Genome-wide meta-analyses of stratified depression in Generation Scotland and UK Biobank.
- Authors
- Hall, Lynsey S; Adams, Mark J; Arnau-Soler, Aleix; Clarke, Toni-Kim; Howard, David M; Zeng, Yanni; Davies, Gail; Hagenaars, Saskia P; Maria Fernandez-Pujals, Ana; Gibson, Jude; Wigmore, Eleanor M; Boutin, Thibaud S; Hayward, Caroline; Scotland, Generation; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Porteous, David J; Deary, Ian J; Thomson, Pippa A; Haley, Chris S; McIntosh, Andrew M
- Year
- 2018
- Journal
- Translational psychiatry
- PMID
- 29317602
- DOI
- 10.1038/s41398-017-0034-1
- PMCID
- PMC5802463
Few replicable genetic associations for Major Depressive Disorder (MDD) have been identified. Recent studies of MDD have identified common risk variants by using a broader phenotype definition in very large samples, or by reducing phenotypic and ancestral heterogeneity. We sought to ascertain whether it is more informative to maximize the sample size using data from all available cases and controls, or to use a sex or recurrent stratified subset of affected individuals. To test this, we compared heritability estimates, genetic correlation with other traits, variance explained by MDD polygenic score, and variants identified by genome-wide meta-analysis for broad and narrow MDD classifications in two large British cohorts - Generation Scotland and UK Biobank. Genome-wide meta-analysis of MDD in males yielded one genome-wide significant locus on 3p22.3, with three genes in this region (CRTAP, GLB1, and TMPPE) demonstrating a significant association in gene-based tests. Meta-analyzed MDD, recurrent MDD and female MDD yielded equivalent heritability estimates, showed no detectable difference in association with polygenic scores, and were each genetically correlated with six health-correlated traits (neuroticism, depressive symptoms, subjective well-being, MDD, a cross-disorder phenotype and Bipolar Disorder). Whilst stratified GWAS analysis revealed a genome-wide significant locus for male MDD, the lack of independent replication, and the consistent pattern of results in other MDD classifications suggests that phenotypic stratification using recurrence or sex in currently available sample sizes is currently weakly justified. Based upon existing studies and our findings, the strategy of maximizing sample sizes is likely to provide the greater gain.
Manhattan plot of P-values from SNP-based association meta-analysis of all depression cases and controls (MDD, n = 43 062), recurrent only cases and all controls (rMDD, n = 39 556), females only cases and controls (fMDD, n = 23 169) and males only cases and controls (mMDD, n = 19 886). The blue line indicates the threshold for genome-wide significance (P < 5 × 10-8), the red line indicates the threshold for suggestive significance (P < 1 × 10-5)
Regional association plot for rs4478037, an intronic SNP in CRTAP, and the top ranking SNP (rs4478037, P = 2.37 × 10-8) in GWAS of depression in males only
Genetic correlation (rG) between meta-analyzed MDD subsets and other health-related traits, derived using GWAS summary statistics and LD score regression. Traits presented showed a significant rG with MDD subsets after multiple testing correction (FDR p ≤ 0.05) and are coloured by category (personality, psychiatric, reproductive and autoimmune). No rG between mMDD and other health-related traits survived multiple testing correction
Heat map of associations between the polygenic profiles scores (PGS) for major depressive disorder (MDD), derived from Psychiatric Genomics Consortium (PGC) MDD29, UK Biobank (UKB) and Generation Scotland: The Scottish Family Health Study (GS:SFHS), and MDD subsets in UKB and GS:SFHS. Stronger associations are indicated by darker shades. The amount of variance (%) explained by PGS is indicated for each association. Further information can be found in Supplementary Tables 15-18
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