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Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Jan 09; Vol. 115 (2), pp. 379-384. Date of Electronic Publication: 2017 Dec 26. - Publication Year :
- 2018
-
Abstract
- A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis -expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.<br />Competing Interests: Conflict of interest statement: S.E.L., J. Laramie, and R.G.T. were employees of Complete Genomics during this study. T.M.T. is an employee of Regeneron Pharmaceuticals. D.A. is an employee of Vertex Pharmaceuticals.
- Subjects :
- Diabetes Mellitus, Type 2 ethnology
Diabetes Mellitus, Type 2 pathology
Family Health
Female
Gene Frequency
Genetic Predisposition to Disease ethnology
Genome-Wide Association Study methods
Genotype
Humans
Male
Pedigree
Phenotype
Quantitative Trait Loci genetics
Whole Genome Sequencing methods
Diabetes Mellitus, Type 2 genetics
Genetic Predisposition to Disease genetics
Genetic Variation
Mexican Americans genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 115
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 29279374
- Full Text :
- https://doi.org/10.1073/pnas.1705859115