Expressive

rs1105223 (CRB2): BMI-associated genetic locus

Key takeaways

  • rs1105223, near CRB2, is one of 906 genome-wide significant BMI loci found in a study of over 1 million people
  • A BMI genetic risk score that includes this variant was associated with 316 different diagnoses, with 96.5% showing higher risk at greater genetically predicted BMI
  • Mendelian randomization supports BMI as causally linked to heart failure, kidney disease, atrial fibrillation, and asthma
  • The ALT allele at rs1105223 reduces expression of a nearby gene in aortic and skeletal muscle tissue
  • The rare protein-altering variant study did not identify CRB2, suggesting rs1105223 is likely a common regulatory variant rather than a protein-altering signal

Key takeaways

  • rs1105223, near CRB2, is one of 906 genome-wide significant BMI loci found in a study of over 1 million people.
  • A BMI genetic risk score that includes this variant was associated with 316 different diagnoses, with 96.5% showing higher risk at greater genetically predicted BMI.
  • Mendelian randomization supports BMI as causally linked to heart failure, kidney disease, atrial fibrillation, and asthma.
  • The ALT allele at rs1105223 reduces expression of a nearby gene (ENSG00000298893) in aortic and skeletal muscle tissue.
  • The rare protein-altering variant study did not identify CRB2, suggesting rs1105223 is likely a common regulatory variant rather than a protein-altering signal.

What the research says A mega-GWAS meta-analysis in the Million Veteran Program and affiliated cohorts identified 906 genome-wide significant loci for BMI in European ancestry participants (N approximately 1.1 million), including 364 novel loci, and 41 loci (6 novel) in African ancestry participants (N approximately 100,000) PMID 37280221. A separate exome-wide meta-analysis across 718,734 individuals identified 14 rare and low-frequency coding variants in 13 genes with BMI effects roughly 10 times larger than those of common variants, implicating neuronal, adipocyte, and energy expenditure pathways PMID 30643258. GTEx v11 tissue expression data (953 donors, FDR<0.05) shows the ALT allele at rs1105223 is associated with reduced expression of ENSG00000298893 in the aorta and in skeletal muscle GTEx Portal.

Reported associations

  • Body mass index: rs1105223 in the CRB2 locus was identified among 906 genome-wide significant loci for BMI in European ancestry populations (N approximately 1.1 million) PMID 37280221.
  • BMI in African ancestry populations: 41 genome-wide significant BMI loci were identified in African ancestry participants (N approximately 100,000), though specific overlap with the CRB2 region is not detailed in the available study text PMID 37280221.
  • Broad disease network (PheWAS): A 2,446-variant BMI genetic risk score was associated with 316 diagnoses in the Million Veteran Program, with 96.5% of those associations reflecting increased disease risk at higher genetically predicted BMI PMID 37280221.
  • Disease comorbidity structure: Co-morbidity network analysis identified seven disease communities, each containing multiple interconnected BMI-associated diseases, with extensive connections between communities PMID 37280221.
  • Cardiovascular disease (Mendelian randomization): BMI shows MR-supported causal links to heart failure, ischemic heart disease, and atrial fibrillation PMID 37280221.
  • Chronic kidney disease (Mendelian randomization): MR analysis supports a causal role for BMI in chronic renal failure PMID 37280221.
  • Respiratory conditions (Mendelian randomization): BMI was causally linked to respiratory failure and asthma through MR analysis PMID 37280221.
  • Musculoskeletal and dermatologic conditions (Mendelian randomization): MR analysis confirmed these as part of the broader BMI-associated disease network PMID 37280221.

Evidence quality The BMI association at this locus is supported by one of the largest GWAS to date, with approximately 1.1 million European ancestry and 100,000 African ancestry participants PMID 37280221. Of the 906 identified loci, 364 were novel at the time of publication, and the phenome-wide Mendelian randomization analysis covering 316 diagnoses extends findings well beyond BMI itself PMID 37280221. The MR associations reflect the causal effect of BMI as a trait (using the full 2,446-variant genetic instrument), not the isolated effect of rs1105223. The protein-altering variant meta-analysis (N = 718,734) did not identify CRB2 among the 13 genes harboring significant rare or low-frequency coding variants for BMI PMID 30643258, consistent with rs1105223 being a common, likely regulatory variant. Individual effect sizes for common BMI loci are not detailed for this specific variant in the available study text and are generally modest. No conflicting findings across the provided studies are noted for this locus.

Tissue-specific expression effects

  • ENSG00000298893: The ALT allele is associated with reduced expression in artery (aorta) tissue and in skeletal muscle tissue GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is rs1105223?

rs1105223 is a common genetic variant located near the CRB2 gene. It has been identified in large-scale genome-wide association studies as one of 906 loci associated with body mass index (BMI).

What does the CRB2 gene do?

The studies provided do not detail CRB2's specific biological function. They identify the CRB2 genomic region as one of hundreds of loci statistically associated with body mass index in large multi-ancestry genetic analyses.

Is rs1105223 linked to heart disease or kidney disease?

The studies link BMI genetics broadly to cardiovascular diseases and chronic kidney disease through Mendelian randomization analysis. These associations reflect the causal effect of BMI as a trait, not the effect of this single variant in isolation.

How was the BMI association for rs1105223 discovered?

A meta-analysis of genome-wide association studies involving approximately 1.1 million people of European ancestry and 100,000 of African ancestry identified this variant as part of a 906-locus BMI signal, with 364 of those loci considered novel at the time.

How large is the effect of rs1105223 on BMI?

The individual effect size for rs1105223 is not reported in the available studies. Common BMI variants typically each explain only a small fraction of BMI variation, and hundreds of loci together contribute to the genetic component of body weight.