Genome-wide linkage and association analysis of cardiometabolic phenotypes in Hispanic Americans.

Hellwege JN, Palmer ND, Dimitrov L, Keaton JM, Tabb KL, Sajuthi S, Taylor KD, Ng MC, Speliotes EK, Hawkins GA, Long J, Ida Chen YD, Lorenzo C, Norris JM, Rotter JI, Langefeld CD, Wagenknecht LE, Bowden DW
J Hum Genet. 2017 62 (2): 175-184

PMID: 27535031 · PMCID: PMC5266668 · DOI:10.1038/jhg.2016.103

Linkage studies of complex genetic diseases have been largely replaced by genome-wide association studies, due in part to limited success in complex trait discovery. However, recent interest in rare and low-frequency variants motivates re-examination of family-based methods. In this study, we investigated the performance of two-point linkage analysis for over 1.6 million single-nucleotide polymorphisms (SNPs) combined with single variant association analysis to identify high impact variants, which are both strongly linked and associated with cardiometabolic traits in up to 1414 Hispanics from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of all 50 phenotypes yielded 83 557 000 LOD (logarithm of the odds) scores, with 9214 LOD scores ⩾3.0, 845 ⩾4.0 and 89 ⩾5.0, with a maximal LOD score of 6.49 (rs12956744 in the LAMA1 gene for tumor necrosis factor-α (TNFα) receptor 2). Twenty-seven variants were associated with P<0.005 as well as having an LOD score >4, including variants in the NFIB gene under a linkage peak with TNFα receptor 2 levels on chromosome 9. Linkage regions of interest included a broad peak (31 Mb) on chromosome 1q with acute insulin response (max LOD=5.37). This region was previously documented with type 2 diabetes in family-based studies, providing support for the validity of these results. Overall, we have demonstrated the utility of two-point linkage and association in comprehensive genome-wide array-based SNP genotypes.

MeSH Terms (20)

Adolescent Adult Aged Aged, 80 and over Diabetes Mellitus, Type 2 Female Genetic Linkage Genome-Wide Association Study Genotype Hispanic Americans Humans Insulin Resistance Laminin Lod Score Male Middle Aged NFI Transcription Factors Polymorphism, Single Nucleotide Tumor Necrosis Factor-alpha Young Adult

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