rs11039149 (NR1H3): Metabolic Syndrome Variant

Key takeaways

• This intronic variant in NR1H3 was one of only three genomic loci found to associate with all five metabolic syndrome components simultaneously in a study of 291,107 UK Biobank participants
• The five associated traits are blood glucose, systolic blood pressure, blood triglycerides, waist circumference, and HDL ("good") cholesterol
• Independent prior GWAS studies had also identified this same NR1H3 locus in relation to all five metabolic syndrome traits, adding corroborating evidence
• GTEx data link this variant to reduced NR1H3 expression in ovary tissue and altered expression of four neighboring genes across skin, fat, pituitary, and pancreatic tissue
• Evidence is based primarily on UK Biobank participants and has not yet been broadly replicated in diverse populations

What the research says A GWAS conducted in 291,107 UK Biobank participants identified the NR1H3 locus as one of just three genomic regions simultaneously associated (FDR < 0.05) with all five canonical components of metabolic syndrome (MetS): fasting glucose, systolic blood pressure, triglycerides, waist circumference, and HDL-cholesterol; the locus was described as the most scientifically compelling of the three because independent prior GWAS studies had separately linked it to all five MetS components, suggesting a possible shared biological mechanism underlying this risk-factor clustering. GTEx v11 data confirm that rs11039149 acts as an expression quantitative trait locus (eQTL - a variant that influences how much a nearby gene is expressed) at this region, with reduced expression of NR1H3 itself detected in ovary tissue GTEx Portal.

Reported associations

• Metabolic syndrome (all five components simultaneously - glucose, systolic blood pressure, triglycerides, waist circumference, HDL-cholesterol): All five associations reached FDR < 0.05 at the NR1H3 intronic locus in 291,107 UK Biobank participants; prior independent GWAS datasets had also linked this locus to all five components, providing cross-sample corroboration

Evidence quality The core association data derive from a single large GWAS (n = 291,107, UK Biobank) using FDR < 0.05 - a less conservative threshold than the standard genome-wide significance cutoff (p < 5 × 10^-8). The authors noted convergent evidence from independent prior GWAS datasets identifying the same locus in connection with all five MetS components. Specific effect sizes (beta coefficients, odds ratios, or percentage of variance explained) for individual MetS traits at this locus were not reported in the available study text. The sample is drawn primarily from European-ancestry UK Biobank participants, limiting generalizability to other ancestries. For broader genomic context: large neuroticism GWAS meta-analyses using overlapping biobank cohorts - including one in 449,484 participants identifying 136 independent genome-wide significant loci, and an item-level analysis demonstrating that 12 neuroticism items show genetic correlations ranging 0.38-0.91 (mean rg = 0.63) - have mapped the genetic architecture of mood-related traits in this genomic region; however, a direct rs11039149-specific association with neuroticism is not documented in the available text. Overall, the MetS signal at this locus is internally consistent and cross-referenced across independent datasets, but should be considered preliminary pending multi-ancestry replication and functional validation.

Tissue-specific expression effects

• MADD (MAP kinase activating death domain protein): Reduced expression in pituitary tissue and in the muscular layer of the esophagus GTEx Portal
• C1QTNF4 (complement C1q and TNF-related protein 4): Increased expression in sun-exposed lower-leg skin, subcutaneous (beneath-the-skin) fat, and non-sun-exposed skin GTEx Portal
• NR1H3: Reduced expression in ovary tissue GTEx Portal
• LRP4 (LDL receptor-related protein 4): Increased expression in pancreatic tissue GTEx Portal
• ENSG00000303744 (unannotated transcript): Increased expression in testis tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.