TY - JOUR
T1 - Genome-wide linkage and association analysis of cardiometabolic phenotypes in Hispanic Americans
AU - Hellwege, Jacklyn N.
AU - Palmer, Nicholette D.
AU - Dimitrov, Latchezar
AU - Keaton, Jacob M.
AU - Tabb, Keri L.
AU - Sajuthi, Satria
AU - Taylor, Kent D.
AU - Ng, Maggie C.Y.
AU - Speliotes, Elizabeth K.
AU - Hawkins, Gregory A.
AU - Long, Jirong
AU - Ida Chen, Yii Der
AU - Lorenzo, Carlos
AU - Norris, Jill M.
AU - Rotter, Jerome I.
AU - Langefeld, Carl D.
AU - Wagenknecht, Lynne E.
AU - Bowden, Donald W.
N1 - Funding Information:
This work was supported by the Grants R01 HG007112 (to DWB and CDL) and R01 DK087914 (to MCYN). The GUARDIAN study, which contributed the IRASFS GWAS genotypes to this project is supported by Grant R01 DK085175 (to LEW), and the IRASFS study was supported by HL060944, HL061019 and HL060919. The provision of GWAS genotyping data was supported, in part, by UL1TR000124 (CTSI), and DK063491 (DRC). The provision of exome chip data was supported, in part, by the Department of Internal Medicine at University of Michigan, the Doris Duke Medical Foundation and R01 DK106621 (to EKS). Computational support was provided, in part, by the Center for Public Health Genomics at Wake Forest School of Medicine.
Publisher Copyright:
© 2017 The Japan Society of Human Genetics All rights reserved.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
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U2 - 10.1038/jhg.2016.103
DO - 10.1038/jhg.2016.103
M3 - Article
C2 - 27535031
AN - SCOPUS:85010874865
SN - 1434-5161
VL - 62
SP - 175
EP - 184
JO - Journal of Human Genetics
JF - Journal of Human Genetics
IS - 2
ER -