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.

CNS microRNA profiles: a database for cell type enriched microRNA expression across the mouse central nervous system

“…This includes Rett syndrome 23 , fragile X syndrome 24 , bipolar disorder 25 and schizophrenia 26 . Further genomic-level analyses have revealed that the miR-383 locus and target genes are associated with an increased risk for autism spectrum disorder and linked behaviors, such as rumination 27,28 . These studies suggest that alterations in miR-383 levels and its corresponding targets may be detrimental to maintaining the proper function of neurons, particularly excitatory cortical neurons.…”

Catenin Alpha 2 May Be a Biomarker or Potential Drug Target in Psychiatric Disorders with Perseverative Negative Thinking

“…Although the genetic background of rumination has been extensively investigated in previous studies [ 27 , 28 , 29 ], only a few studies have considered the possible endophenotypic nature of rumination, namely its putative causal role on the pathways between specific genes and specific disorders. These few studies, implicating the roles of synaptic plasticity candidate genes BDNF [ 30 ] and CREB1 [ 31 ], as well as serotonin receptor gene HTR2A [ 28 ] and folate pathway gene MTHFD1L [ 32 ], have exclusively focused on depression as a relevant disorder, or on depressive symptoms.…”

Sculpting Dendritic Spines during Initiation and Maintenance of Neuropathic Pain

“…If the truncation of srGAP3 occurs after the IF-BAR domain, then intellectual disability does not occur and patients are otherwise normal (Ba et al, 2013;Ellery et al, 2014). Additionally, microduplication of the 3p25 locus of the srGAP3 gene has been associated with hereditary psychotic illness, further implicating srGAP3 in neuronal processing (Wilson et al, 2011;Waltereit et al, 2012;Eszlari et al, 2019). This association was confirmed in an animal model in which mice lacking a critical exon within the IF-BAR domain coding region exhibited profound deficits in learning and memory-related functions (Carlson et al, 2011).…”