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Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):379-384. doi: 10.1073/pnas.1705859115. Epub 2017 Dec 26.

Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees.

Author information

1
Department of Biostatistics, University of Michigan, Ann Arbor, MI 48105; goo.jun@uth.tmc.edu.
2
Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48105.
3
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77225.
4
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142.
5
South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, Brownsville and Edinburg, TX 78520.
6
Department of Biostatistics, University of Michigan, Ann Arbor, MI 48105.
7
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, United Kingdom.
8
Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591.
9
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lubeck, 39100 Bolzano, Italy.
10
Génome Québec Innovation Centre, McGill University, Montreal, QC H3A 0E9, Canada.
11
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom.
12
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118.
13
Center for Precision Health, School of Public Health and School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030.
14
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
15
The Research Institute of Basic Sciences, Seoul National University, Seoul 08826, Republic of Korea.
16
Department of Medicine, Section of Genetic Medicine, The University of Chicago, Chicago, IL 60637.
17
Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, Republic of Korea.
18
Complete Genomics, Mountain View, CA 95134.
19
Invitae, San Francisco, CA 94103.
20
Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO 80045.
21
Department of Statistics, Seoul National University, Seoul 08826, Republic of Korea.
22
Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do 28159, Republic of Korea.
23
Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore 117549.
24
Clinical Research Centre, Centre for Molecular Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom.
25
Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, United Kingdom.
26
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.
27
Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201.
28
Program in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.
29
Department of Genetics, Harvard Medical School, Boston, MA 02115.
30
Life Sciences Institute, National University of Singapore, Singapore 117549.
31
Department of Statistics and Applied Probability, National University of Singapore, Singapore 117549.
32
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Bethesda, MD 20892.
33
Department of Medicine, The University of Chicago, Chicago, IL 60637.
34
Department of Human Genetics, The University of Chicago, Chicago, IL 60637.
35
Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN 37332.
36
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114.
37
Department of Medicine, Harvard Medical School, Boston, MA.
38
Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114.
39
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599.
40
Department of Laboratory Medicine, University of California, San Francisco, CA 94143.
41
Institute for Human Genetics, University of California, San Francisco, CA 94143.
42
Blood Systems Research Institute, San Francisco, CA 94118.
43
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216.
44
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461.
45
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461.
46
Department of Natural Science, University of Haifa, 3498838 Haifa, Israel.
47
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702.
48
Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229.
49
School of Public Health, Seoul National University, Seoul 08826, Republic of Korea.
50
Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada.
51
Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
52
Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA 02115.
53
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142.
54
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom.
55
Oxford National Institute for Health Research Biomedical Research Centre, Oxford University Hospitals Trust, Oxford OX4 2PG, United Kingdom.

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.

KEYWORDS:

eQTL; genetics; rare variants; sequencing; type 2 diabetes

PMID:
29279374
PMCID:
PMC5777025
DOI:
10.1073/pnas.1705859115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

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.

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