title: A genome-wide linkage and association analysis of imputed insertions and deletions with cardiometabolic phenotypes in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study.
abstract: 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.
authors.affiliation: Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Chuan
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Fang-Chi
authors.initials: FC
authors.lastname: Hsu
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Latchezar M
authors.initials: LM
authors.lastname: Dimitrov
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Hayrettin
authors.initials: H
authors.lastname: Okut
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.|Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Yii-Der I
authors.initials: YI
authors.lastname: Chen
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.|Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.|Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Nicholette D
authors.identifier: 0000-0002-4877-2072
authors.initials: ND
authors.lastname: Palmer
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000235:genetics*; D003710:Demography; D005190:Family; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D008040:Genetic Linkage; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D017058:Mexican Americans / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
keywords: cardiometabolic disease; genome-wide association analysis; imputation; insertion/deletions; linkage analysis