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Identification of 15 genetic loci associated with risk of major depression in individuals of European descent

Nature Genetics volume 48, pages 10311036 (2016) | Download Citation


Despite strong evidence supporting the heritability of major depressive disorder (MDD), previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used self-report data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 individuals reporting no history of depression through 23andMe and carried out meta-analysis of these results with published MDD genome-wide association study results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with a P value <1.0 × 10−5 in the meta-analysis were further analyzed in a replication data set (45,773 cases and 106,354 controls) from 23andMe. A total of 17 independent SNPs from 15 regions reached genome-wide significance after joint analysis over all three data sets. Some of these loci were also implicated in genome-wide association studies of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to data collected from traditional means of ascertainment for neuropsychiatric disease genomics.

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  1. 1.

    , , & Mortality of patients with mood disorders: follow-up over 34-38 years. J. Affect. Disord. 68, 167–181 (2002).

  2. 2.

    , , , & Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 367, 1747–1757 (2006).

  3. 3.

    et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur. Neuropsychopharmacol. 21, 655–679 (2011).

  4. 4.

    et al. Recurrence risks for schizophrenia in a Swedish national cohort. Psychol. Med. 36, 1417–1425 (2006).

  5. 5.

    , & Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187–1192 (2003).

  6. 6.

    CONVERGE Consortium. Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature 523, 588–591 (2015).

  7. 7.

    et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489, 391–399 (2012).

  8. 8.

    et al. MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J. Med. Genet. 47, 22–29 (2010).

  9. 9.

    et al. MEF2C haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways. Neurogenetics 14, 99–111 (2013).

  10. 10.

    et al. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proc. Natl. Acad. Sci. USA 105, 9391–9396 (2008).

  11. 11.

    et al. Imipramine treatment and resiliency exhibit similar chromatin regulation in the mouse nucleus accumbens in depression models. J. Neurosci. 29, 7820–7832 (2009).

  12. 12.

    Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

  13. 13.

    Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371–1379 (2013).

  14. 14.

    Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium. A mega-analysis of genome-wide association studies for major depressive disorder. Mol. Psychiatry 18, 497–511 (2013).

  15. 15.

    Meta-Analysis of Controlled Clinical Trials (John Wiley & Sons, 2002).

  16. 16.

    et al. Meis2 is a Pax6 co-factor in neurogenesis and dopaminergic periglomerular fate specification in the adult olfactory bulb. Development 141, 28–38 (2014).

  17. 17.

    , , , & Genetic and physical interaction of Meis2, Pax3 and Pax7 during dorsal midbrain development. BMC Dev. Biol. 12, 10 (2012).

  18. 18.

    et al. Biological interpretation of genome-wide association studies using predicted gene functions. Nat. Commun. 6, 5890 (2015).

  19. 19.

    , & Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19, 149–150 (2003).

  20. 20.

    et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).

  21. 21.

    et al. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nat. Genet. 48, 624–633 (2016).

  22. 22.

    Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat. Genet. 43, 977–983 (2011).

  23. 23.

    et al. Results of the DSM-IV mood disorders field trial. Am. J. Psychiatry 152, 843–849 (1995).

  24. 24.

    et al. DSM-5 field trials in the United States and Canada, Part II: test–retest reliability of selected categorical diagnoses. Am. J. Psychiatry 170, 59–70 (2013).

  25. 25.

    et al. Can phase III trial results of antidepressant medications be generalized to clinical practice? A STAR*D report. Am. J. Psychiatry 166, 599–607 (2009).

  26. 26.

    et al. Validation of electronic health record phenotyping of bipolar disorder cases and controls. Am. J. Psychiatry 172, 363–372 (2015).

  27. 27.

    et al. Web-based, participant-driven studies yield novel genetic associations for common traits. PLoS Genet. 6, e1000993 (2010).

  28. 28.

    et al. Efficient replication of over 180 genetic associations with self-reported medical data. PLoS One 6, e23473 (2011).

  29. 29.

    1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).

  30. 30.

    & Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am. J. Hum. Genet. 81, 1084–1097 (2007).

  31. 31.

    , & minimac2: faster genotype imputation. Bioinformatics 31, 782–784 (2015).

  32. 32.

    , , & Ancestry Composition: a novel, efficient pipeline for ancestry deconvolution. Preprint at bioRxiv (2014).

  33. 33.

    et al. Cryptic distant relatives are common in both isolated and cosmopolitan genetic samples. PLoS One 7, e34267 (2012).

  34. 34.

    , & ARPACK Users' Guide: Solution of Large-Scale Eigenvalue Problems with Implicitly Restarted Arnoldi Methods (SIAM, 1998).

  35. 35.

    , & Improving the power of GWAS and avoiding confounding from population stratification with PC-Select. Genetics 197, 1045–1049 (2014).

  36. 36.

    et al. Gene expression analysis identifies global gene dosage sensitivity in cancer. Nat. Genet. 47, 115–125 (2015).

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We would like to thank the research participants and employees of 23andMe for making this work possible. The authors thank the investigators and patient participants of the Psychiatric Genomic Consortium Major Depressive Disorder study for making the PGC MDD phase 1 results available for download. This study was supported in part by Pfizer, Inc. R.H.P. is supported in part by the National Institute of Mental Health and the National Human Genome Research Institute (P50 MH106933). We also thank the Social Science Genetics Association Consortium (SSGAC) for sharing results for subjective well-being, depressive symptoms, and neuroticism.

Author information

Author notes

    • Ashley R Winslow

    Present address: Orphan Disease Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.


  1. Statistics, Pfizer Global Research and Development, Pfizer, Inc., Cambridge, Massachusetts, USA.

    • Craig L Hyde
    •  & Xing Chen
  2. Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Pfizer, Inc., Cambridge, Massachusetts, USA.

    • Michael W Nagle
    • , Sara A Paciga
    • , Jens R Wendland
    •  & Ashley R Winslow
  3. 23andMe, Inc., Mountain View, California, USA.

    • Chao Tian
    • , Joyce Y Tung
    •  & David A Hinds
  4. Center for Experimental Drugs and Diagnostics, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Roy H Perlis


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A.R.W., C.L.H., and J.R.W. conceived the meta-analysis and statistical analysis. A.R.W., C.L.H., and R.H.P. oversaw data set analysis and primary data interpretation. C.L.H. designed and performed meta-analysis and further statistical analysis of the three data sets. X.C. provided statistical support and data visualization for the meta-analysis. M.W.N. provided DEPICT functional annotation and LD score regression analyses. R.H.P., A.R.W., and C.L.H. wrote the manuscript. A.R.W., R.H.P., C.L.H., D.A.H., S.A.P., and M.W.N. provided data interpretation and revised the manuscript. J.Y.T. and D.A.H. conceived and designed the 23andMe MDD GWAS. D.A.H. and C.T. performed GWAS for 23andMe data sets and statistical support.

Competing interests

R.H.P. has served on scientific advisory boards for or consulted to Genomind, Healthrageous, Perfect Health, Proteus Biomedical, Psybrain, and RID Ventures and receives royalties through Massachusetts General Hospital from Concordant Rater Systems (now Bracket). C.L.H., X.C., M.W.N., and S.A.P. are all employees and stockholders of Pfizer, Inc. C.T., D.A.H., and J.Y.T. are employees of and own stock or stock options in 23andMe, Inc. A.R.W. is a former employee and stockholder of Pfizer, Inc., and a current employee of the Perelman School of Medicine at the University of Pennsylvania Orphan Disease Center in partnership with the Loulou Foundation. J.R.W. is a former employee and stockholder of Pfizer, Inc., and a current employee and stockholder of Nestlé Health Science.

Corresponding authors

Correspondence to David A Hinds or Roy H Perlis or Ashley R Winslow.

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    Supplementary Text and Figures

    Supplementary Figures 1 and 2.

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  1. 1.

    Supplementary Tables 1–11, 13 and 14

    Supplementary Tables 1–11, 13 and 14.

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    Supplementary Table 12

    Summary statistics from the most significant 10,000 SNPs from the 23andMe discovery data set.

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