Genetic architecture of four smoking behaviors using partitioned SNP heritability

Abstract

Background and Aims Although genome-wide association studies have identified many loci that influence smoking behaviors, much of the genetic variance remains unexplained. We characterized the genetic architecture of four smoking behaviors using single nucleotide polymorphism (SNP) heritability (h 2 SNP ). This is an estimate of narrow-sense heritability specifically estimating the proportion of phenotypic variation due to causal variants (CVs) tagged by SNPs. Design Partitioned h 2 SNP analysis of smoking behavior traits. Setting UK Biobank. Participants UK Biobank participants of European ancestry. The number of participants varied depending on the trait, from 54 792 to 323 068. Measurements Smoking initiation, age of initiation, cigarettes per day (CPD; count, log-transformed, binned and dichotomized into heavy versus light) and smoking cessation with imputed genome-wide SNPs. Findings We estimated that, in aggregate, approximately 18% of the phenotypic variance in smoking initiation was captured by imputed SNPs [h 2 SNP = 0.18, standard error (SE) = 0.01] and 12% [SE = 0.02] for smoking cessation, both of which were more than twice the previously reported estimates. Estimated age of initiation (h 2 SNP = 0.05, SE = 0.01) and binned CPD (h 2 SNP = 0.1, SE = 0.01) were substantially below published twin-based h 2 of 50%. CPD encoding influenced estimates, with dichotomized CPD h 2 SNP = 0.28. There was no evidence of dominance genetic variance for any trait. Conclusion A biobank study of smoking behavior traits suggested that the phenotypic variance explained by SNPs of smoking initiation, age of initiation, cigarettes per day and smoking cessation is modest overall.

Rare genetic variants explain missing heritability in smoking

“…The influence phenotypic scaling was reported in recent study of Evans et al 2021 where CigDay showed higher heritability when it was dichotomized versus the ordinal version analyzed here 52 . Estimation of heritability for binned variable (e.g., CigDay in this study) may be improved by different modeling choice including liability threshold model 54 .…”

“…AgeSmk tended to show higher rare variant heritability when extreme observations were included than they were not. Extreme observations may induce model misspecification or alternatively, are enriched in causal rare variants, possibly leading to higher heritability estimates 23,52,53 .…”

Genome-wide methylation data improves dissection of the effect of smoking on body mass index

“…Under this scenario smoking status would be capturing smoking associated variants, and the genome-by-smoking interaction would represent GxG instead of GxE. However, given the relatively small heritability of tobacco smoking (SNP heritability ~18% 45 ), it is unlikely that all the variation we detected is driven by GxG.…”

Polygenic scores for tobacco use provide insights into systemic health risks in a diverse EHR-linked biobank in Los Angeles

“…Tobacco use causes signi cant global mortality and morbidity, contributing to several systemic conditions, including cardiometabolic diseases and cancers 1,2 . Tobacco use has historically been studied as an environmental risk factor for other diseases; however, tobacco use could instead be viewed as a complex psychiatric trait with environmental risk factors 3 and signi cant genetic contributions 4,5 . Multiancestry genetic studies report an estimated heritability (i.e., the proportion of the phenotypic variance explained by genetics) of tobacco use behaviors ranging between 5-18% 4,5 .…”

“…Tobacco use has historically been studied as an environmental risk factor for other diseases; however, tobacco use could instead be viewed as a complex psychiatric trait with environmental risk factors 3 and signi cant genetic contributions 4,5 . Multiancestry genetic studies report an estimated heritability (i.e., the proportion of the phenotypic variance explained by genetics) of tobacco use behaviors ranging between 5-18% 4,5 . Prevention and management strategies for tobacco use can bene t from precision medicine approaches, with the inclusion of baseline genetic risk to develop individualized preventive and therapeutic strategies for tobacco use.…”