Genome-wide association studies of antidepressant class response and treatment-resistant depression

Abstract

The "antidepressant efficacy" survey (AES) was deployed to > 50,000 23andMe, Inc. research participants to investigate the genetic basis of treatment-resistant depression (TRD) and non-treatment-resistant depression (NTRD). Genome-wide association studies (GWAS) were performed, including TRD vs. NTRD, selective serotonin reuptake inhibitor (SSRI) responders vs. non-responders, serotonin-norepinephrine reuptake inhibitor (SNRI) responders vs. non-responders, and norepinephrine-dopamine reuptake inhibitor responders vs. non-responders. Only the SSRI association reached the genome-wide significance threshold (p < 5 × 10^-8): one genomic region in RNF219-AS1 (SNP rs4884091, p = 2.42 × 10^-8, OR = 1.21); this association was also observed in the meta-analysis (13,130 responders vs. 6,610 non-responders) of AES and an earlier "antidepressant efficacy and side effects" survey (AESES) cohort. Meta-analysis for SNRI response phenotype derived from AES and AESES (4030 responders vs. 3049 non-responders) identified another genomic region (lead SNP rs4955665, p = 1.62 × 10^-9, OR = 1.25) in an intronic region of MECOM passing the genome-wide significance threshold. Meta-analysis for the TRD phenotype (31,068 NTRD vs 5,714 TRD) identified one additional genomic region (lead SNP rs150245813, p = 8.07 × 10^-9, OR = 0.80) in 10p11.1 passing the genome-wide significance threshold. A stronger association for rs150245813 was observed in current study (p = 7.35 × 10^-7, OR = 0.79) than the previous study (p = 1.40 × 10^-3, OR = 0.81), and for rs4955665, a stronger association in previous study (p = 1.21 × 10^-6, OR = 1.27) than the current study (p = 2.64 × 10^-4, OR = 1.21). In total, three novel loci associated with SSRI or SNRI (responders vs. non-responders), and NTRD vs TRD were identified; gene level association and gene set enrichment analyses implicate enrichment of genes involved in immune process.

Fig. 1. Genome-wide significant association signals.

(A) Manhattan plots for SSRI GWAS in AES cohort; (B) SNRI responders vs. non-responders GWAS meta-analysis; (C) NTRD vs. TRD GWAS meta-analysis; (D) Regional plot for chromosome 13; (E) Regional plot for chromosome 3; (F) Regional plot for chromosome 10; (G) Circos plot for chromosomes 13; (H) Circos plot for chromosomes 3; (I) Circos plot for chromosomes 10. The dotted line indicates genome-wide significance threshold of 5 × 10⁻⁸. For the regional association plot generated by LocusZoom, SNPs in genomic risk loci are color-coded as a function of their r² to the index SNP in the locus, as follows: red (r² > 0.8), orange (r² > 0.6), green (r² > 0.4) and light blue (r² > 0.2). SNPs that are not in LD with the index SNP (with r² ≤ 0.2) are dark blue, while SNPs with missing LD information are shown in gray. For the circos plot, the outer most layer is Manhattan plot and the middle layer highlights genomic risk loci (as defined by FUMA using minimum P-value of lead SNPs of 1 × 10^-5 and default values for other parameters) in blue in, while the inner most layer highlights eQTLs and/or chromatin interactions. Only SNPs with p < 0.05 are displayed in the outer ring. SNPs in genomic risk loci are color-coded as a function of their maximum r² to the one of the independent significant SNPs in the locus, as follows: red (r² > 0.8), orange (r² > 0.6), green (r² > 0.4) and blue (r² > 0.2). SNPs that are not in LD with any of the independent significant SNPs (with r² ≤ 0.2) are gray. The rsID of the top SNPs in each risk locus are displayed in the most outer layer. For the inner most layer, if the gene is mapped only by chromatin interactions or only by eQTLs, it is colored orange or green, respectively. It is colored red when the gene is mapped by both. AES Antidepressant Efficacy Survey, GWAS genome-wide association analysis, SSRI selective serotonin reuptake inhibitor, SNRI serotonin-norepinephrine reuptake inhibitor, TRD treatment-resistant depression.