Sex-stratified genome-wide association meta-analysis of major depressive disorder

Abstract

There are striking sex differences in the prevalence and symptomology of Major Depressive Disorder. Here, we conduct the largest sex-stratified genome wide association and genotype-by-sex interaction meta-analyses of Major Depressive Disorder to date (Females: 130,471 cases, 159,521 controls. Males: 64,805 cases, 132,185 controls). We identify 16 and eight independent genome-wide significant variants in females and males, respectively, including one novel variant on the X chromosome. Major Depressive Disorder in females and males shows substantial genetic overlap with a large proportion of variants displaying similar effect sizes across sexes. However, we also provide evidence for a higher burden of genetic risk in females which could be due to female-specific variants. Additionally, sex-specific pleiotropic effects may contribute to the higher prevalence of metabolic symptoms in females with Major Depressive Disorder. These findings underscore the importance of considering sex-specific genetic architectures in the study of health conditions, including Major Depressive Disorder, paving the way for more targeted treatment strategies.

Fig. 1. Miami plot of sex-stratified genome-wide association study (GWAS) meta-analysis of Major Depressive Disorder (MDD), with female and male meta-analyses shown on the top and bottom, respectively.

The two-sided, unadjusted –log10 p values for GWAS results of each single nucleotide polymorphism (SNP) are shown with positions according to human genome build 37 (GRCh37 assembly). Chromosome 23 is the X chromosome. The darker grey and lighter grey dotted horizontal lines indicate genome-wide significance (P = 5 × 10⁻⁸) and nominal significance (P = 1 × 10⁻⁶), respectively. SNPs in dark purple indicate the lead independent genome-wide significant SNPs, and any SNPs in linkage disequilibrium with them. Females: 130,471 cases, 159,521 controls. Males: 64,805 cases, 132,185 controls.

Fig. 2. Comparisons of genetic architecture and polygenic overlap across the two sexes.

a Autosomal SNP-based heritability (h_SNP) on the liability scale using a population prevalence of 0.1 in males and 0.2 in females, b Polygenicity, and (c) Selection parameter. d Autosomal SNP-based genetic correlation (r_g) between males and females using our sex-stratified meta-analysis results, and meta-analysis of r_g estimated in all six male-female within cohort, 30 male-female across cohort, 15 male-male across cohort and 15 female-female across cohort combinations. e Pearson correlation of the Major Depressive Disorder (MDD) effect sizes of SNPs known to be associated with sex-combined MDD for males vs females using our sex-stratified meta-analysis results, and meta-analysis of Pearson correlations estimated in all six male-female within cohort, 30 male-female across cohort, 15 male-male across cohort and 15 female-female across cohort combinations. f Venn diagram depicting the number of causal variants explaining 90% of MDD h²_SNP in females only, males only, or both sexes, as identified by MiXeR. g Venn diagram depicting the number of genomic regions that contain a causal variant for MDD in females only, males only or both sexes, as identified by gwas-pw. Females or female-female comparisons are in yellow, males or male-male comparisons in dark purple and female-male comparisons in green. For a–c a Bayesian framework was used. Estimates were obtained using SBayesS with summary statistics from the sex-stratified GWAS meta-analysis (females: 130,471 cases and 159,521 controls; males: 64,805 cases and 132,185 controls). Violin plots display the posterior distributions, points represent the mean posterior value, error bars are the 95% highest posterior density interval and percentages are the posterior probability that female value > male value. For d and e frequentist statistics were used. Background points represent individual values from each study included in the meta-analysis, and overlaid points and error bars represent the mean estimate and 95% confidence interval from the meta-analysis. Stars represent the r_g / R being significantly different to 1, based on a two-sided Z-test with p values adjusted for five comparisons using the Benjamini-Hochberg method. Exact p-values are provided in the Results section.

Fig. 3. Manhattan plot of genome-wide genotype-by-sex (GxS) interaction meta-analysis for Major Depressive Disorder (MDD).

The two-sided, unadjusted –log10 p values for GxS results of each single nucleotide polymorphism (SNP) are shown with positions according to human genome build 37 (GRCh37 assembly). Chromosome 23 is the X chromosome. The darker grey and lighter grey dotted horizontal lines indicate genome-wide significance (P = 5 × 10⁻⁸) and nominal significance (P = 1 × 10⁻⁶), respectively. SNPs in dark purple indicate the lead independent nominally significant SNPs, and any SNPs in linkage disequilibrium with them. Females: 130,471 cases, 159,521 controls. Males: 64,805 cases, 132,185 controls.

Fig. 4. Genetic correlations (r_g) and polygenic overlap to identify sex-specific pleiotropy.

a R_g of Major Depressive Disorder (MDD) in females and males with other psychiatric disorders, metabolic and substance use traits. b R_g of MDD in females and males with BMI in females and males. c Venn diagrams depicting the number of causal variants explaining 90% of h²_SNP in MDD only, BMI/metS only, or both traits as identified by MiXeR in females (yellows) and males (purples). d Venn diagrams depicting the number of genomic regions that contain a causal variant for both MDD and BMI/metS in females only, both sexes, or males only as identified in gwas-pw. Females are in yellow and males in dark purple. R_g in panels a, b were estimated using linkage disequilibrium score regression (LDSC) using our sex-stratified GWAS summary statistics (Females: 130,471 cases, 159,521 controls. Males: 64,805 cases, 132,185 controls) and publicly available GWAS datasets for the other traits (Supplementary Data 21). Points represent the r_g point estimates and error bars denote the 95% confidence interval. Stars indicate a significant difference in r_g between females and males for a given trait, assessed using the jack-knife method and a two-sided Z-test on the difference in r_g across the 200 jack-knife pseudo-values. P values were adjusted using the Benjamini Hochberg method for 11 tests (all traits, panel a) or two tests (sex-specific BMI, b). Exact p values are provided in Supplementary Data 23 and 25. PTSD = post-traumatic stress disorder, ADHD = attention deficit hyperactivity disorder, BMI = body mass index, Waist/hip ratio = waist to hip ratio adjusted for BMI, metS = metabolic syndrome.