Genome-wide association study of smoking trajectory and meta-analysis of smoking status in 842,000 individuals

Ke Xu,Cecilia Dao,Boyang Li,Va Million Veteran Program ,Henry R Kranzler,Rachel L Kember,Amy C Justice,Rachel Vickers-Smith,Kathleen A Mcginnis,Hang Zhou,William C Becker,Joel Gelernter,Hongyu Zhao,Ning Sun

doi:10.1038/s41467-020-18489-3

Abstract

Here we report a large genome-wide association study (GWAS) for longitudinal smoking phenotypes in 286,118 individuals from the Million Veteran Program (MVP) where we identified 18 loci for smoking trajectory of current versus never in European Americans, one locus in African Americans, and one in Hispanic Americans. Functional annotations prioritized several dozen genes where significant loci co-localized with either expression quantitative trait loci or chromatin interactions. The smoking trajectories were genetically correlated with 209 complex traits, for 33 of which smoking was either a causal or a consequential factor. We also performed European-ancestry meta-analyses for smoking status in the MVP and GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN) (Ntotal = 842,717) and identified 99 loci for smoking initiation and 13 loci for smoking cessation. Overall, this large GWAS of longitudinal smoking phenotype in multiple populations, combined with a meta-GWAS for smoking status, adds new insights into the genetic vulnerability for smoking behavior.

Highlights

We report a large genome-wide association study (GWAS) for longitudinal smoking phenotypes in 286,118 individuals from the Million Veteran Program (MVP) where we identified 18 loci for smoking trajectory of current versus never in European Americans, one locus in African Americans, and one in Hispanic Americans
Using a previously validated approach[22] and data from over 2.2 million clinical encounters where smoking status was recorded in the electronic medical records (EMRs) for a total of 286,118 veterans (209,915 European American (EA), 54,867 AAs, and 21,336 Hispanic American (HA)), we identified three distinct longitudinal trajectory groups for smoking in each population group
The two phenotypes were highly correlated, by comparing their performance we evaluated their relative utility for detecting genetic variants contributing to smoking behavior

Summary

Introduction

We report a large genome-wide association study (GWAS) for longitudinal smoking phenotypes in 286,118 individuals from the Million Veteran Program (MVP) where we identified 18 loci for smoking trajectory of current versus never in European Americans, one locus in African Americans, and one in Hispanic Americans. We performed European-ancestry meta-analyses for smoking status in the MVP and GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN) (Ntotal = 842,717) and identified 99 loci for smoking initiation and 13 loci for smoking cessation Overall, this large GWAS of longitudinal smoking phenotype in multiple populations, combined with a meta-GWAS for smoking status, adds new insights into the genetic vulnerability for smoking behavior. Large meta-GWASs have been reported, including a study from the UK Biobank (UKBB) and the Tobacco and Genetics Consortium (TAG) with a total of 518,633 individuals that identified 223 loci for ever versus (vs.) never smokers[10] These genetic variants accounted for 10.9% of the phenotypic variation for this single trait[10]. None of the large GWAS studies identified genetic variants for smoking trajectories

Methods

Results

Conclusion