Genetic variation in CADM2 as a link between psychological traits and obesity

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.

The Role of Genetic Variation of BMI, Body Composition, and Fat Distribution for Mental Traits and Disorders: A Look-Up and Mendelian Randomization Study

“…Cell adhesion molecule 2 (CADM2) belongs to the immunoglobulin superfamily and interacts with other cytoskeletal proteins (Biederer, 2006). It is predominantly expressed in the central and peripheral nervous systems (Pellissier et al, 2007;Morris et al, 2019; Supplementary Figure S3) and regulates, e.g., synapse formation (Rathjen et al, 2017). Obesity risk variants (Yan et al, 2018;Morris et al, 2019) were associated with increased CADM1 and CADM2 expression in the hypothalamus with a complex interplay of CADM1 and CADM2 (Rathjen et al, 2017).…”

“…The expression of both CADM1 and CADM2 in several neuronal circuits suggests an intertwining of body weight maintenance with motor control, but also behavioral aspects, cognition, and memory (Rathjen et al, 2017). In addition to associations with obesity risk genes (SNP rs13078807 located in the second intron of CADM2) novel associations of CADM2 genetic variants with systolic blood pressure (SBP), CRP levels (Morris et al, 2019), as well as with diverse psychological traits (neuroticism, mood instability, and risk-taking) have been detected. Interestingly, other loci identified by SNPs for BMI and/or body fat distribution in the current study are involved in the immune system, too ( Supplementary Table S8): ITIH4 (Murakami et al, 2015; locus 5, 3p21.1; BP, schizophrenia), SLC39A8 (Liu et al, 2013b; locus 9, 4q24; schizophrenia, intelligence), and HLA-DRB1 (Arango et al, 2017; locus 34, 6p21.32; schizophrenia).…”

Copy Number Variation of the CADM2 Gene and Its Association with Growth Traits in Yak

“…Secondly, body weight and energy metabolism are maintained by the central nervous system and previous studies have identified that CADM2 is expressed more abundantly in different regions of the brain than in any other tissue [52]. Furthermore, plenty of studies have reported that CADM2 can significantly improve body weight and decrease leptin sensitivity via the brain and adipose tissue [32,53]. Moreover, genome-wide association studies in humans have demonstrated clear evidence that the CADM2 gene is strongly associated with the body mass index through the encoding of membrane proteins that mediate synaptic assembly [31,52,54].…”

Does Cannabis Intake Protect Against Non-alcoholic Fatty Liver Disease? A Two-Sample Mendelian Randomization Study

“…These five independent genome-wide significant SNPs are located in CADM2, NCAM1, ATP2A1, ZNF704, and SMG6, which are associated with lifetime cannabis use (yes or no), were used as genetic instruments under the p-value threshold 5E-08. The CADM2 gene encodes a member of the synaptic cell adhesion molecules 1 family, and is associated with a range of behavioral and metabolic traits, such as educational attainment, alcohol and obesity (Morris et al, 2019). NCAM1 (Neural Cell Adhesion Molecule 1) belongs to the immunoglobin superfamily, and has been considered a susceptibility gene for schizophrenia and bipolar disorder (Chen et al, 2012).…”