studentship [to KPG]) and partially funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. We thank participants and scientists involved in making the UK Biobank resource available (http://www.ukbiobank.ac.uk/). UK Biobank data used in this study were obtained under approved application 18177, which was supported by funding from the Medical Research Council (Grant No. MR/N015746/1). We are deeply indebted to the investigators who comprise the PGC and to the hundreds of thousands of participants who have shared their life experiences with PGC investigators. The PGC has received major funding from the United States National Institute of Mental Health (Grant No. U01 MH109528-03 [principal investigator, P.F. Sullivan]), the United States National Institute of Drug Abuse (Grant No. U01 MH1095320 [principal investigator A. Agrawal]), the Netherlands Scientific Organization (Grant No. 480-05-003 [principal investigator, D. Posthuma]), and the Dutch Brain Foundation and the Vrije Universiteit Amsterdam (principal investigator, D. Posthuma). We thank contributors to the primary studies constituting the PGC-MDD sample in this article. BOMA: Funding support was provided by Deutsche Forschungsgemeinschaft, Germany (Grant Nos. RI 908/11-1, NO246/10-1 and Excellence Cluster ImmunoSensation [principal investigators, M. Rietschel and M.M. N?then]), the German Federal Ministry for Education and Research (BMBF) IntegraMent, Germany (Grant Nos. 01ZX1314A/01ZX1614A and 01ZX1314G/01ZX1614G [principal investigators, M.M. N?then, M. Rietschel, and S. Cichon]), and BMBF NGFNplus MooDS, Germany (Grant Nos. 01GS08144 and 01GS08147 [principal investigators, M.M. N?then, M. Rietschel, and S. Cichon]). CoFaMS ? Adelaide: Funding support was provided by National Health and Medical Research Council, Australia (Grant No. APP1060524 [principal investigator, B.T. Baune]). Danish Radiant: Funding support was provided by H?jteknologifonden, Denmark (Grant No. 0001-2009-2 [principal investigators, T. Werge (controls) and O. Mors (cases)]) and Lundbeck Foundation, Denmark (Grant No. R24-A3242 [principal investigators, T. Werge (controls) and O. Mors (cases)]), EDINBURGH: Genotyping was conducted at the Genetics Core Laboratory at the Clinical Research Facility (University of Edinburgh). Funding support was provided by Wellcome Trust, UK (Grant No. 104036/Z/14/Z [principal investigator, A.M. McIntosh]). GenPod/Newmeds: Funding support was provided by the Medical Research Council, UK (Grant No. G0200243 [principal investigators, G. Lewis and M. O'Donovan]), EU 6th framework, UK (Grant No. LSHB-CT-2003-503428 [principal investigator, R. Uher]), and EU Innovative Medicines Initiative Joint Undertaking, UK (Grant No. 15008 [principal investigator, G. Lewis]). GSK-MUNICH: We thank all participants in the GSK-Munich study. We thank numerous people at GSK and Max Planck Institute, BKH Augsburg, and Klinikum Ingolstadt in Germany who contributed to this project. Harvard i2b2: Funding support was provided by the National Institute of Mental Health (NIMH) (Grant Nos. R01 MH085542 and R01 MH086026 [principal investigators, J.W. Smoller and R.H. Perlis]), MARS: This work was funded by the Max Planck Society, the Max Planck Excellence Foundation, the BMBF in the National Genome Research Network framework (NGFN2 and NGFN-Plus) (Grant No. FKZ 01GS0481), and by the BMBF Program (Grant No. FKZ 01ES0811). We acknowledge all study participants. We thank numerous people at Max Planck Institute, and all study sites in Germany and Switzerland who contributed to this project. Controls were from the Dortmund Health Study, which was supported NGFNplus MooDS by the German Migraine and Headache Society and by unrestricted grants to the University of M?nster from Almirall, AstraZeneca, Berlin Chemie, Boehringer, Boots Health Care, Glaxo-Smith-Kline, Janssen Cilag, McNeil Pharma, MSD Sharp and Dohme, and Pfizer. Blood collection was funded by the Institute of Epidemiology and Social Medicine, University of M?nster. Genotyping was supported by the BMBF (Grant No. 01ER0816). NESDA: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organization for Health Research and Development (ZonMw) (Grant No. 10-000-1002) and financial contributions by participating universities and mental health care organizations (Vrije Universiteit Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, and Rob Giel Onderzoekscentrum). Genotyping was supported by the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL) and National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health, Grand Opportunity Grnat Nos. 1RC2 MH089951 and 1RC2 MH089995 [principal investigator, BJWH Penninx]). NTR: NTR is supported by the Netherlands Organization for Scientific Research (NOW) (Grant No. 480-15-001/674), BBMRI-NL: Funding support was provided by Biobanking and Biomolecular Resources Research Infrastructure (Grant Nos. 184.021.007 and BBMRI-NL2.0 184.033.111). Genotyping was supported by BBMRI-NL, the Avera Institute, Sioux Falls, SD, and National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health, Grand Opportunity Grant Nos. 1RC2 MH089951 and 1RC2 MH089995 [principal investigator, D.I. Boomsma]). PsyColaus: Funding support was provided by the Swiss National Science Foundation, Switzerland (Grant Nos. 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, and 33CS30-148401 [principal investigator, M. Preisig]). PsyCoLaus/CoLaus received additional support from research grants from GlaxoSmithKline and the Faculty of Biology and Medicine of Lausanne. QIMR: We thank the twins and their families for their willing participation in our studies. Funding support was provided by the National Health and Medical Research Council, Australia (Grant Nos. 941177, 971232, 3399450, and 443011 [principal investigator, N.G. Martin]) and National Institute on Alcohol Abuse and Alcoholism (Grant Nos. AA07535, AA07728, and AA10249 [principal investigator, A.C. Heath]). RADIANT: This report represents independent research funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding support was provided by the Medical Research Council, UK (Grant Nos. G0701420 and G0901245 [principal investigators, C. Lewis and G. Breen]) and NIMH, UK (Grant No. U01 MH109528 [principal investigator, G. Breen]). Rotterdam Study: Funding support was provided by the Netherlands Organization of Scientific Research (NWO) Investments (Grant No. 175.010.2005.011, 911-03-012 [principal investigator, A.G. Uitterlinden]). The Rotterdam Study is also funded by Erasmus Medical Center and Erasmus University. SHIP-LEGEND/TREND: SHIP is part of the Community Medicine Research net of the University of Greifswald, which is funded by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genotyping in SHIP was funded by Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. The SHIP-LEGEND/TREND Study is also funded by the German Research Foundation (Grant No. DFG: GR 1912/5-1 [principal investigator, H.J. Grabe]). Genotyping in SHIP-TREND-0 was supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012). STAR*D: The authors appreciate the efforts of the STAR*D investigator team for acquiring, compiling, and sharing the STAR*D clinical data set. Funding support was provided by NIMH (Grant No. R01 MH-072802 [principal investigator, S.P. Hamilton]). TwinGene: Thanks the Karolinska Institutet for infrastructural support of the Swedish Twin Registry. Funding support was provided by GenomeEUtwin, EU (Grant Nos. EU/QLRT-2001-01254 and QLG2-CT-2002-01254 [principal investigator, N. Pedersen]), the Heart and Lung foundation, Sweden (Grant No. 20070481 [principal investigator, P. Magnusson]), SSF, Sweden and Vetenskapsr?det, Sweden (Grant No. M-2005-1112 [principal investigator, U. de Faire]). Funding support for the Genome-Wide Association of Schizophrenia Study was provided by NIMH (Grant Nos. R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289 U01 MH46318, U01 MH79469, and U01 MH79470), and the genotyping of samples was provided through GAIN. The data sets used for the analyses described in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v3.p2. Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (principal investigator, Pablo V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, IL). Statistical analyses were performed on the NL Genetic Cluster computer (http://www.geneticcluster.org/) hosted by SURFsara, and the King's Health Partners High Performance Compute Cluster funded with capital equipment grants from the Guy's and St Thomas' Charity (Grant No. TR130505) and Maudsley Charity (Grant No. 980). JE is an employee of GlaxoSmithKline Pharmaceuticals. PFS is on the scientific advisory board for Pfizer and the advisory committee for Lundbeck. All other authors report no biomedical financial interests or potential conflicts of interest. Due to the highly sensitive nature of genetic information used in this study, supporting data cannot be made openly available. Researchers may apply to the Psychiatric Genomics Consortium (https://www.med.unc.edu/pgc/shared-methods/) and/or UK Biobank (https://www.ukbiobank.ac.uk/) to gain access to the supporting data. Naomi R. Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski 1, Enda M. Byrne1, Abdel Abdellaoui9, Mark J. Adams10, Esben Agerbo11,12,13, Tracy M. Air14, Till F.M. Andlauer15,16, Silviu-Alin Bacanu17, Marie B?kvad-Hansen13,18, Aartjan T.F. Beekman19, Tim B. Bigdeli17,20, Elisabeth B. Binder15,21, Julien Bryois22, Henriette N. Buttensch?n13,23,24, Jonas Bybjerg-Grauholm13,18, Na Cai25,26, Enrique Castelao27, Jane Hvarregaard Christensen8,13,24, Toni-Kim Clarke10, Jonathan R.I. Coleman28, Luc?a Colodro-Conde29, Baptiste Couvy-Duchesne2,30, Nick Craddock31, Gregory E. Crawford32,33, Gail Davies34, Ian J. Deary34, Franziska Degenhardt35, Eske M. Derks29, Nese Direk36,37, Conor V. Dolan9, Erin C. Dunn38,39,40, Thalia C. Eley28, Valentina Escott-Price41, Farnush Farhadi Hassan Kiadeh42, Hilary K. Finucane43,44, Jerome C. Foo45, Andreas J. Forstner35,46,47,48, Josef Frank45, H?l?na A. Gaspar28, Michael Gill49, Fernando S. Goes50, Scott D. Gordon29, Jakob Grove8,13,24,51, Lynsey S. Hall10,52, Christine S?holm Hansen13,18, Thomas F. Hansen53,54,55, Stefan Herms35,47, Ian B. Hickie56, Per Hoffmann35,47, Georg Homuth57, Carsten Horn58, Jouke-Jan Hottenga9, David M. Hougaard13,18, David M. Howard10,28, Marcus Ising59, Rick Jansen19, Ian Jones60, Lisa A. Jones61, Eric Jorgenson62, James A. Knowles63, Isaac S. Kohane64,65,66, Julia Kraft4, Warren W. Kretzschmar67, Zolt?n Kutalik68,69, Yihan Li67, Penelope A. Lind29, Donald J. MacIntyre70,71, Dean F. MacKinnon50, Robert M. Maier2, Wolfgang Maier72, Jonathan Marchini73, Hamdi Mbarek9, Patrick McGrath74, Peter McGuffin28, Sarah E. Medland29, Divya Mehta2,75, Christel M. Middeldorp9,76,77, Evelin Mihailov78, Yuri Milaneschi19, Lili Milani78, Francis M. Mondimore50, Grant W. Montgomery1, Sara Mostafavi79,80, Niamh Mullins28, Matthias Nauck81,82, Bernard Ng80, Michel G. Nivard9, Dale R. Nyholt83, Paul F. O'Reilly28, Hogni Oskarsson84, Michael J. Owen60, Jodie N. Painter29, Carsten B?cker Pedersen11,12,13, Marianne Gi?rtz Pedersen11,12,13, Roseann E. Peterson17,85, Erik Pettersson22, Wouter J. Peyrot19, Giorgio Pistis27, Danielle Posthuma86,87, Jorge A. Quiroz88, Per Qvist8,13,24, John P. Rice89, Brien P. Riley17, Margarita Rivera28,90, Saira Saeed Mirza36, Robert Schoevers91, Eva C. Schulte92,93, Ling Shen62, Jianxin Shi94, Stanley I. Shyn95, Engilbert Sigurdsson96, Grant C. B. Sinnamon97, Johannes H. Smit19, Daniel J. Smith98, Hreinn Stefansson99, Stacy Steinberg99, Fabian Streit45, Jana Strohmaier45, Katherine E. Tansey100, Henning Teismann101, Alexander Teumer102, Wesley Thompson13,54,103,104, Pippa A. Thomson105, Thorgeir E. Thorgeirsson99, Matthew Traylor106, Jens Treutlein45, Vassily Trubetskoy4, Andr?s G. Uitterlinden107, Daniel Umbricht108, Sandra Van der Auwera109, Albert M. van Hemert110, Alexander Viktorin22, Peter M. Visscher1,2, Yunpeng Wang13,54,104, Bradley T. Webb111, Shantel Marie Weinsheimer13,54, J?rgen Wellmann101, Gonneke Willemsen9, Stephanie H. Witt45, Yang Wu1, Hualin S. Xi112, Jian Yang2,113, Futao Zhang1, Volker Arolt114, Bernhard T. Baune115,116,117, Klaus Berger101, Dorret I. Boomsma9, Sven Cichon35,47,118,119, Udo Dannlowski114, EJC. de Geus9,120, J. Raymond DePaulo50, Enrico Domenici121, Katharina Domschke122,123, T?nu Esko5,78, Hans J. Grabe109, Steven P. Hamilton124, Caroline Hayward125, Andrew C. Heath89, Kenneth S. Kendler17, Stefan Kloiber59,126,127, Glyn Lewis128, Qingqin S. Li129, Susanne Lucae59, Pamela AF. Madden89, Patrik K. Magnusson22, Nicholas G. Martin29, Andrew M. McIntosh10,34, Andres Metspalu78,130, Ole Mors13,131, Preben Bo Mortensen11,12,13,24, Bertram M?ller-Myhsok15,132,133, Merete Nordentoft13,134, Markus M. N?then35, Michael C. O'Donovan60, Sara A. Paciga135, Nancy L. Pedersen22, Brenda W.J.H. Penninx19, Roy H. Perlis38,136, David J. Porteous105, James B. Potash137, Martin Preisig27, Marcella Rietschel45, Catherine Schaefer62, Thomas G. Schulze45,93,138,139,140, Jordan W. Smoller38,39,40, Kari Stefansson99,141, Henning Tiemeier36,142,143, Rudolf Uher144, Henry V?lzke102, Myrna M. Weissman74,145, Thomas Werge13,54,146, Cathryn M. Lewis28,147, Douglas F. Levinson148, Gerome Breen28,149, Anders D. B?rglum8,13,24, Patrick F. Sullivan22,150,151 Funding Information: SHIP-LEGEND/TREND : SHIP is part of the Community Medicine Research net of the University of Greifswald, which is funded by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603 , 01ZZ0103 , and 01ZZ0403 ), the Ministry of Cultural Affairs , and the Social Ministry of the Federal State of Mecklenburg-West Pomerania . Genotyping in SHIP was funded by Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania . The SHIP-LEGEND/TREND Study is also funded by the German Research Foundation (Grant No. DFG: GR 1912/5-1 [principal investigator, H.J. Grabe]). Genotyping in SHIP-TREND-0 was supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012 ). Funding Information: RADIANT : This report represents independent research funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust , and King{\textquoteright}s College London . The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding support was provided by the Medical Research Council, UK (Grant Nos. G0701420 and G0901245 [principal investigators, C. Lewis and G. Breen]) and NIMH, UK (Grant No. U01 MH109528 [principal investigator, G. Breen]). Funding Information: BBMRI-NL: Funding support was provided by Biobanking and Biomolecular Resources Research Infrastructure (Grant Nos. 184.021.007 and BBMRI-NL2.0 184.033.111 ). Genotyping was supported by BBMRI-NL , the Avera Institute , Sioux Falls , SD , and National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health, Grand Opportunity Grant Nos. 1RC2 MH089951 and 1RC2 MH089995 [principal investigator, D.I. Boomsma]). Publisher Copyright: {\textcopyright} 2019 Society of Biological Psychiatry",

year = "2020",

month = mar,

day = "1",

doi = "10.1016/j.biopsych.2019.06.031",

language = "English",

volume = "87",

pages = "419--430",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "5",

}

TY - JOUR

T1 - Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Glanville, Kylie P.

AU - Coleman, Jonathan R.I.

AU - Hanscombe, Ken B.

AU - Euesden, Jack

AU - Choi, Shing Wan

AU - Purves, Kirstin L.

AU - Breen, Gerome

AU - Air, Tracy M.

AU - Andlauer, Till F.M.

AU - Baune, Bernhard T.

AU - Binder, Elisabeth B.

AU - Blackwood, Douglas H.R.

AU - Boomsma, Dorret I.

AU - Buttenschøn, Henriette N.

AU - Colodro-Conde, Lucía

AU - Dannlowski, Udo

AU - Direk, Nese

AU - Dunn, Erin C.

AU - Forstner, Andreas J.

AU - de Geus, Eco J.C.

AU - Grabe, Hans J.

AU - Hamilton, Steven P.

AU - Jones, Ian

AU - Jones, Lisa A.

AU - Knowles, James A.

AU - Kutalik, Zoltán

AU - Levinson, Douglas F.

AU - Lewis, Glyn

AU - Lind, Penelope A.

AU - Lucae, Susanne

AU - Magnusson, Patrik K.

AU - McGuffin, Peter

AU - McIntosh, Andrew M.

AU - Milaneschi, Yuri

AU - Mors, Ole

AU - Mostafavi, Sara

AU - Müller-Myhsok, Bertram

AU - Pedersen, Nancy L.

AU - Penninx, Brenda W.J.H.

AU - Potash, James B.

AU - Preisig, Martin

AU - Ripke, Stephan

AU - Shi, Jianxin

AU - Shyn, Stanley I.

AU - Smoller, Jordan W.

AU - Streit, Fabian

AU - Sullivan, Patrick F.

AU - Tiemeier, Henning

AU - Uher, Rudolf

AU - Van der Auwera, Sandra

N1 - Funding Information: GenPod/Newmeds : Funding support was provided by the Medical Research Council, UK (Grant No. G0200243 [principal investigators, G. Lewis and M. O'Donovan]), EU 6th framework, UK (Grant No. LSHB-CT-2003-503428 [principal investigator, R. Uher]), and EU Innovative Medicines Initiative Joint Undertaking, UK (Grant No. 15008 [principal investigator, G. Lewis]). Funding Information: Rotterdam Study : Funding support was provided by the Netherlands Organization of Scientific Research (NWO) Investments (Grant No. 175.010.2005.011 , 911-03-012 [principal investigator, A.G. Uitterlinden]). The Rotterdam Study is also funded by Erasmus Medical Center and Erasmus University . Funding Information: NTR : NTR is supported by the Netherlands Organization for Scientific Research (NOW) (Grant No. 480-15-001/674 ) Funding Information: NESDA: The infrastructure for the NESDA study ( www.nesda.nl ) is funded through the Geestkracht program of the Netherlands Organization for Health Research and Development (ZonMw) (Grant No. 10-000-1002 ) and financial contributions by participating universities and mental health care organizations (Vrije Universiteit Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, and Rob Giel Onderzoekscentrum). Genotyping was supported by the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL) and National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health, Grand Opportunity Grnat Nos. 1RC2 MH089951 and 1RC2 MH089995 [principal investigator, BJWH Penninx]). Funding Information: We thank participants and scientists involved in making the UK Biobank resource available ( http://www.ukbiobank.ac.uk/ ). UK Biobank data used in this study were obtained under approved application 18177, which was supported by funding from the Medical Research Council (Grant No. MR/N015746/1 ). Funding Information: QIMR : We thank the twins and their families for their willing participation in our studies. Funding support was provided by the National Health and Medical Research Council, Australia (Grant Nos. 941177 , 971232 , 3399450 , and 443011 [principal investigator, N.G. Martin]) and National Institute on Alcohol Abuse and Alcoholism (Grant Nos. AA07535 , AA07728 , and AA10249 [principal investigator, A.C. Heath]). Funding Information: Harvard i2b2 : Funding support was provided by the National Institute of Mental Health (NIMH) (Grant Nos. R01 MH085542 and R01 MH086026 [principal investigators, J.W. Smoller and R.H. Perlis]) Funding Information: We are deeply indebted to the investigators who comprise the PGC and to the hundreds of thousands of participants who have shared their life experiences with PGC investigators. The PGC has received major funding from the United States National Institute of Mental Health (Grant No. U01 MH109528-03 [principal investigator, P.F. Sullivan]), the United States National Institute of Drug Abuse (Grant No. U01 MH1095320 [principal investigator A. Agrawal]), the Netherlands Scientific Organization (Grant No. 480-05-003 [principal investigator, D. Posthuma]), and the Dutch Brain Foundation and the Vrije Universiteit Amsterdam (principal investigator, D. Posthuma). Funding Information: This work was supported by the UK Medical Research Council (Grant No. MR/N015746/1 Grant No. MR/N015746/1 , Ph.D. studentship [to KPG]) and partially funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King’s College London . The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Funding Information: BOMA : Funding support was provided by Deutsche Forschungsgemeinschaft, Germany (Grant Nos. RI 908/11-1 , NO246/10-1 and Excellence Cluster ImmunoSensation [principal investigators, M. Rietschel and M.M. Nöthen]), the German Federal Ministry for Education and Research (BMBF) IntegraMent, Germany (Grant Nos. 01ZX1314A/01ZX1614A and 01ZX1314G/01ZX1614G [principal investigators, M.M. Nöthen, M. Rietschel, and S. Cichon]), and BMBF NGFNplus MooDS, Germany (Grant Nos. 01GS08144 and 01GS08147 [principal investigators, M.M. Nöthen, M. Rietschel, and S. Cichon]). Funding Information: Funding support for the Genome-Wide Association of Schizophrenia Study was provided by NIMH (Grant Nos. R01 MH67257 , R01 MH59588 , R01 MH59571 , R01 MH59565 , R01 MH59587 , R01 MH60870 , R01 MH59566 , R01 MH59586 , R01 MH61675 , R01 MH60879 , R01 MH81800 , U01 MH46276 , U01 MH46289 U01 MH46318 , U01 MH79469 , and U01 MH79470 ), and the genotyping of samples was provided through GAIN. The data sets used for the analyses described in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v3.p2. Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (principal investigator, Pablo V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, IL). Funding Information: EDINBURGH : Genotyping was conducted at the Genetics Core Laboratory at the Clinical Research Facility (University of Edinburgh). Funding support was provided by Wellcome Trust, UK (Grant No. 104036/Z/14/Z [principal investigator, A.M. McIntosh]). Funding Information: Statistical analyses were performed on the NL Genetic Cluster computer ( http://www.geneticcluster.org/ ) hosted by SURFsara, and the King's Health Partners High Performance Compute Cluster funded with capital equipment grants from the Guy's and St Thomas' Charity (Grant No. TR130505 ) and Maudsley Charity (Grant No. 980 ). Funding Information: PsyColaus : Funding support was provided by the Swiss National Science Foundation, Switzerland (Grant Nos. 3200B0-105993 , 3200B0-118308 , 33CSCO-122661 , 33CS30-139468 , and 33CS30-148401 [principal investigator, M. Preisig]). PsyCoLaus/CoLaus received additional support from research grants from GlaxoSmithKline and the Faculty of Biology and Medicine of Lausanne . Funding Information: CoFaMS – Adelaide : Funding support was provided by National Health and Medical Research Council, Australia (Grant No. APP1060524 [principal investigator, B.T. Baune]). Funding Information: STAR*D : The authors appreciate the efforts of the STAR*D investigator team for acquiring, compiling, and sharing the STAR*D clinical data set. Funding support was provided by NIMH (Grant No. R01 MH-072802 [principal investigator, S.P. Hamilton]). Funding Information: TwinGene : Thanks the Karolinska Institutet for infrastructural support of the Swedish Twin Registry . Funding support was provided by GenomeEUtwin, EU (Grant Nos. EU/QLRT-2001-01254 and QLG2-CT-2002-01254 [principal investigator, N. Pedersen]), the Heart and Lung foundation, Sweden (Grant No. 20070481 [principal investigator, P. Magnusson]), SSF, Sweden and Vetenskapsrådet, Sweden (Grant No. M-2005-1112 [principal investigator, U. de Faire]). Funding Information: MARS : This work was funded by the Max Planck Society , the Max Planck Excellence Foundation , the BMBF in the National Genome Research Network framework (NGFN2 and NGFN-Plus) (Grant No. FKZ 01GS0481 ), and by the BMBF Program (Grant No. FKZ 01ES0811 ). We acknowledge all study participants. We thank numerous people at Max Planck Institute, and all study sites in Germany and Switzerland who contributed to this project. Controls were from the Dortmund Health Study, which was supported NGFNplus MooDS by the German Migraine and Headache Society and by unrestricted grants to the University of Münster from Almirall , AstraZeneca , Berlin Chemie , Boehringer , Boots Health Care , Glaxo-Smith-Kline , Janssen Cilag , McNeil Pharma , MSD Sharp and Dohme , and Pfizer . Blood collection was funded by the Institute of Epidemiology and Social Medicine , University of Münster. Genotyping was supported by the BMBF (Grant No. 01ER0816 ). Funding Information: Danish Radiant : Funding support was provided by Højteknologifonden, Denmark (Grant No. 0001-2009-2 [principal investigators, T. Werge (controls) and O. Mors (cases)]) and Lundbeck Foundation, Denmark (Grant No. R24-A3242 [principal investigators, T. Werge (controls) and O. Mors (cases)]) Funding Information: This work was supported by the UK Medical Research Council (Grant No. MR/N015746/1 Grant No. MR/N015746/1, Ph.D. studentship [to KPG]) and partially funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. We thank participants and scientists involved in making the UK Biobank resource available (http://www.ukbiobank.ac.uk/). UK Biobank data used in this study were obtained under approved application 18177, which was supported by funding from the Medical Research Council (Grant No. MR/N015746/1). We are deeply indebted to the investigators who comprise the PGC and to the hundreds of thousands of participants who have shared their life experiences with PGC investigators. The PGC has received major funding from the United States National Institute of Mental Health (Grant No. U01 MH109528-03 [principal investigator, P.F. Sullivan]), the United States National Institute of Drug Abuse (Grant No. U01 MH1095320 [principal investigator A. Agrawal]), the Netherlands Scientific Organization (Grant No. 480-05-003 [principal investigator, D. Posthuma]), and the Dutch Brain Foundation and the Vrije Universiteit Amsterdam (principal investigator, D. Posthuma). We thank contributors to the primary studies constituting the PGC-MDD sample in this article. BOMA: Funding support was provided by Deutsche Forschungsgemeinschaft, Germany (Grant Nos. RI 908/11-1, NO246/10-1 and Excellence Cluster ImmunoSensation [principal investigators, M. Rietschel and M.M. N?then]), the German Federal Ministry for Education and Research (BMBF) IntegraMent, Germany (Grant Nos. 01ZX1314A/01ZX1614A and 01ZX1314G/01ZX1614G [principal investigators, M.M. N?then, M. Rietschel, and S. Cichon]), and BMBF NGFNplus MooDS, Germany (Grant Nos. 01GS08144 and 01GS08147 [principal investigators, M.M. N?then, M. Rietschel, and S. Cichon]). CoFaMS ? Adelaide: Funding support was provided by National Health and Medical Research Council, Australia (Grant No. APP1060524 [principal investigator, B.T. Baune]). Danish Radiant: Funding support was provided by H?jteknologifonden, Denmark (Grant No. 0001-2009-2 [principal investigators, T. Werge (controls) and O. Mors (cases)]) and Lundbeck Foundation, Denmark (Grant No. R24-A3242 [principal investigators, T. Werge (controls) and O. Mors (cases)]), EDINBURGH: Genotyping was conducted at the Genetics Core Laboratory at the Clinical Research Facility (University of Edinburgh). Funding support was provided by Wellcome Trust, UK (Grant No. 104036/Z/14/Z [principal investigator, A.M. McIntosh]). GenPod/Newmeds: Funding support was provided by the Medical Research Council, UK (Grant No. G0200243 [principal investigators, G. Lewis and M. O'Donovan]), EU 6th framework, UK (Grant No. LSHB-CT-2003-503428 [principal investigator, R. Uher]), and EU Innovative Medicines Initiative Joint Undertaking, UK (Grant No. 15008 [principal investigator, G. Lewis]). GSK-MUNICH: We thank all participants in the GSK-Munich study. We thank numerous people at GSK and Max Planck Institute, BKH Augsburg, and Klinikum Ingolstadt in Germany who contributed to this project. Harvard i2b2: Funding support was provided by the National Institute of Mental Health (NIMH) (Grant Nos. R01 MH085542 and R01 MH086026 [principal investigators, J.W. Smoller and R.H. Perlis]), MARS: This work was funded by the Max Planck Society, the Max Planck Excellence Foundation, the BMBF in the National Genome Research Network framework (NGFN2 and NGFN-Plus) (Grant No. FKZ 01GS0481), and by the BMBF Program (Grant No. FKZ 01ES0811). We acknowledge all study participants. We thank numerous people at Max Planck Institute, and all study sites in Germany and Switzerland who contributed to this project. Controls were from the Dortmund Health Study, which was supported NGFNplus MooDS by the German Migraine and Headache Society and by unrestricted grants to the University of M?nster from Almirall, AstraZeneca, Berlin Chemie, Boehringer, Boots Health Care, Glaxo-Smith-Kline, Janssen Cilag, McNeil Pharma, MSD Sharp and Dohme, and Pfizer. Blood collection was funded by the Institute of Epidemiology and Social Medicine, University of M?nster. Genotyping was supported by the BMBF (Grant No. 01ER0816). NESDA: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organization for Health Research and Development (ZonMw) (Grant No. 10-000-1002) and financial contributions by participating universities and mental health care organizations (Vrije Universiteit Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, and Rob Giel Onderzoekscentrum). Genotyping was supported by the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL) and National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health, Grand Opportunity Grnat Nos. 1RC2 MH089951 and 1RC2 MH089995 [principal investigator, BJWH Penninx]). NTR: NTR is supported by the Netherlands Organization for Scientific Research (NOW) (Grant No. 480-15-001/674), BBMRI-NL: Funding support was provided by Biobanking and Biomolecular Resources Research Infrastructure (Grant Nos. 184.021.007 and BBMRI-NL2.0 184.033.111). Genotyping was supported by BBMRI-NL, the Avera Institute, Sioux Falls, SD, and National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health, Grand Opportunity Grant Nos. 1RC2 MH089951 and 1RC2 MH089995 [principal investigator, D.I. Boomsma]). PsyColaus: Funding support was provided by the Swiss National Science Foundation, Switzerland (Grant Nos. 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, and 33CS30-148401 [principal investigator, M. Preisig]). PsyCoLaus/CoLaus received additional support from research grants from GlaxoSmithKline and the Faculty of Biology and Medicine of Lausanne. QIMR: We thank the twins and their families for their willing participation in our studies. Funding support was provided by the National Health and Medical Research Council, Australia (Grant Nos. 941177, 971232, 3399450, and 443011 [principal investigator, N.G. Martin]) and National Institute on Alcohol Abuse and Alcoholism (Grant Nos. AA07535, AA07728, and AA10249 [principal investigator, A.C. Heath]). RADIANT: This report represents independent research funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding support was provided by the Medical Research Council, UK (Grant Nos. G0701420 and G0901245 [principal investigators, C. Lewis and G. Breen]) and NIMH, UK (Grant No. U01 MH109528 [principal investigator, G. Breen]). Rotterdam Study: Funding support was provided by the Netherlands Organization of Scientific Research (NWO) Investments (Grant No. 175.010.2005.011, 911-03-012 [principal investigator, A.G. Uitterlinden]). The Rotterdam Study is also funded by Erasmus Medical Center and Erasmus University. SHIP-LEGEND/TREND: SHIP is part of the Community Medicine Research net of the University of Greifswald, which is funded by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genotyping in SHIP was funded by Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. The SHIP-LEGEND/TREND Study is also funded by the German Research Foundation (Grant No. DFG: GR 1912/5-1 [principal investigator, H.J. Grabe]). Genotyping in SHIP-TREND-0 was supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012). STAR*D: The authors appreciate the efforts of the STAR*D investigator team for acquiring, compiling, and sharing the STAR*D clinical data set. Funding support was provided by NIMH (Grant No. R01 MH-072802 [principal investigator, S.P. Hamilton]). TwinGene: Thanks the Karolinska Institutet for infrastructural support of the Swedish Twin Registry. Funding support was provided by GenomeEUtwin, EU (Grant Nos. EU/QLRT-2001-01254 and QLG2-CT-2002-01254 [principal investigator, N. Pedersen]), the Heart and Lung foundation, Sweden (Grant No. 20070481 [principal investigator, P. Magnusson]), SSF, Sweden and Vetenskapsr?det, Sweden (Grant No. M-2005-1112 [principal investigator, U. de Faire]). Funding support for the Genome-Wide Association of Schizophrenia Study was provided by NIMH (Grant Nos. R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289 U01 MH46318, U01 MH79469, and U01 MH79470), and the genotyping of samples was provided through GAIN. The data sets used for the analyses described in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v3.p2. Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (principal investigator, Pablo V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, IL). Statistical analyses were performed on the NL Genetic Cluster computer (http://www.geneticcluster.org/) hosted by SURFsara, and the King's Health Partners High Performance Compute Cluster funded with capital equipment grants from the Guy's and St Thomas' Charity (Grant No. TR130505) and Maudsley Charity (Grant No. 980). JE is an employee of GlaxoSmithKline Pharmaceuticals. PFS is on the scientific advisory board for Pfizer and the advisory committee for Lundbeck. All other authors report no biomedical financial interests or potential conflicts of interest. Due to the highly sensitive nature of genetic information used in this study, supporting data cannot be made openly available. Researchers may apply to the Psychiatric Genomics Consortium (https://www.med.unc.edu/pgc/shared-methods/) and/or UK Biobank (https://www.ukbiobank.ac.uk/) to gain access to the supporting data. Naomi R. Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski 1, Enda M. Byrne1, Abdel Abdellaoui9, Mark J. Adams10, Esben Agerbo11,12,13, Tracy M. Air14, Till F.M. Andlauer15,16, Silviu-Alin Bacanu17, Marie B?kvad-Hansen13,18, Aartjan T.F. Beekman19, Tim B. Bigdeli17,20, Elisabeth B. Binder15,21, Julien Bryois22, Henriette N. Buttensch?n13,23,24, Jonas Bybjerg-Grauholm13,18, Na Cai25,26, Enrique Castelao27, Jane Hvarregaard Christensen8,13,24, Toni-Kim Clarke10, Jonathan R.I. Coleman28, Luc?a Colodro-Conde29, Baptiste Couvy-Duchesne2,30, Nick Craddock31, Gregory E. Crawford32,33, Gail Davies34, Ian J. Deary34, Franziska Degenhardt35, Eske M. Derks29, Nese Direk36,37, Conor V. Dolan9, Erin C. Dunn38,39,40, Thalia C. Eley28, Valentina Escott-Price41, Farnush Farhadi Hassan Kiadeh42, Hilary K. Finucane43,44, Jerome C. Foo45, Andreas J. Forstner35,46,47,48, Josef Frank45, H?l?na A. Gaspar28, Michael Gill49, Fernando S. Goes50, Scott D. Gordon29, Jakob Grove8,13,24,51, Lynsey S. Hall10,52, Christine S?holm Hansen13,18, Thomas F. Hansen53,54,55, Stefan Herms35,47, Ian B. Hickie56, Per Hoffmann35,47, Georg Homuth57, Carsten Horn58, Jouke-Jan Hottenga9, David M. Hougaard13,18, David M. Howard10,28, Marcus Ising59, Rick Jansen19, Ian Jones60, Lisa A. Jones61, Eric Jorgenson62, James A. Knowles63, Isaac S. Kohane64,65,66, Julia Kraft4, Warren W. Kretzschmar67, Zolt?n Kutalik68,69, Yihan Li67, Penelope A. Lind29, Donald J. MacIntyre70,71, Dean F. MacKinnon50, Robert M. Maier2, Wolfgang Maier72, Jonathan Marchini73, Hamdi Mbarek9, Patrick McGrath74, Peter McGuffin28, Sarah E. Medland29, Divya Mehta2,75, Christel M. Middeldorp9,76,77, Evelin Mihailov78, Yuri Milaneschi19, Lili Milani78, Francis M. Mondimore50, Grant W. Montgomery1, Sara Mostafavi79,80, Niamh Mullins28, Matthias Nauck81,82, Bernard Ng80, Michel G. Nivard9, Dale R. Nyholt83, Paul F. O'Reilly28, Hogni Oskarsson84, Michael J. Owen60, Jodie N. Painter29, Carsten B?cker Pedersen11,12,13, Marianne Gi?rtz Pedersen11,12,13, Roseann E. Peterson17,85, Erik Pettersson22, Wouter J. Peyrot19, Giorgio Pistis27, Danielle Posthuma86,87, Jorge A. Quiroz88, Per Qvist8,13,24, John P. Rice89, Brien P. Riley17, Margarita Rivera28,90, Saira Saeed Mirza36, Robert Schoevers91, Eva C. Schulte92,93, Ling Shen62, Jianxin Shi94, Stanley I. Shyn95, Engilbert Sigurdsson96, Grant C. B. Sinnamon97, Johannes H. Smit19, Daniel J. Smith98, Hreinn Stefansson99, Stacy Steinberg99, Fabian Streit45, Jana Strohmaier45, Katherine E. Tansey100, Henning Teismann101, Alexander Teumer102, Wesley Thompson13,54,103,104, Pippa A. Thomson105, Thorgeir E. Thorgeirsson99, Matthew Traylor106, Jens Treutlein45, Vassily Trubetskoy4, Andr?s G. Uitterlinden107, Daniel Umbricht108, Sandra Van der Auwera109, Albert M. van Hemert110, Alexander Viktorin22, Peter M. Visscher1,2, Yunpeng Wang13,54,104, Bradley T. Webb111, Shantel Marie Weinsheimer13,54, J?rgen Wellmann101, Gonneke Willemsen9, Stephanie H. Witt45, Yang Wu1, Hualin S. Xi112, Jian Yang2,113, Futao Zhang1, Volker Arolt114, Bernhard T. Baune115,116,117, Klaus Berger101, Dorret I. Boomsma9, Sven Cichon35,47,118,119, Udo Dannlowski114, EJC. de Geus9,120, J. Raymond DePaulo50, Enrico Domenici121, Katharina Domschke122,123, T?nu Esko5,78, Hans J. Grabe109, Steven P. Hamilton124, Caroline Hayward125, Andrew C. Heath89, Kenneth S. Kendler17, Stefan Kloiber59,126,127, Glyn Lewis128, Qingqin S. Li129, Susanne Lucae59, Pamela AF. Madden89, Patrik K. Magnusson22, Nicholas G. Martin29, Andrew M. McIntosh10,34, Andres Metspalu78,130, Ole Mors13,131, Preben Bo Mortensen11,12,13,24, Bertram M?ller-Myhsok15,132,133, Merete Nordentoft13,134, Markus M. N?then35, Michael C. O'Donovan60, Sara A. Paciga135, Nancy L. Pedersen22, Brenda W.J.H. Penninx19, Roy H. Perlis38,136, David J. Porteous105, James B. Potash137, Martin Preisig27, Marcella Rietschel45, Catherine Schaefer62, Thomas G. Schulze45,93,138,139,140, Jordan W. Smoller38,39,40, Kari Stefansson99,141, Henning Tiemeier36,142,143, Rudolf Uher144, Henry V?lzke102, Myrna M. Weissman74,145, Thomas Werge13,54,146, Cathryn M. Lewis28,147, Douglas F. Levinson148, Gerome Breen28,149, Anders D. B?rglum8,13,24, Patrick F. Sullivan22,150,151 Funding Information: SHIP-LEGEND/TREND : SHIP is part of the Community Medicine Research net of the University of Greifswald, which is funded by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603 , 01ZZ0103 , and 01ZZ0403 ), the Ministry of Cultural Affairs , and the Social Ministry of the Federal State of Mecklenburg-West Pomerania . Genotyping in SHIP was funded by Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania . The SHIP-LEGEND/TREND Study is also funded by the German Research Foundation (Grant No. DFG: GR 1912/5-1 [principal investigator, H.J. Grabe]). Genotyping in SHIP-TREND-0 was supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012 ). Funding Information: RADIANT : This report represents independent research funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust , and King’s College London . The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding support was provided by the Medical Research Council, UK (Grant Nos. G0701420 and G0901245 [principal investigators, C. Lewis and G. Breen]) and NIMH, UK (Grant No. U01 MH109528 [principal investigator, G. Breen]). Funding Information: BBMRI-NL: Funding support was provided by Biobanking and Biomolecular Resources Research Infrastructure (Grant Nos. 184.021.007 and BBMRI-NL2.0 184.033.111 ). Genotyping was supported by BBMRI-NL , the Avera Institute , Sioux Falls , SD , and National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health, Grand Opportunity Grant Nos. 1RC2 MH089951 and 1RC2 MH089995 [principal investigator, D.I. Boomsma]). Publisher Copyright: © 2019 Society of Biological Psychiatry

PY - 2020/3/1

Y1 - 2020/3/1

N2 - Background: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. Methods: We fine-mapped the classical MHC (chr6: 29.6–33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10−6) and a candidate threshold (1.6 × 10−4). Results: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97–0.99). Conclusions: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

AB - Background: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. Methods: We fine-mapped the classical MHC (chr6: 29.6–33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10−6) and a candidate threshold (1.6 × 10−4). Results: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97–0.99). Conclusions: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

UR - http://www.scopus.com/inward/record.url?scp=85072749953&partnerID=8YFLogxK

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U2 - 10.1016/j.biopsych.2019.06.031

DO - 10.1016/j.biopsych.2019.06.031

M3 - Article

C2 - 31570195

AN - SCOPUS:85072749953

SN - 0006-3223

VL - 87

SP - 419

EP - 430

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 5

ER -

Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

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