Identity-by-Descent Mapping Identifies Major Locus for Serum Triglycerides in Amerindians Largely Explained by an APOC3 Founder Mutation

• Published in: Circulation. Cardiovascular genetics Vol. 10; no. 6; p. e001809
• Main Authors: Hsueh, Wen-Chi, Nair, Anup K, Kobes, Sayuko, Chen, Peng, Göring, Harald H H, Pollin, Toni I, Malhotra, Alka, Knowler, William C, Baier, Leslie J, Hanson, Robert L
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.12.2017
• Subjects: Alleles; Apolipoprotein A-V - genetics; Apolipoprotein C-III - genetics; Chromosome 11; Chromosomes, Human, Pair 11 - genetics; Founder Effect; Gene Frequency; Gene mapping; Genome-Wide Association Study; Genotype; Haplotypes; Humans; Indians, North American - genetics; Linkage analysis; Linkage Disequilibrium; Lipids - blood; Localization; Mutation; Polymorphism; Polymorphism, Single Nucleotide; Population genetics; Single-nucleotide polymorphism; Triglycerides; Triglycerides - blood; mutation; triglycerides; chromosome; genome-wide association study; alleles
• ISSN: 1942-325X; 1942-3268
• DOI: 10.1161/CIRCGENETICS.117.001809

Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization. Through identity-by-descent mapping, using ≈400 000 single-nucleotide polymorphisms (SNPs), of serum lipid profiles, we identified a major linkage signal for triglycerides in 1007 Pima Indians (LOD=9.23; =3.5×10 on chromosome 11q). In subsequent fine-mapping and replication association studies in ≈7500 Amerindians, we determined that this signal reflects effects of a loss-of-function Ala43Thr substitution in (rs147210663) and 3 established functional SNPs in . The association with rs147210663 was particularly strong; each copy of the Thr allele conferred 42% lower triglycerides (β=-0.92±0.059 SD unit; =9.6×10 in 4668 Pimas and 2793 Southwest Amerindians combined). The Thr allele is extremely rare in most global populations but has a frequency of 2.5% in Pimas. We further demonstrated that 3 SNPs with established functional impact could explain the association with the most well-replicated SNP (rs964184) for triglycerides identified by genome-wide association studies. Collectively, these 4 SNPs account for 6.9% of variation in triglycerides in Pimas (and 4.1% in Southwest Amerindians), and their inclusion in the original linkage model reduced the linkage signal to virtually null. constitutes a major locus for serum triglycerides in Amerindians, especially the Pimas, and these results provide an empirical example for the concept that population-based linkage analysis is a useful strategy to identify complex trait variants.