Abstract
CADM2 has been associated with a range of behavioural and metabolic traits, including physical activity, risk-taking, educational attainment, alcohol and cannabis use and obesity. Here, we set out to determine whether CADM2 contributes to mechanisms shared between mental and physical health disorders. We assessed genetic variants in the CADM2 locus for association with phenotypes in the UK Biobank, IMPROVE, PROCARDIS and SCARFSHEEP studies, before performing meta-analyses. A wide range of metabolic phenotypes were meta-analysed. Psychological phenotypes analysed in UK Biobank only were major depressive disorder, generalised anxiety disorder, bipolar disorder, neuroticism, mood instability and risk-taking behaviour. In UK Biobank, four, 88 and 172 genetic variants were significantly (p < 1 × 10−5) associated with neuroticism, mood instability and risk-taking respectively. In meta-analyses of 4 cohorts, we identified 362, 63 and 11 genetic variants significantly (p < 1 × 10−5) associated with BMI, SBP and CRP respectively. Genetic effects on BMI, CRP and risk-taking were all positively correlated, and were consistently inversely correlated with genetic effects on SBP, mood instability and neuroticism. Conditional analyses suggested an overlap in the signals for physical and psychological traits. Many significant variants had genotype-specific effects on CADM2 expression levels in adult brain and adipose tissues. CADM2 variants influence a wide range of both psychological and metabolic traits, suggesting common biological mechanisms across phenotypes via regulation of CADM2 expression levels in adipose tissue. Functional studies of CADM2 are required to fully understand mechanisms connecting mental and physical health conditions.
Highlights
We identified novel associations between cell adhesion molecule 2 (CADM2) genetic variants and SBP, CRP levels, neuroticism and mood instability, and have highlighted a possible link between SNPs associated with psychological traits and adiposity via CADM2 expression levels in adipose tissue
It is possible that the associations of CADM2 SNPs with CRP and SBP are secondary to the effects on obesity, as increased fat accumulation is associated with systemic inflammation[2] and reduced cardiovascular www.nature.com/scientificreports fitness[48]
Pleiotropy can be classified as biological, mediated or spurious[49]
Summary
Www.nature.com/scientificreports health behaviours, hormone dysregulation and shared genetic risk factors[1,2]. A number of potential shared pathways between mood disorders and cardiometabolic disease have been suggested, including abnormal circadian rhythms, hypothalamic-pituitary-adrenal (HPA) axis dysfunction and inflammation. Single nucleotide polymorphisms (SNPs) in the locus encoding the synaptic cell adhesion molecule 2 (CADM2) on chromosome 3 have been associated with a number of psychological traits, including educational attainment[3], alcohol consumption[4], cannabis use[5], physical activity habits[6], risk-taking behaviour[7,8], attention-deficit/hyperactivity disorder[9] and obesity[10]. Several lines of evidence point to CADM2 being the gene through which SNPs are having their effects, including genotype-specific effects on CADM2 mRNA expression levels[7,8], CADM2 being predominantly expressed in the brain, and cadm[2] knockout models demonstrating relevant phenotypes. We set out to systematically evaluate the relationship between CADM2 SNPs and psychological and physical traits, and assess whether there is evidence for distinct signals influencing metabolic versus psychological traits
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