Analysis of Whole Exome Sequencing with Cardiometabolic Traits Using Family-Based Linkage and Association in the IRAS Family Study

Keri L. Tabb, Jacklyn N. Hellwege, Nicholette D. Palmer, Latchezar Dimitrov, Satria Sajuthi, Kent D. Taylor, Maggie C.Y. Ng, Gregory A. Hawkins, Yii der Ida Chen, W. Mark Brown, David McWilliams, Adrienne Williams, Carlos Lorenzo, Jill M. Norris, Jirong Long, Jerome I. Rotter, Joanne E. Curran, John Blangero, Lynne E. Wagenknecht, Carl D. LangefeldDonald W. Bowden

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two-point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two-point linkage analysis yielded 10,580,600 logarithm of the odds (LOD) scores with 1148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD scores ≥5. The maximal novel LOD score was 5.50 for rs2289043:T>C, in UNC5C with subcutaneous adipose tissue volume. Association analysis identified 13 variants attaining genome-wide significance (P < 5 × 10−08), with the strongest association between rs651821:C>T in APOA5 and triglyceride levels (P = 3.67 × 10−10). Overall, there was a 5.2-fold increase in the number of informative variants detected by WES compared to exome chip analysis in this population, nearly 30% of which were novel variants relative to the Database of Single Nucleotide Polymorphisms (dbSNP) build 138. Thus, integration of results from two-point linkage and single-variant association analysis from WES data enabled identification of novel signals potentially contributing to cardiometabolic traits.

Original languageEnglish (US)
Pages (from-to)49-58
Number of pages10
JournalAnnals of Human Genetics
Volume81
Issue number2
DOIs
StatePublished - Mar 1 2017

Keywords

  • Cohort study
  • Hispanic
  • genetic variance
  • novel variants

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Tabb, K. L., Hellwege, J. N., Palmer, N. D., Dimitrov, L., Sajuthi, S., Taylor, K. D., Ng, M. C. Y., Hawkins, G. A., Chen, Y. D. I., Brown, W. M., McWilliams, D., Williams, A., Lorenzo, C., Norris, J. M., Long, J., Rotter, J. I., Curran, J. E., Blangero, J., Wagenknecht, L. E., ... Bowden, D. W. (2017). Analysis of Whole Exome Sequencing with Cardiometabolic Traits Using Family-Based Linkage and Association in the IRAS Family Study. Annals of Human Genetics, 81(2), 49-58. https://doi.org/10.1111/ahg.12184