rs10948615 (WTAPP2/RPS15AP20): Tobacco Use GWAS

Key takeaways

• This variant was identified in a study of tobacco and alcohol use genetics spanning up to 1.2 million individuals.
• The study found 566 genetic variants across 406 genomic loci linked to smoking initiation, cessation, heaviness, age of onset, and alcohol use.
• Genetic risk for greater alcohol use was unexpectedly associated with lower genetic risk for most diseases in the dataset, a finding that conflicts with the direction seen for smoking.
• GTEx v11 data links this variant to increased expression of the immune gene IL17F specifically in testis tissue.

What the research says A multi-phenotype genome-wide association study (GWAS - a method that scans hundreds of thousands of genetic positions across the genome to find variants statistically linked to a trait) of tobacco and alcohol use involving up to 1.2 million participants reported 566 conditionally independent genome-wide significant common variants across 406 loci, with the WTAPP2 - RPS15AP20 region catalogued among the associated loci. Those 566 variants collectively explained 0.1% of phenotypic variance in smoking cessation up to 2.3% in smoking initiation, and SNP heritability (the share of trait variation attributable to measured genetic variants) ranged from 4.2% for drinks per week to 8.0% for cigarettes per day, indicating a highly polygenic architecture in which no single variant drives a large fraction of trait variance. GTEx v11 tissue-expression data (953 donors, cis-window, FDR below 0.05) additionally associates this variant with increased IL17F expression in testis (p=1.0e-4) GTEx Portal.

Reported associations

• Tobacco and alcohol use behaviors: This variant was reported in the context of a GWAS covering five substance use outcomes - smoking initiation (N=1,232,091; 378 genome-wide significant variants study-wide), cigarettes per day (N=337,334; 55 variants), smoking cessation (N=547,219; 24 variants), age of smoking initiation (N=341,427; 10 variants), and drinks per week (N=941,280; 99 variants). Variant-level effect sizes and specific phenotype assignment for this locus are not reported in the available source text.

Evidence quality The source study is one of the largest GWAS efforts on substance use behaviors conducted to date, with samples drawn from cohorts across Western Europe and the United States and total sample sizes reaching 1.2 million individuals. Polygenic scores built from the study's significant variants explained roughly 1% (age of initiation, smoking cessation) to 4% (cigarettes per day, smoking initiation) of variance in independent replication samples - approximately half the estimated SNP heritability - consistent with the authors' conclusion that most genetic signal remains below standard significance thresholds. However, the provided text does not include per-variant summary statistics (p-value, odds ratio, beta coefficient, or phenotype assignment) specific to this locus, so the direction, magnitude, and precise trait association for rs10948615 cannot be confirmed from the available materials. One notable finding in the broader dataset that warrants attention: smoking-associated genetic variants were positively correlated with disease risk while alcohol-use-associated genetic variants were negatively correlated with most disease outcomes - a directional conflict between the two substance use phenotypes that the authors flag but do not fully resolve. Replication of the association at this specific locus is not described in the provided source.

Tissue-specific expression effects

• IL17F: Carriers of the alternate allele show increased expression in testis tissue, based on GTEx v11 data from 953 donors (p=1.0e-4). IL17F encodes a cytokine - a protein that carries signals between immune cells. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.