Genome-wide association analysis reveals KCTD12 and miR-383-binding genes in the background of rumination

Abstract

Ruminative response style is a passive and repetitive way of responding to stress, associated with several disorders. Although twin and candidate gene studies have proven the genetic underpinnings of rumination, no genome-wide association study (GWAS) has been conducted yet. We performed a GWAS on ruminative response style and its two subtypes, brooding and reflection, among 1758 European adults recruited in the general population of Budapest, Hungary, and Manchester, United Kingdom. We evaluated single-nucleotide polymorphism (SNP)-based, gene-based and gene set-based tests, together with inferences on genes regulated by our most significant SNPs. While no genome-wide significant hit emerged at the SNP level, the association of rumination survived correction for multiple testing with KCTD12 at the gene level, and with the set of genes binding miR-383 at the gene set level. SNP-level results were concordant between the Budapest and Manchester subsamples for all three rumination phenotypes. SNP-level results and their links to brain expression levels based on external databases supported the role of KCTD12, SRGAP3, and SETD5 in rumination, CDH12 in brooding, and DPYSL5, MAPRE3, KCNK3, ATXN7L3B, and TPH2 in reflection, among others. The relatively low sample size is a limitation of our study. Results of the first GWAS on rumination identified genes previously implicated in psychiatric disorders underscoring the transdiagnostic nature of rumination, and pointed to the possible role of the dorsolateral prefrontal cortex, hippocampus, and cerebellum in this cognitive process.