Genetic variation in circadian regulator gene BMAL1 in psychiatric, psychological and cardiometabolic traits: a trans-ancestry UK Biobank study

Abstract

Background: The link between cardiometabolic disease and mental illness has been well established but remains incompletely explained. One hypothesis suggests that circadian rhythm dysregulation links cardiometabolic disease and mental illnesses. BMAL1 is a circadian rhythm regulatory gene. Human genetic studies have implicated BMAL1 in depression, schizophrenia, bipolar disorder as well as body mass index, blood pressure and lipid levels.

Objective: We investigated the BMAL1 locus genetic variants for associations with both cardiometabolic and mental illness.

Methods: Genetic and phenotypic data from UK Biobank (~500 000 participants) of White British, African-Caribbean, South Asian, white European and Multiple ancestries were used. Regression analyses using Plink 1.09 was used to identify significant associations, with Bonferroni multiple testing correction. Multiple ancestry meta-analyses using METAL software was used to investigate trans-ancestry consistency in genetic effects.

Findings: We identified associations for body mass index, anhedonia, diastolic and systolic blood pressure, waist-hip ratio, major depressive disorder, neuroticism and risk-taking. Meta-analyses indicated that there are ancestry-wide and ancestry-specific effects on cardiometabolic, mental illness and related traits.

Conclusions: Our results suggest that the associations for mental illness (and related traits) and those for cardiometabolic traits are distinct rather than shared and that these associations were consistent across ancestry groups.

Clinical implications: Further investigation into the tissue-specific roles of BMAL1 is required to fully understand the clinical impact of these findings.

Keywords: Cross-Sectional Studies; Data Interpretation, Statistical; PSYCHIATRY.

Figure 1. Regional association plots of meta-analyses results of (A) neuroticism score, (B) neuroticism score (Isq=0), (C) risk-taking, (D) T2D, (E) DBPadj, (F) DBPadj (Isq=0), (G) SBPadj, (H) SBPadj (Isq=0), (I) BMI, (J) BMI (Isq=0), (K) WHR, (L) WHR (Isq=0). The lead variant is represented by a purple diamond. The other variants are colours according to LD r² values. The horizontal dashed line represents the Bonferonni-corrected threshold for significance. BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure; T2D, type 2 diabetes; WHR, waist:hip ratio.