rs10992828 (PHF2): Tobacco and Alcohol Use Genetics

Key takeaways

• The ALT allele at rs10992828 near the PHF2 gene raises expression of two nearby genes in brain regions including frontal cortex and cerebellum
• rs10992828 was identified in a 3.4-million-person multi-ancestry study of tobacco and alcohol use behaviors spanning 60 research cohorts
• Five phenotypes were studied: smoking initiation, cigarettes per day, smoking cessation, age of smoking onset, and drinks per week
• Roughly 21% of participants were of non-European ancestry, improving the precision of genetic fine-mapping at this locus
• Polygenic risk scores from this study did not transfer well across different ancestry populations, highlighting the need for further diverse replication

What the research says A multi-ancestry genome-wide association study (GWAS - a method of scanning the genomes of many people to find genetic variants statistically linked to a trait) of 3.4 million individuals from 60 research cohorts identified 3,823 independently associated variants across 2,143 loci tied to tobacco and alcohol use behaviors, applying a discovery threshold of P < 5 x 10-9 and requiring each sentinel variant to have a posterior probability of replication greater than 0.99; only 17 of 3,823 variants (0.7%) were removed for failing this standard. The study found that incorporating approximately 21% non-European participants - spanning African (up to n=119,589), American admixed (n=286,026), East Asian (n=296,438), and European (n=2,669,029) ancestry groups - improved both locus discovery and fine-mapping resolution, though polygenic risk scores built from the study performed poorly when applied across ancestry groups. Tissue-specific expression data from GTEx v11 (953 donors) shows that the ALT allele at this locus is linked to increased expression of two nearby genes across a range of tissues, with signals in brain frontal cortex (BA9), brain cerebellum, lymphocytes, skin, and several other tissues GTEx Portal.

Reported associations

• Tobacco and alcohol use behaviors (multi-phenotype): rs10992828 is among the variants identified in a multi-ancestry GWAS (n=3.4 million, 60 cohorts) covering smoking initiation (n=3,383,199), cigarettes per day (n=784,353), smoking cessation (n=1,400,535), age of smoking onset (n=728,826), and drinks per week (n=2,965,643); the study identified 2,143 loci and 3,823 variants overall, but phenotype-specific effect sizes for rs10992828 individually are not included in the available study text

Evidence quality Evidence for rs10992828 comes from a single large-scale discovery meta-analysis (Saunders et al., Nature, 2023) of 3.4 million individuals. The study used a stringent discovery threshold (P < 5 x 10-9, more conservative than the conventional GWAS cutoff of P < 5 x 10-8) and cross-validated all sentinel variants for replication confidence, removing the 0.7% that did not meet the threshold. The multi-ancestry design strengthens generalizability compared to European-only GWAS, though the authors explicitly note that polygenic risk scores transferred poorly across ancestry populations, meaning the full replication landscape for variants like rs10992828 in non-European samples is not yet established. No variant-specific odds ratio, beta coefficient, or p-value for rs10992828 is available in the provided study text.

Tissue-specific expression effects

• ENSG00000307539: The ALT allele is associated with increased expression in EBV-transformed lymphocytes, brain frontal cortex (BA9), prostate, coronary artery, sigmoid colon, sun-exposed skin (lower leg), and esophageal mucosa GTEx Portal
• ENSG00000237385: The ALT allele is associated with increased expression in brain cerebellum GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.