The genetic architecture of depression in samples with East Asian ancestry

Importance: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European (EUR) descent. This limits our understanding of the underlying biology of depression and raises questions about the transferability of findings between populations. Objectives: to investigate the genetics of depression across East Asian and European cultural contexts and outcome definitions. Design: Genome-wide association studies, followed by meta-analysis. Setting: Nine cohort and case-control studies from China, Taiwan, USA and UK. Participants: 15,771 depression cases and 178,777 controls of East Asian descent (EAS). Exposures: Associations of genetic variants with depression risk were assessed using generalised linear mixed models and logistic regression. The results were combined across studies using fixed effects meta-analyses. These were subsequently also meta-analysed with the largest published GWAS for depression in EUR samples. Additional meta-analyses were carried out separately by outcome definition (clinical vs symptom-based) and region (East Asian countries vs Western countries). Main outcomes and measures: Depression status was defined based on health records and self-report questionnaires. Results: In total we identified five novel associations, including one in the EAS meta-analysis for broad depression: rs4656484 (beta=-0.018, SE=0.003, P=4.43x10-8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (P=5.03x10-9). Both associations were specific to EAS samples (P=0.53 and P=0.28 in EUR, respectively). Only 11% of depression loci previously identified in EUR reached nominal significance levels in the EAS samples. The trans-ancestry genetic correlation estimates with depression in EUR ranged from 0.223 to 0.558, depending on the outcome definition. Clinical depression risk was negatively genetically correlated with BMI in EAS (rg=-0.212), contrary to findings from EUR samples. Conclusions and relevance: Our results suggest that cultural differences further add to the heterogeneity of depression and thereby impact on the genetic architecture. This cautions against generalising findings about depression risk factors across populations and highlights the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.