Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies

Abstract

We report a genome-wide association study (GWAS) of major depressive disorder (MDD) in 1221 cases from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 1636 screened controls. No genome-wide evidence for association was detected. We also carried out a meta-analysis of three European-ancestry MDD GWAS data sets: STAR*D, Genetics of Recurrent Early-onset Depression and the publicly available Genetic Association Information Network-MDD data set. These data sets, totaling 3957 cases and 3428 controls, were genotyped using four different platforms (Affymetrix 6.0, 5.0 and 500 K, and Perlegen). For each of 2.4 million HapMap II single-nucleotide polymorphisms (SNPs), using genotyped data where available and imputed data otherwise, single-SNP association tests were carried out in each sample with correction for ancestry-informative principal components. The strongest evidence for association in the meta-analysis was observed for intronic SNPs in ATP6V1B2 (P=6.78 x 10⁻⁷), SP4 (P=7.68 x 10⁻⁷) and GRM7 (P=1.11 x 10⁻⁶). Additional exploratory analyses were carried out for a narrower phenotype (recurrent MDD with onset before age 31, N=2191 cases), and separately for males and females. Several of the best findings were supported primarily by evidence from narrow cases or from either males or females. On the basis of previous biological evidence, we consider GRM7 a strong MDD candidate gene. Larger samples will be required to determine whether any common SNPs are significantly associated with MDD.

Figure 1. Overview of STAR*D GWAS results for 260,474 SNPs

(A) Q-Q plot of observed vs. expected -log (P-value). λ, the genomic inflation factor, is estimated at 1.022. (B) Manhattan plot of all results by chromosomal location.

Figure 2. Meta-analysis results

Shown are association test results (-log₁₀[P-values] on the Y-axis) for the meta-analyses of the GenRED, STAR*D and GAIN MDD datasets, for the Broad phenotype (primary analysis) and the Narrow phenotype (recurrent early-onset cases). The X-axis shows the start position of each chromosome. Plots for males and females separately are available in online Supplementary Figures S15 and S16.

Figure 3. Best-supported regions in the meta-analysis

Shown are plots of association test results (males+females unless noted otherwise) for the three gene-containing regions with the lowest P-values in the primary (Broad) meta-analysis (see Table 5): ATP6V1B2 (Panel A), SP4 (B), GRM7 (C). Shown in each panel from top to bottom are: an ideogram of the chromosome with the plotted area marked in red; locations in base pairs; RefSeq genes with arrows representing direction of transcription; association test results as the -log10 of the P-value for each genotyped and imputed SNP; and color-coded marker-marker linkage disequiibrium results for phased HapMap II CEU genotypes (UCSC browser). Similar plots for additional top findings are available as online Supplementary Figures.