title: Genome-wide linkage and association analysis of cardiometabolic phenotypes in Hispanic Americans.
abstract: 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.
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: Jacklyn N
authors.initials: JN
authors.lastname: Hellwege
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.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Molecular Genetics and Genomics Program, 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 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.|Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Keaton
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.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Keri L
authors.initials: KL
authors.lastname: Tabb
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Molecular Genetics and Genomics Program, 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.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Speliotes
authors.affiliation: Center for Genomics and Personalized Medicine 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: Gregory A
authors.initials: GA
authors.lastname: Hawkins
authors.affiliation: Division of Epidemiology, Department of Medicine, 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: Yii-Der
authors.initials: YD
authors.lastname: Ida Chen
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: 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: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Molecular Genetics and Genomics Program, 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: 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 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.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D007797:Laminin / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D051839:NFI Transcription Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D055815:Young Adult
chemical_list: D007797:Laminin; D051839:NFI Transcription Factors; C110754:NFIB protein, human; D014409:Tumor Necrosis Factor-alpha; C084098:laminin A