rs11246991 (GALNT9): BMI and Metabolic Syndrome Locus

Key takeaways

• Identified as a body mass index (BMI)-associated locus in genome-wide association studies of approximately 1.1 million individuals of European ancestry
• Also connected to the genetic landscape of metabolic syndrome, with a multivariate GWAS in nearly five million people finding 1,307 shared loci enriched in brain tissues
• The alternate allele consistently reduces LINC02361 expression across eight tissue types, with the largest reductions in the heart
• BMI heritability is estimated at approximately 0.55 +/- 0.07 from sibling identity-by-descent analysis, and GWAS loci account for only part of that total
• No per-variant p-value, odds ratio, or beta coefficient for rs11246991 is available in the provided study texts

What the research says A genome-wide association meta-analysis identified 906 BMI-associated loci (364 novel) across approximately 1.1 million individuals of European ancestry and 41 additional loci in approximately 100,000 individuals of African ancestry; a BMI genetic risk score built from 2,446 variants was associated with 316 distinct diagnoses in a large biobank, with 96.5% of those associations showing increased risk. A multivariate GWAS of five metabolic syndrome components in nearly five million individuals found 1,307 associated loci enriched primarily in brain tissues, extending associations beyond cardiometabolic disease to a broader range of conditions. GTEx v11 data show that the alternate allele at rs11246991 is associated with reduced expression of LINC02361 (a long intergenic non-coding RNA near GALNT9) across eight tissues, most notably both chambers of the heart GTEx Portal.

Reported associations

• Body mass index (BMI): identified among 906 genome-wide significant BMI loci in a meta-analysis of approximately 1.1 million Europeans and approximately 100,000 individuals of African ancestry; a polygenic risk score built from 2,446 BMI-associated variants was linked to 316 distinct diagnoses in an independent biobank, with 96.5% of associations showing increased risk
• Metabolic syndrome and components: the locus falls within the landscape of 1,307 genetic variants found by a multivariate GWAS covering BMI, waist circumference, type 2 diabetes, fasting glucose, hypertension, HDL cholesterol, and triglycerides in nearly five million individuals; brain tissue expression was the primary enrichment signal, and phenome-wide analyses connected these loci to conditions beyond cardiometabolic disease

Evidence quality The BMI evidence comes from a meta-analysis of approximately 1.1 million individuals of European ancestry and approximately 100,000 of African ancestry, providing strong statistical power for genome-wide significant findings. The metabolic syndrome multivariate GWAS is among the largest published, with an observed sample of approximately 4.9 million individuals. A third analysis using recombination rate-stratified identity-by-descent sharing in 119,000 sibling pairs estimated BMI heritability at 0.55 +/- 0.07, confirmed that GWAS loci colocalize with independent linkage signals, and showed that polygenic score adjustment reduces those linkage signals, consistent with a polygenic architecture for this locus. However, the available study texts do not report a specific p-value, odds ratio, or beta coefficient for rs11246991 individually, and no explicit per-variant replication data are present in the provided evidence. The GTEx eQTL associations (all FDR below 0.05) for LINC02361 across eight tissues provide mechanistic context but describe gene-expression regulation rather than phenotypic outcomes directly. No conflicts were identified across the three studies.

Tissue-specific expression effects

• LINC02361: the alternate allele is associated with reduced expression across eight tissues; the largest reductions appear in both heart chambers (left ventricle and atrial appendage), with additional effects in colon sigmoid, tibial nerve, cultured fibroblasts, aorta, and two skin regions (sun-exposed lower leg and non-sun-exposed suprapubic); all eight associations are below FDR 0.05; LINC02361 is a long intergenic non-coding RNA near GALNT9, and its specific biological role in these tissues is not described in the available studies GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.