title: Analysis of Whole Exome Sequencing with Cardiometabolic Traits Using Family-Based Linkage and Association in the IRAS Family Study.
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.
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Keri L
authors.initials: KL
authors.lastname: Tabb
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jacklyn N
authors.initials: JN
authors.lastname: Hellwege
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Latchezar
authors.initials: L
authors.lastname: Dimitrov
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Satria
authors.initials: S
authors.lastname: Sajuthi
authors.affiliation: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hawkins
authors.affiliation: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Yii-der Ida
authors.initials: YI
authors.lastname: Chen
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: W Mark
authors.initials: WM
authors.lastname: Brown
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: David
authors.initials: D
authors.lastname: McWilliams
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Williams
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lorenzo
authors.affiliation: Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Norris
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jirong
authors.initials: J
authors.lastname: Long
authors.affiliation: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D052242:Adiponectin / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics*; D059472:Exome; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; D008055:Lipids
keywords: Cohort study; Hispanic; genetic variance; novel variants