Genetic Variation in the ASTN2 Locus in Cardiovascular, Metabolic and Psychiatric Traits: Evidence for Pleiotropy Rather Than Shared Biology

Abstract

Background: The link between cardiometabolic and psychiatric illness has long been attributed to human behaviour, however recent research highlights shared biological mechanisms. The ASTN2 locus has been previously implicated in psychiatric and cardiometabolic traits, therefore this study aimed to systematically investigate the genetic architecture of ASTN2 in relation to a wide range of relevant traits. Methods: Baseline questionnaire, assessment and genetic data of 402111 unrelated white British ancestry individuals from the UK Biobank was analysed. Genetic association analyses were conducted using PLINK 1.07, assuming an additive genetic model and adjusting for age, sex, genotyping chip, and population structure. Conditional analyses and linkage disequilibrium assessment were used to determine whether cardiometabolic and psychiatric signals were independent. Results: Associations between genetic variants in the ASTN2 locus and blood pressure, total and central obesity, neuroticism, anhedonia and mood instability were identified. All analyses support the independence of the cardiometabolic traits from the psychiatric traits. In silico analyses provide support for the central obesity signal acting through ASTN2, however most of the other signals are likely acting through other genes in the locus. Conclusions: Our systematic analysis demonstrates that ASTN2 has pleiotropic effects on cardiometabolic and psychiatric traits, rather than contributing to shared pathology.

Comprehensive analysis of genetic associations and single-cell expression profiles reveals potential links between migraine and multiple diseases: a phenome-wide association study

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Identification and validation of key genes associated with atrial fibrillation in the elderly

“…Behesti et al ( 37 ) demonstrated that ASTN2 binds to and regulates the surface expression of multiple synaptic proteins in postmigratory neurons by endocytosis, resulting in the modulation of synaptic activity. In addition, by systematic analysis, Burt et al ( 38 ) found that ASTN2 has pleiotropic effects on cardiometabolic and psychiatric traits. However, ASTN2 role in AF remains unclear.…”

Candidate genes for domestication and resistance to cold climate according to whole genome sequencing data of Russian cattle and sheep breeds

“…At the same time, deletion in the ASTN2 gene results in a reversal of normal orientation of hair follicles in adult mice (parallel to "from head to tail") to the opposite direction (parallel to "from tail to head") (Chang et al, 2015). In humans, the ASTN2 gene is associated with the level of triglycerides in the blood (Jiao et al, 2015) and the development of obesity (Burt et al, 2021). Signatures of selection in this gene have been found in ethnic groups of southern Ethiopia, who have lived in high-altitude conditions for over a thousand years (Scheinfeldt et al, 2012).…”