rs1169286 (HNF1A): Liver and Metabolic Traits

Key takeaways

• rs1169286 is a common variant in the HNF1A gene (hepatocyte nuclear factor 1 alpha, also called TCF1), a transcription factor with prominent activity in liver tissue
• Large genome-wide studies covering up to 3.4 million individuals have examined this genomic region in relation to metabolic, cardiometabolic, and behavioral traits
• GTEx data show this variant alters expression of six genes across whole blood, thyroid, brain regions, pancreas, tibial nerve, and esophagus
• Reduced SPPL3 expression in pancreas and increased OASL expression in whole blood are among the strongest tissue-specific expression signals for this variant
• Specific per-trait effect sizes for rs1169286 are not detailed in the available study excerpts

What the research says rs1169286 is located in the HNF1A gene (hepatocyte nuclear factor 1 alpha, also called TCF1) on chromosome 12q24. A sex-specific GWAS of cardiometabolic traits in the UK Biobank (161,906 females and 141,980 males) found that genetic signals for aggregated cardiometabolic scores were enriched for genes differentially expressed in the liver, a tissue relevant to this gene's activity. A cross-population atlas of 220 phenotypes across BioBank Japan, the UK Biobank, and FinnGen (combined n approximately 628,000) identified roughly 5,000 novel loci through meta-analysis and statistical decomposition of shared genetic components PMID 34385711. A GWAS of 58 quantitative traits in 162,255 Japanese individuals identified 1,407 trait-associated loci at P < 5.0 x 10^-8, highlighting pleiotropy and cell-type specificity across clinical measurements PMID 30643258.

Reported associations

• Cardiometabolic aggregate traits (UK Biobank, n = 303,886): A sex-specific GWAS found genetic signals for cardiometabolic sum-scores enriched for liver-differentially-expressed genes in both sexes; specific variant-level associations for rs1169286 are not itemized in the provided study text
• Metabolic and disease biomarkers (cross-population atlas, n approximately 628,000): A 220-phenotype study spanning BioBank Japan, UK Biobank, and FinnGen identified roughly 5,000 novel loci; specific phenotype associations and effect sizes for this variant are not itemized in the provided study text PMID 34385711
• Quantitative clinical measurements (Japanese population, n = 162,255): A GWAS of 58 clinical traits identified 679 novel loci among 1,407 total significant associations; specific associations for this variant are not itemized in the provided study text PMID 30643258
• Tobacco and alcohol use phenotypes (multi-ancestry, n approximately 3.4 million): A meta-regression analysis across 60 cohorts and four ancestry clines identified 2,143 loci for five behavioral phenotypes, with approximately 64% of loci being phenotype-specific; specific effect sizes for this variant are not itemized in the provided study text PMID 36536317

Evidence quality The studies associated with this genomic region represent some of the largest published GWAS efforts. The tobacco and alcohol meta-analysis enrolled approximately 3.4 million individuals from 60 cohorts representing African, American, East Asian, and European ancestry clines, identifying 2,143 loci at P < 5 x 10^-9 PMID 36536317. The cross-population biomarker atlas combined three major biobank datasets to reach approximately 628,000 participants, enabling fine-mapping and latent genetic component analyses across 220 phenotypes PMID 34385711. The Japanese quantitative-traits GWAS (n = 162,255) identified 1,407 significant associations and demonstrated pleiotropy and cell-type specificity across clinical measurements and complex diseases PMID 30643258. One key caveat from the tobacco and alcohol study: polygenic risk scores trained in European ancestry populations showed poor predictive performance when applied to other ancestry groups, a consideration applicable to multi-ancestry interpretation broadly. Specific effect sizes and p-values for rs1169286 individually are not reported in the provided study excerpts, limiting precise quantitative characterization of this locus.

Tissue-specific expression effects

• OASL: Increased expression in whole blood (p = 3.0 x 10^-18), the most statistically significant eQTL signal for this variant across all tissues in the GTEx dataset GTEx Portal
• ACADS: Increased expression in thyroid (p = 1.6 x 10^-13) GTEx Portal
• C12orf43: Increased expression in brain cerebellum (p = 8.5 x 10^-7) and frontal cortex Brodmann area 9 (p = 2.2 x 10^-5), indicating transcriptional effects across central nervous system tissues GTEx Portal
• ENSG00000255946: Reduced expression in brain cerebellar hemisphere (p = 3.1 x 10^-5) GTEx Portal
• SPPL3: Reduced expression in pancreas (p = 5.8 x 10^-6) and tibial nerve (p = 4.4 x 10^-7) GTEx Portal
• MLEC: Increased expression in esophagus at the gastroesophageal junction (p = 9.3 x 10^-7) GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.