Smoking-Interaction Loci Affect Obesity Traits: A Gene-Smoking Stratified Meta-Analysis of 545,131 Europeans

Abstract

<b><i>Introduction:</i></b> Although many studies have investigated the association between smoking and obesity, very few have analyzed how obesity traits are affected by interactions between genetic factors and smoking. Here, we aimed to identify the loci that affect obesity traits via smoking status-related interactions in European samples. <b><i>Methods:</i></b> We performed stratified analysis based on the smoking status using both the UK Biobank (UKB) data (<i>N</i> = 334,808) and the Genetic Investigation of ANthropometric Traits (GIANT) data (<i>N</i> = 210,323) to identify gene-smoking interaction for obesity traits. We divided the UKB subjects into two groups, current smokers and nonsmokers, based on the smoking status, and performed genome-wide association study (GWAS) for body mass index (BMI), waist circumference adjusted for BMI (WCadjBMI), and waist-hip ratio adjusted for BMI (WHRadjBMI) in each group. And then we carried out the meta-analysis using both GWAS summary statistics of UKB and GIANT for BMI, WCadjBMI, and WHRadjBMI and computed the stratified <i>p</i> values (<i>p</i>_stratified) based on the differences between meta-analyzed estimated beta coefficients with standard errors in each group. <b><i>Results:</i></b> We identified four genome-wide significant loci in interactions with the smoking status (<i>p</i>_stratified &#x3c; 5 × 10⁻⁸): rs336396 (<i>INPP4B</i>) and rs12899135 (near <i>CHRNB4</i>) for BMI, and rs998584 (near <i>VEGFA</i>) and rs6916318 (near <i>RSPO3</i>) for WHRadjBMI. Moreover, we annotated the biological functions of the SNPs using expression quantitative trait loci (eQTL) and GWAS databases, along with publications, which revealed possible mechanisms underlying the association between the smoking status-related genetic variants and obesity. <b><i>Conclusions:</i></b> Our findings suggest that obesity traits can be modified by the smoking status via interactions with genetic variants through various biological pathways.