BMAL1 Genetic Variation in Metabolic and Mental Health

Abstract

Aims Epidemiological studies have previously shown a link between cardiometabolic disease and severe mental illness. The extent and mechanisms behind this link are poorly understood currently but links to impairments in the stress response and cortisol regulation have been thought to play a significant role. BMAL1 is a circadian rhythm regulation gene found on chromosome 11 which has been associated with a variety of pro-inflammatory states as well as conditions such as depression, schizophrenia, type 2 diabetes mellitus and myocardial infarction. Our study aimed to investigate the genetic structure of the BMAL1 gene locus and its associations with both cardiometabolic and psychiatric traits and conditions. Methods We used genetic data from the UK Biobank which recruited ~500,000 participants. Of these we used a population of ~430,000 self-reported white British participants and data from a variety of questionnaires and investigations looking at severe mental illness and cardiometabolic traits. We performed association analyses using Plink 1.07 with Bonferroni correction being performed for multiple testing using a number of genetic variants. Our threshold for significance was defined as a p-value < 5.35 × 10−5. Conditional analysis was then performed to identify if there were multiple independent signals for each phenotype. Results BMAL1 variants were associated with BMI, diastolic, systolic blood pressure, waist-hip ratio and neuroticism score, and risk of anhedonia, major depressive disorder and risk-taking behaviour. Multiple significant independent signals were identified for BMI and waist-hip ratio. Linkage disequilibrium (LD) analysis showed significant coinheritance of specific traits which could suggest a role for BMAL1 and the encoded protein as a link between cardiometabolic and mental health traits. Conclusion This is the first study that systematically investigated associations between the BMAL1 locus across a variety of different mental and cardiometabolic phenotypes in a population-level cohort. Our study has shown that there is a link between the BMAL1 locus and both cardiometabolic and mental health phenotypes. Further research is required to investigate the exact biological mechanism by which BMAL1 connects severe mental illness and cardiometabolic disease.