Dataset Information

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-? (TNF?) 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 TNF? 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.

SUBMITTER: Hellwege JN

PROVIDER: S-EPMC5266668 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Genome-wide linkage and association analysis of cardiometabolic phenotypes in Hispanic Americans.

Hellwege Jacklyn N JN Palmer Nicholette D ND Dimitrov Latchezar L Keaton Jacob M JM Tabb Keri L KL Sajuthi Satria S Taylor Kent D KD Ng Maggie C Y MC Speliotes Elizabeth K EK Hawkins Gregory A GA Long Jirong J Ida Chen Yii-Der YD Lorenzo Carlos C Norris Jill M JM Rotter Jerome I JI Langefeld Carl D CD Wagenknecht Lynne E LE Bowden Donald W DW

Journal of human genetics 20160818 2

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, whi ...[more]

PMID: 27535031

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Project description:Insertions and deletions (INDELs) represent a significant fraction of interindividual variation in the human genome yet their contribution to phenotypes is poorly understood. To confirm the quality of imputed INDELs and investigate their roles in mediating cardiometabolic phenotypes, genome-wide association and linkage analyses were performed for 15 phenotypes with 1,273,952 imputed INDELs in 1,024 Mexican-origin Americans. Imputation quality was validated using whole exome sequencing with an average kappa of 0.93 in common INDELs (minor allele frequencies [MAFs] ≥ 5%). Association analysis revealed one genome-wide significant association signal for the cholesterylester transfer protein gene (CETP) with high-density lipoprotein levels (rs36229491, P = 3.06 × 10-12 ); linkage analysis identified two peaks with logarithm of the odds (LOD) > 5 (rs60560566, LOD = 5.36 with insulin sensitivity (SI ) and rs5825825, LOD = 5.11 with adiponectin levels). Suggestive overlapping signals between linkage and association were observed: rs59849892 in the WSC domain containing 2 gene (WSCD2) was associated and nominally linked with SI (P = 1.17 × 10-7 , LOD = 1.99). This gene has been implicated in glucose metabolism in human islet cell expression studies. In addition, rs201606363 was linked and nominally associated with low-density lipoprotein (P = 4.73 × 10-4 , LOD = 3.67), apolipoprotein B (P = 1.39 × 10-3 , LOD = 4.64), and total cholesterol (P = 1.35 × 10-2 , LOD = 3.80) levels. rs201606363 is an intronic variant of the UBE2F-SCLY (where UBE2F is ubiquitin-conjugating enzyme E2F and SCLY is selenocysteine lyase) fusion gene that may regulate cholesterol through selenium metabolism. In conclusion, these results confirm the feasibility of imputing INDELs from array-based single nucleotide polymorphism (SNP) genotypes. Analysis of these variants using association and linkage replicated previously identified SNP signals and identified multiple novel INDEL signals. These results support the inclusion of INDELs into genetic studies to more fully interrogate the spectrum of genetic variation.

Dataset Information

Genome-wide linkage and association analysis of cardiometabolic phenotypes in Hispanic Americans.

Publications

Genome-wide linkage and association analysis of cardiometabolic phenotypes in Hispanic Americans.

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