rs11128158 (LRIG1): BMI and Disease Risk Variant

Key takeaways

• rs11128158 near LRIG1 is a genome-wide significant BMI variant found in a study of more than 1.1 million people.
• A BMI genetic risk score that includes this and related variants was linked to 316 diagnoses, with 96.5% showing increased disease risk alongside higher BMI.
• Conditions associated with BMI genetics span seven disease communities covering the heart, kidneys, lungs, skin, and musculoskeletal system.
• The variant's alternate allele increases expression of SLC25A26, a mitochondrial carrier gene, in stomach and artery tissue.
• The disease associations were assessed using Mendelian randomization, which estimates causal effects from genetics rather than simple observations.

What the research says A genome-wide association study (GWAS, a method that scans the entire genome for variants linked to a trait) identified 906 loci for BMI, including 364 novel findings, in approximately 1.1 million European-ancestry participants and 41 loci in approximately 100,000 African-ancestry participants, with the LRIG1 (Leucine Rich Repeats and Immunoglobulin Like Domains 1) - TCEAL8P1 region among those identified. Applying a BMI genetic risk score built from 2,446 variants to the Million Veteran Program electronic health record, 316 diagnoses were significantly associated with higher BMI, with 96.5% showing increased risk. Mendelian randomization (a technique that uses genetic variants as proxies for life-course exposure to estimate causal rather than correlational effects) confirmed associations between elevated BMI and conditions spanning the circulatory, genitourinary, respiratory, musculoskeletal, and dermatologic systems, organized into seven interconnected disease communities.

Reported associations

• Body mass index (BMI): This locus was among 906 genome-wide significant BMI associations (including 364 novel findings) in approximately 1.1 million European-ancestry participants and among 41 associations (including 6 novel findings) in approximately 100,000 African-ancestry participants.
• Heart failure, ischemic heart disease, and atrial fibrillation: Mendelian randomization confirmed these circulatory conditions were associated with elevated BMI within a broad multi-disease network.
• Chronic renal failure: Elevated BMI showed a Mendelian randomization-confirmed association with this genitourinary condition.
• Respiratory failure and asthma: These respiratory conditions were identified within the disease network associated with elevated BMI.
• Musculoskeletal and dermatologic conditions: Both systems were represented within the seven interconnected disease communities linked to elevated BMI.

Evidence quality The GWAS draws on approximately 1.1 million European-ancestry participants combined across the Million Veteran Program, multiple large consortia, and UK Biobank, plus approximately 100,000 African-ancestry participants, representing one of the largest BMI genetic analyses to date. The phenome-wide analysis covered 316 diagnoses from the Million Veteran Program electronic health records; the study participants were predominantly male (93% in the European-ancestry group and 87.6% in the African-ancestry group), which may limit generalizability to broader populations. No variant-specific effect size, odds ratio, or p-value for rs11128158 individually is reported in the available study text, so the locus-specific contribution to BMI variance or any downstream condition cannot be quantified from this source alone. Mendelian randomization assumes the genetic instruments act on outcomes only through BMI; pleiotropic effects (where a single variant influences multiple traits independently of BMI) could affect those causal estimates.

Tissue-specific expression effects

• SLC25A26: The alternate allele at this locus is associated with increased expression of SLC25A26, a mitochondrial carrier gene, in stomach tissue and in tibial artery tissue. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.