Analysis of Whole Exome Sequencing with Cardiometabolic Traits Using Family‐Based Linkage and Association in the IRAS Family Study |
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| Authors: | 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. Langefeld Donald W. Bowden |
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| Affiliation: | 1. Department of Biochemistry, Wake Forest School of Medicine, Winston‐Salem, NC, USA;2. Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston‐Salem, NC, USA;3. Center for Diabetes Research, Wake Forest School of Medicine, Winston‐Salem, NC, USA;4. Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA;5. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA;6. Center for Public Health Genomics, Wake Forest School of Medicine, Winston‐Salem, NC, USA;7. Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston‐Salem, NC, USA;8. Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles BioMedical Research Institute at Harbor‐UCLA Medical Center, Torrance, CA, USA;9. Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA;10. Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA;11. South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA;12. Division of Public Health Sciences, Wake Forest School of Medicine, Winston‐Salem, NC, USA |
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| 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. |
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| Keywords: | Cohort study genetic variance Hispanic novel variants |
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