A mega-analysis of genome-wide association studies for major depressive disorder
Open accessAbstract
Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.
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Genetic association and epidemiological studies have not yet explained the non-complete genetic correlation between monozygotic twins in schizophrenia (41-65%), Bipolar Disorder (~60%), and Major Depression (~40%).
“Genetic association studies (Ripke et al., 2014) as well as epidemiological studies addressing the impact of the environment (van Os, Kenis, & Rutten, 2010) on disease burden, have not yet explained the non-complete genetic correlation between monozygotic twins in conditions such as schizophrenia (SCZ) (41–65%), Bipolar Disorder (BD) (~60%) (Craddock, O'Donovan, & Owen, 2005) or Major Depression (”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Ripke et al., 2013
The Discussion reports that the study found no genome-wide significant locus for major depressive disorder, supporting the narrower point that its genetic association analysis had not explained MDD risk. The Introduction gives MDD heritability as 31–42%, but that is not a monozygotic-twin concordance figure. The paper does not establish the claimed twin figures or explain discordance for schizophrenia, bipolar disorder, or major depression. (LLM, conf=0.83)
Experimental — accuracy not yet measuredTwo earlier efforts, a mega-analysis of 9 cohorts and a meta-analysis of 17 cohorts, did not find replicated depression-associated variants.
“However, both of these studies failed to find any replicated variants associated with depression.”
From Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions (2019) · cites this paper as [4]
Depression is a polygenic condition shaped by numerous genetic variants, each with a small effect.
“however depression is a polygenic trait influenced by many genetic variants each of small effect 4”
From Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions (2019) · cites this paper as [4]
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Self-citationThe Genetics of Major Depression
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The current state of play on the molecular genetics of depression
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Genome-wide association studies in psychiatry: what have we learned?
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Autism Spectrum Disorder Genetics: Diverse Genes with Diverse Clinical Outcomes
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Self-citationDNA Modification Study of Major Depressive Disorder: Beyond Locus-by-Locus Comparisons
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“3 We used results from six GWAS datasets: ASD, schizophrenia (SCZ), major depressive disorder 4 (MDD), and attention deficit hyperactive disorder (ADHD), which are all positively genetically 5 correlated with ASD and with each other; educational attainment (EA), which is positively 6 correlated with ASD and negatively…”
MethodSelf-citation
- Authors
- Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, Ripke, S., Wray, N. R., Lewis, C. M., Hamilton, S. P., Weissman, M. M., Breen, G., Byrne, E. M., Blackwood, D. H. R., Boomsma, D. I., Cichon, S., Heath, A. C., Holsboer, F., Lucae, S., Madden, P. A. F., Martin, N. G., McGuffin, P., Muglia, P., Noethen, M. M., Penninx, B. P., Pergadia, M. L., Potash, J. B., Rietschel, M., Lin, D., Müller-Myhsok, B., Shi, J., Steinberg, S., Grabe, H. J., Lichtenstein, P., Magnusson, P., Perlis, R. H., Preisig, M., Smoller, J. W., Stefansson, K., Uher, R., Kutalik, Z., Tansey, K. E., Teumer, A., Viktorin, A., Barnes, M. R., Bettecken, T., Binder, E. B., Breuer, R., Castro, V. M., Churchill, S. E., Coryell, W. H., Craddock, N., Craig, I. W., Czamara, D., De Geus, E. J., Degenhardt, F., Farmer, A. E., Fava, M., Frank, J., Gainer, V. S., Gallagher, P. J., Gordon, S. D., Goryachev, S., Gross, M., Guipponi, M., Henders, A. K., Herms, S., Hickie, I. B., Hoefels, S., Hoogendijk, W., Hottenga, J. J., Iosifescu, D. V., Ising, M., Jones, I., Jones, L., Jung-Ying, T., Knowles, J. A., Kohane, I. S., Kohli, M. A., Korszun, A., Landen, M., Lawson, W. B., Lewis, G., MacIntyre, D., Maier, W., Mattheisen, M., McGrath, P. J., McIntosh, A., McLean, A., Middeldorp, C. M., Middleton, L., Montgomery, G. M., Murphy, S. N., Nauck, M., Nolen, W. A., Nyholt, D. R., O'Donovan, M., Oskarsson, H., Pedersen, N., Scheftner, W. A., Schulz, A., Schulze, T. G., Shyn, S. I., Sigurdsson, E., Slager, S. L., Smit, J. H., Stefansson, H., Steffens, M., Thorgeirsson, T., Tozzi, F., Treutlein, J., Uhr, M., van den Oord, E. J. C. G., Van Grootheest, G., Völzke, H., Weilburg, J. B., Willemsen, G., Zitman, F. G., Neale, B., Daly, M., Levinson, D. F., & Sullivan, P. F.
- Affiliations
- Broad Institute (US)
- The University of Queensland (AU)
- King's College London (GB)
- University of California, San Francisco (US)
- Columbia University (US)
- QIMR Berghofer Medical Research Institute (AU)
- University of Edinburgh (GB)
- Vrije Universiteit Amsterdam (NL)
- University of Bonn (DE)
- Washington University in St. Louis (US)
- Max Planck Institute of Psychiatry (DE)
- GlaxoSmithKline (Italy) (IT)
- University of Iowa (US)
- Heidelberg University (DE)
- National Cancer Institute (US)
- deCODE Genetics (Iceland) (IS)
- Universität Greifswald (DE)
- Karolinska Institutet (SE)
- Massachusetts General Hospital (US)
- University of Lausanne (CH)
- GlaxoSmithKline (United Kingdom) (GB)
- Cardiff University (GB)
- University of Geneva (CH)
- The University of Sydney (AU)
- Erasmus MC (NL)
- University of Birmingham (GB)
- University of Southern California (US)
- Brigham and Women's Hospital (US)
- Queen Mary University of London (GB)
- Howard University (US)
- University of Bristol (GB)
- Imperial College London (GB)
- University Medical Center Groningen (NL)
- Rush University Medical Center (US)
- University of Göttingen (DE)
- University of Washington (US)
- Mayo Clinic (US)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Leiden University Medical Center (NL)
- Stanford University (US)
- Corresponding author
- Sullivan, Patrick F
- ORCID
- Ripke, Stephan
- Wray, Naomi R
- Lewis, Cathryn M
- Hamilton, Steven P
- Weissman, Myrna M
- Breen, Gerome
- Byrne, Enda M
- Blackwood, Douglas H R
- Boomsma, Dorret I
- Cichon, Sven
- Heath, Andrew C
- Lucae, Susanne
- Madden, Pamela A F
- Martin, Nicholas G
- McGuffin, Peter
- Muglia, Pierandrea
- Potash, James B
- Rietschel, Marcella
- Lin, Danyu
- Shi, Jianxin
- Steinberg, Stacy
- Grabe, Hans J
- Lichtenstein, Paul
- Magnusson, Patrik
- Perlis, Roy H
- Preisig, Martin
- Smoller, Jordan W
- Uher, Rudolf
- Tansey, Katherine E
- Teumer, Alexander
- Viktorin, Alexander
- Barnes, Michael R
- Binder, Elisabeth B
- Castro, Victor M
- Coryell, William H
- Craddock, Nick
- Craig, Ian W
- Czamara, Darina
- Degenhardt, Franziska
- Frank, Josef
- Gordon, Scott D
- Guipponi, Michel
- Henders, Anjali K
- Herms, Stefan
- Hickie, Ian B
- Hoogendijk, Witte
- Hottenga, Jouke Jan
- Iosifescu, Dan V
- Jones, Lisa
- Knowles, James A
- Kohane, Isaac S
- Lawson, William B
- Lewis, Glyn
- MacIntyre, Donald
- Mattheisen, Manuel
- McGrath, Patrick J
- McIntosh, Andrew
- Middeldorp, Christel M
- Middleton, Lefkos
- Murphy, Shawn N
- Nauck, Matthias
- Nyholt, Dale R
- Pedersen, Nancy
- Schulze, Thomas G
- Shyn, Stanley I
- Slager, Susan L
- Smit, Johannes H
- Steffens, Michael
- Thorgeirsson, Thorgeir
- Tozzi, Federica
- Treutlein, Jens
- Völzke, Henry
- Weilburg, Jeffrey B
- Willemsen, Gonneke
- Zitman, Frans G
- Neale, Benjamin
- Daly, Mark
- Levinson, Douglas F
- Sullivan, Patrick F
- Venue
- Molecular Psychiatry
- Published
- 2012-04-03
- Volume
- 18
- Issue
- 4
- Pages
- 497-511
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3837431
- OpenAlex
- W2065692954
- Cited by
- 1,120
- References
- 76
- Citations by year
- 2026: 16 · 2025: 23 · 2024: 34 · 2023: 44 · 2022: 50 · 2021: 64 · 2020: 69 · 2019: 101 · 2018: 112 · 2017: 178 · 2016: 129 · 2015: 128 · 2014: 90 · 2013: 58 · 2012: 22
- FWCI
- 11.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- IRIS (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- VU Research Portal (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- National Science Foundation (FP7/2007-2013)
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline (3200B0–105993)
- Sanofi
- University of Texas Southwestern Medical Center
- University of Pittsburgh
- South London and Maudsley NHS Foundation Trust
- National Alliance for Research on Schizophrenia and Depression
- Wellcome Trust (FP7/2007–2013, 085475, 076113)
- QIMR Berghofer Medical Research Institute
- Broad Institute
- National Institute for Health and Care Research (FP7/2007–2013)
- King's College London
- European Commission (QLG2-CT-2002-01254, LSHM-CT-2006-037761, LSHB-CT-2003–503428, 503428, 2007–2013, 230374, 01ZZ0103, FP7 2007-2013, 218251, 201413, FP7/2007, 01ZZ0403, 01254, 03ZIK012, 01ZZ9603, 115008, 223423, LSHB-CT-2003)
- European Science Foundation (2001-01254, EU/QLRT-2001-01254, HEALTH-F4-2007-201413)
- Deutsche Forschungsgemeinschaft (Gr1912/5‐1, 01ZZ0403, DFG: GR 1912/5‐1, FP7/2007–2013, 01ZZ9603, 03ZIK012, 01ZZ0103)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (FP7/2007-2013, 122661, 105993, 230374, 218251, 201413, 3200B0)
- Stiftelsen för Strategisk Forskning
- ZonMw (985-10-002, 400‐05‐717, 56-464-14192, 904-61-193, 904-61-090, 480‐04‐004, 10‐000‐1002)
- Vrije Universiteit Amsterdam (FP7/2007-2013, 2008.024)
- Bundesministerium für Bildung und Forschung (01GS0481, 01ZZ9603, 01ZZ0103, and 01ZZ0403, 115008, 01GS08145, 01GS08147, 03ZIK012, 01ZZ0403, and 01ZZ0403, 01GS08144, 01ES0811, 01ZZ0103, 01ZZ9603)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (10-000-1002, 400‐05‐717, Grant 10-000-1002, 904-61-193, 904-61-090, FP7 2007-2013, 56‐464‐14192, 916-76-125, Spinozapremie 56-464-14192, 985-10002, 480-04-004, 904-61-090, 985-10-002)
- Eisai
- Vetenskapsrådet (FP7/2007-2013, M-2005-1112)
- China Scholarship Council (01GS08144, 01GS08147)
- Siemens
- Servier
- Norwegian Biodiversity Information Centre
- Universität Greifswald
- Ministry of Cultural Affairs
- National Institutes of Health (FP7/2007-2013, 389875, n01mh90003-26-0-0, EU/QLRT-2001-01254, 6u54rr020278-06, 1r01mh081802-01, MH66206, N01MH90003, AA13321, MH059542, AA13320, MH059541, DA12854, 400-05-717)
- Medical Research Council (G0701420)
- Australian Research Council (FT0991360, FT0991022, 389875, QLG2-CT-2002-01254)
- National Health and Medical Research Council (496739, 613674, 613602, 389927, 389891, 552485, 619667, 552498, 442981, 613608, 389938, 241944, 339462, 442915, 389875, 496675, 389892)
- National Institute on Alcohol Abuse and Alcoholism (AA-10248, K05AA017688, R01AA013321, AA13320, AA13321, R01AA013326, AA13326, R01AA013320, R01AA014041, AA14041, R01AA007535)
- National Institute of Mental Health (MH075131, MH66206, N01‐MH‐90003, R01MH072802, MH080403, R01MH059541, N01 MH090003, MH072802, MH059542, MH-081802, U01MH085520, HEALTH-F4-2007-201413, MH059541, MH-059552, RC2MH089916, R01MH059542, U01MH094421, MH-086026, MH085520, MH061686, R01MH060912, R01MH075131, R01MH066206, R01MH059552, R01MH061686, R01 MH081802, R01MH086026, R01MH080403, MH060912)
- National Institute on Drug Abuse (R56DA012854, DA 019951, DA12854, K08DA019951, R01DA012854)
- National Cancer Institute (R01CA082659)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK066134)
- U.S. National Library of Medicine (U54LM008748)
- National Center for Research Resources (U54-RR020278)
- Cilag
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- major depressive disorder, genetic loci, bipolar disorder, single nucleotide polymorphisms, replication, sample size limitations, age of onset, recurrent depression
- MeSH terms
- Bipolar Disorder, Depressive Disorder, Major, Major Depressive Disorder, Female, Humans, Male, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, Genome-Wide Association Study
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