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

Abstract

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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Figure 1: Discovery-phase meta-analysis of 23andMe self-report ascertainment of major depression (75,607 cases and 231,747 controls) and PGC MDD (9,240 cases and 9,519 controls).
Figure 2: Regional association plots for genome-wide-significant regions and secondary independent signals identified in each region.

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Acknowledgements

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.

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Authors

Contributions

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.

Corresponding authors

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

Ethics declarations

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.

Integrated supplementary information

Supplementary Figure 1 Discovery-phase GWAS of 23andMe self-report ascertainment of major depression (75,607 cases and 231,747 controls).

Manhattan plot of 23andMe self-report ascertainment of major depression (75,607 cases and 231,747 controls). The threshold for genome-wide significance (P < 1 × 10−8) is indicated by the horizontal line. Red dots represent SNPs with P values smaller than the genome-wide significance threshold. Peaks with P values less than 5 × 10−8 (standard GWAS significance threshold) are labelled in black. (b) Quantile–quantile plot for the 23andMe MDD GWAS.

Supplementary Figure 2 The proportion of variance explained by each principal component in the subset of 23andMe participants with European ancestry.

(a,b) The proportion of variance explained by each principal component (a) and the proportion of each component’s variance that is explained by country of ancestry, for a set of individuals reporting four grandparents from a single country (b). The first five principal components are largely explained by geographical ancestry, whereas higher-order principal components are not.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2. (PDF 238 kb)

Supplementary Tables 1–11, 13 and 14

Supplementary Tables 1–11, 13 and 14. (XLSX 80 kb)

Supplementary Table 12

Summary statistics from the most significant 10,000 SNPs from the 23andMe discovery data set. (XLSX 1012 kb)

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Hyde, C., Nagle, M., Tian, C. et al. Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nat Genet 48, 1031–1036 (2016). https://doi.org/10.1038/ng.3623

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