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.
Highlights
Individuals with serious mental illnesses (SMI, such as schizophrenia, bipolar disorder, and major depressive disorder) suffer from physical diseases at a higher frequency than unaffected individuals and have excess mortality to reflect this—the life expectancy is 25 years shorter on average than the general population, largely attributable to cardiovascular disease [1,2]
We investigated the effects of lead single nucleotide polymorphisms (SNPs) on gene expression levels using GTEx data and the LDexpress tool
In conditional analyses, where the primary SNP from each analysis was included as a covariate, no secondary signals were observed for SBP (Figure 2B), but secondary signals were evident for DBP (rs34432054-T, primary analyses values 0.174 (0.038), p = 4.97 × 10−6
Summary
Individuals with serious mental illnesses (SMI, such as schizophrenia, bipolar disorder, and major depressive disorder) suffer from physical diseases at a higher frequency than unaffected individuals and have excess mortality to reflect this—the life expectancy is 25 years shorter on average than the general population, largely attributable to cardiovascular disease [1,2]. Non-genetic factors are commonly used to explain the co-existence between mental and cardiometabolic health conditions, such as lifestyle factors, illnessrelated factors, and treatment-related factors. Through numerous genome-wide association studies (GWAS), the ASTN2 locus has been identified as associated with both cardiometabolic and psychiatric traits. The ASTN2 locus has been previously implicated in psychiatric and cardiometabolic traits, this study aimed to systematically investigate the genetic architecture of ASTN2 in relation to a wide range of relevant traits. Results: Associations between genetic variants in the ASTN2 locus and blood pressure, total and central obesity, neuroticism, anhedonia and mood instability were identified. In silico analyses provide support for the central obesity signal acting through ASTN2, 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
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