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

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    Author
    Hsueh, W.-C.
    Nair, A.K.
    Kobes, S.
    Date
    2017
    Journal
    Circulation: Cardiovascular Genetics
    Publisher
    Lippincott Williams and Wilkins
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://www.doi.org/10.1161/CIRCGENETICS.117.001809
    Abstract
    Background—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. Methods and Results— 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; P=3.5×10−11 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 APOC3 (rs147210663) and 3 established functional SNPs in APOA5. The association with rs147210663 was particularly strong; each copy of the Thr allele conferred 42% lower triglycerides (β=−0.92±0.059 SD unit; P=9.6×10−55 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 APOA5 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. Conclusions—APOC3/APOA5 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. Copyright 2017 American Heart Association, Inc.
    Keyword
    alleles
    chromosome
    genome-wide association study
    mutation
    triglycerides
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85038627516&doi=10.1161%2fCIRCGENETICS.117.001809&partnerID=40&md5=258998cf8027a828a2197c50c4453e5a; http://hdl.handle.net/10713/9960
    ae974a485f413a2113503eed53cd6c53
    10.1161/CIRCGENETICS.117.001809
    Scopus Count
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    UMB Open Access Articles 2017

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