Abstract
Neuroticism is associated with poor health, cardiovascular disease (CVD) risk factors and coronary artery disease (CAD). The conditional/conjunctional false discovery rate method (cond/conjFDR) was applied to genome wide association study (GWAS) summary statistics on neuroticism (n = 432,109), CAD (n = 184,305) and 12 CVD risk factors (n = 188,577–339,224) to investigate genetic overlap between neuroticism and CAD and CVD risk factors. CondFDR analyses identified 729 genomic loci associated with neuroticism after conditioning on CAD and CVD risk factors. The conjFDR analyses revealed 345 loci jointly associated with neuroticism and CAD (n = 30), body mass index (BMI) (n = 96) or another CVD risk factor (n = 1–60). Several loci were jointly associated with neuroticism and multiple CVD risk factors. Seventeen of the shared loci with CAD and 61 of the shared loci with BMI are novel for neuroticism. 21 of 30 (70%) neuroticism risk alleles were associated with higher CAD risk. Functional analyses of the genes mapped to the shared loci implicated cell division, nuclear receptor, elastic fiber formation as well as starch and sucrose metabolism pathways. Our results indicate polygenic overlap between neuroticism and CAD and CVD risk factors, suggesting that genetic factors may partly cause the comorbidity. This gives new insight into the shared molecular genetic basis of these conditions.
Highlights
Neuroticism is a personality trait that involves the tendency to experience negative emotions[1], and is associated with psychiatric illnesses such as depression and anxiety disorders[2]
Polygenic overlap To visually determine the presence of polygenic enrichment across traits, which is a measure of polygenic overlap, we generated conditional Q–Q plots for neuroticism conditioned on coronary artery disease (CAD) and cardiovascular disease (CVD) risk factors, excluding CIGPRDAY
We identified 345 unique genetic loci underlying the shared genetic architecture, and increased the number of loci associated with neuroticism to n = 729, due to the boost in power from combined analysis of genome wide association study (GWAS) from two phenotypes using the cond/conjFDR method
Summary
Neuroticism is a personality trait that involves the tendency to experience negative emotions[1], and is associated with psychiatric illnesses such as depression and anxiety disorders[2]. Some prospective clinical and epidemiological studies indicate that neuroticism increases the risk of coronary artery disease (CAD) and mortality compared to the general population[5,6]. The mechanisms underlying the associations between neuroticism and CVD risk factors and CAD are not known. Neuroticism may contribute to CAD through behavioral mechanisms such as poor health-related behaviors (smoking, sedentary life style, and unhealthy diet) and low adherence to medication and rehabilitation[10,11]. Different biological pathways have been proposed to explain the higher incidence of CAD in people with neuroticism; dysregulation of the hypothalamic-pituitary-adrenal axis results in increased cortisol levels due to stress, leading to higher daytime cortisol levels which in turn elevates blood pressure, autonomic dysregulation, subclinical inflammation and oxidative stress, while reducing the number of stem cells[11]. It has been hypothesized that the association between neuroticism and CAD, and its related risk
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