Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees
Proceedings of the National Academy of Sciences
National Academy of Sciences
© 2018 National Academy of Sciences. Published version under the PNAS license: http://www.pnas.org/page/authors/licenses
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-variantcis-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.
We warmly thank the participants of the SAFHS and SAFDGS for their contribution, enthusiasm, and cooperation. This study is part of the Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) Consortium, funded by the European Commission (HEALTH-F4-2007-201413), Wellcome Trust (090367, 090532, 098381), Medical Research Council (G0601261), and NIH/NIDDK (RC2-DK08839, DK105535, DK085524, DK085545, DK085584, DK085501, DK098032, DK078616, DK085526). The whole-genome sequencing was done commercially by Complete Genomics, Inc. Additional genetic and phenotypic data were provided by the San Antonio Family Heart Study and San Antonio Family Diabetes/Gallbladder Study, which are supported by NIH Grants R01 HL0113323, P01 HL045222, R01 DK047482, and R01 DK053889. SAFHS gene expression data were generated through a donation from the Azar and Shepperd families. J.G.W. was supported by U54GM115428 from the National Institute of General Medical Sciences. S.C., S.L., J.K., J. Lee, and T.P. were supported by the Bio-Synergy Research Project (2013M3A9C4078158) of the Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea, and Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare (HI15C2165, HI16C2037). A.K.M. was supported by American Diabetes Association Mentor-Based Postdoctoral Fellowship #7-12-MN-02. M.I.M. is a Wellcome Trust Senior Investigator. The research was supported by the National Institute for Health Research (NIHR), Oxford Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or Department of Health, United Kingdom.
This is the author accepted manuscript. The final version is available from the National Academy of Sciences via the DOI in this record
Vol. 115 (2), pp. 379 - 384
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