The Genetic Architecture of Depression in Individuals of East Asian Ancestry: A Genome-Wide Association Study

Abstract

Importance: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations.

Objective: To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression.

Design, setting, and participants: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021.

Exposures: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts.

Main outcomes and measures: Depression status was defined based on health records and self-report questionnaires.

Results: There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = -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 (β = 0.028, SE = 0.005, P = 6.48x10-9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = -0.003, SE = 0.005, P = .53 for rs4656484 and β = -0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent.

Conclusions and relevance: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.

Figure 1.. Manhattan Plot of the Genetic Associations With Depression in Ancestrally East Asian Samples Using All 9 Studies and the Transancestry Meta-analysis Between East Asian and European Ancestry Samples

The y-axes show the −log₁₀P values of the association between each single-nucleotide variant and the outcome. The x-axes show the chromosomal position (GRCh37). The red line represents the genome-wide significance threshold of 5 x 10⁻⁸ and the blue line, 10⁻⁵.

Figure 2.. Regional Association Plots of the Depression Associations for 1q24.1 and 7p21.2

The y-axes show the −log₁₀P values of the association between each SNV and the outcome. The x-axes show the chromosomal position (GRCh37). A Genetic associations for 1q24.1 in the meta-analysis of all 9 studies with ancestrally East Asian samples. B, Genetic associations for 7p21.2 in studies conducted in East Asian countries. C, Genetic associations for 1q24.1 in the largest European depression GWAS. D, Genetic associations for 7p21.2 based on the largest European depression GWAS. The purple diamond shows the lead SNV in each region; the color coding depicts the linkage disequilibrium with the lead SNV based on the 1000 Genomes East Asian reference panel.

Figure 3.. Genetic Correlations for Clinical and Symptom-Based Depression With Cardiometabolic and Mental Health Traits

Correlations are shown for samples with East Asian ancestry (A) and European ancestry (B) for the depression studies. For the cardiometabolic and mental health traits, publicly available summary statistics from studies with European ancestry samples were used. Blue bars represent the clinical outcome definition, and orange bars the symptom-based outcome. BMI indicates body mass index; CAD, coronary artery disease; T2D, type 2 diabetes. ^aGenetic correlations statistically different from zero.