Genome wide association study identifies KCNMA1contributing to human obesity

Abstract

BackgroundRecent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity.MethodsWe performed a GWA analysis in 164 morbidly obese subjects (BMI:body mass index > 40 kg/m2) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for14 adults.ResultsPotassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830*G and BDNF rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830*G with P = 2.82 × 10-10 and an odds ratio (OR) based on cases vs controls of 1.26 [95% C.I. 1.12-1.41] and for BDNF rs988712*G with P = 5.2 × 10-17and an OR of 1.36 [95% C.I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P = 0.0001) and fat cell (P = 0.04) expression of KCNMA1 was increased in obesity.ConclusionsWe have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level.

Investigating causality in associations between smoking initiation and schizophrenia using Mendelian randomization

“…However, this result was somewhat hard to interpret as only four SNPs were used in this risk score, and all of these were from the same gene region ( BDNF ). These SNPs are all highly correlated, and although correlation was taken in to account in the MR model, the risk of biological pleiotropy (i.e., an effect of gene on the outcome not via smoking) was much harder to rule out; BDNF and its associated SNPs have reached genomewide significance in a number of other GWAS, including those of obesity and body mass index1920, and caffeine consumption21.…”

Gene and environment interaction: Is the differential susceptibility hypothesis relevant for obesity?

“…Genome-wide Association Studies (GWAS) have made significant headway in identifying genetic variants underlying obesity (Cotsapas et al , 2009; Meyre et al , 2009; Jiao et al , 2011; Paternoster et al , 2011; Wang et al , 2011; Melka et al , 2012; Pei et al , 2014; Locke et al , 2015). However, most of these studies focused on body mass index as the main outcome, failing to take into consideration behavioral differences that can precede the development of obesity.…”

Transduction of Voltage and Ca2+Signals by Slo1 BK Channels

“…Other physiological phenomena involving BK channels include skeletal muscle fatigue (75,155), regulation of circadian rhythm (96), ethanol tolerance (27), and nociception (48). As expected from these diverse roles, a variety of pathological consequences may arise from BK channel dysfunction, including erectile dysfunction (166), incontinence (166), hypertension (18, 43), epilepsy (32), dyskinesia (32), seizure (16), asthma (136), and possibly obesity (68). Consequently, pharmaceutical agents targeting BK channels may prove therapeutically useful (33, 101).…”