rs113928341 (GNG12-AS1): Carotid Thickness Variant

Key takeaways

• rs113928341 lies in the GNG12-AS1 region, a locus linked to carotid artery wall thickness (cIMT), a surrogate measure of atherosclerosis risk
• This variant was studied in a cohort of 7,894 sub-Saharan African adults, a population historically underrepresented in genetic research
• Known cIMT genetic variants collectively explain only about 1.1% of cIMT variance despite heritability estimates of 20-65%
• The ALT allele is associated with increased WLS gene expression in hippocampal brain tissue based on GTEx data, though functional significance is not established

What the research says Carotid intima-media thickness (cIMT) - the thickness of the inner layers of the carotid artery wall measured by ultrasound - is a widely accepted surrogate marker for generalized atherosclerosis (the hardening and narrowing of arteries) and is used in large-scale research on genetic associations with future cardiovascular events PMID 35538082. The GNG12-AS1 locus, previously associated with cIMT in primarily European-ancestry populations, was examined for cross-ancestry replication in the AWI-Gen cohort comprising 7,894 adults (3,963 women, 3,931 men; ages 40-60) from Burkina Faso, Ghana, Kenya, and South Africa PMID 35538082. African genomes have shorter haplotype blocks (a haplotype block is a stretch of DNA variants typically inherited together; these average approximately 8.8 kb in Africans versus approximately 20.7 kb in Europeans), which can facilitate more precise localization of causal variants at replicated loci PMID 35538082.

Reported associations

• Carotid intima-media thickness (cIMT): This locus was examined as part of cross-ancestry replication of cIMT signals in 7,894 sub-Saharan African adults from the AWI-Gen cohort; replication used lead SNPs in linkage disequilibrium with signals originally identified in European-ancestry populations, and known cIMT GWAS signals account for approximately 1.1% of cIMT variance overall PMID 35538082

Evidence quality The source study (n=7,894, ages 40-60, four sub-Saharan African countries) was a discovery-and-replication GWAS for cIMT representing one of the few large-scale genomic investigations in populations from sub-Saharan Africa PMID 35538082. For this locus specifically, the study describes replication of a prior European-ancestry association rather than an independent discovery, and no specific effect size or p-value for rs113928341 appears in the provided study text. Family and twin studies estimate cIMT heritability at 20-65%, yet known GWAS signals explain only 1.1% of cIMT variance overall, indicating a substantial gap between the estimated genetic contribution and what has been mapped to date PMID 35538082. Evidence at this locus should be considered preliminary given the absence of per-SNP effect sizes in the available study text and the historically limited number of African-ancestry GWAS for this trait.

Tissue-specific expression effects

• WLS: The ALT allele is associated with increased expression of WLS in Brain_Hippocampus tissue; the direction of effect is toward higher WLS transcript levels in hippocampal tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.