Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Abstract

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci

“…As done in a previous large meta-analysis of BMI (Justice et al in press), trans-ethnic LD estimates were generated from a sample of 17,437 individuals from 1000 Genomes YRI (pilot), ARIC, MEC, HCHS/SOL and WHI, which was both closely proportionate to the racial/ethnic groups of our trans-ethnic meta-analysis (37% African, 26% Hispanic/Latino, 20% Asian, 17% European descent; compared to 35%, 26%, 22%, 18%, respectively, in the full trans-ethnic sample) and also representative of the PAGE studies with the greatest amount of within racial/ethnic group diversity (e.g. HCHS/SOL for Hispanic/Latinos, WHI for Asian Americans; see section on Study Population for more information).…”

A unified method for rare variant analysis of gene‐environment interactions

“…The CHRNB4 gene has been reported to be associated with higher BMI in never smokers and lower BMI in current smokers, implying that genetics variants may influence BMI via the weight‐reducing effects of smoking in opposite directions . INPP4B gene is a novel locus identified in the meta‐analysis by Justice et al but to our knowledge, this finding has not yet been replicated in other studies. We cannot exclude the possibility that there are no rare variants interacting with smoking in INPP4B gene .…”

Prospective Studies Exploring the Possible Impact of an ID3 Polymorphism on Changes in Obesity Measures

“…Obviously, when taking into account the number of tests performed, none of the associations were very strong. The findings of the cross‐sectional data were not confirmed by lookups in GWAS databases for anthropometric traits (Supporting Information Table S6). No GWAS database on prospective traits exists to compare with our findings for the ID3 rs11574‐A.…”