AJHG - Whole-Exome Sequencing of 2,000 Danish Individuals and the Role of Rare Coding Variants in Type 2 Diabetes
Copyright © 2013 The American Society of Human Genetics All rights reserved.
The American Journal of Human Genetics, Volume 93, Issue 6, 1072-1086, 27 November 2013
doi:10.1016/j.ajhg.2013.11.005
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Article
Whole-Exome Sequencing of 2,000 Danish Individuals and the Role of Rare Coding Variants in Type 2 Diabetes
Kirk E. Lohmueller1, 18, 19, Thomas Sparsø2, 18, Qibin Li3, Ehm Andersson2, Thorfinn Korneliussen4, Anders Albrechtsen5, Karina Banasik2, Niels Grarup2, Ingileif Hallgrimsdottir6, Kristoffer Kiil2, Tuomas O. Kilpeläinen2, Nikolaj T. Krarup2, Tune H. Pers7, 8, 9, Gaston Sanchez6, Youna Hu1, Michael DeGiorgio1, 20, Torben Jørgensen10, 11, 12, Annelli Sandbæk13, Torsten Lauritzen13, Søren Brunak7, Karsten Kristiansen3, 5, Yingrui Li3, Torben Hansen2, 14, Jun Wang2, 3, 5, Rasmus Nielsen1, 5, 15, 
, 
and Oluf Pedersen2, 16, 17, ,
1 Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA
2 The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
3 BGI-Shenzhen, Yantian District, 518083 Shenzhen, China
4 Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen, Denmark
5 Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
6 Center for Theoretical Evolutionary Genomics, University of California, Berkeley, Berkeley, CA 94720, USA
7 Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark
8 Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA
9 Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA 02115, USA
10 Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
11 Faculty of Medicine, University of Aalborg, 9220 Aalborg, Denmark
12 Research Center for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark
13 Department of Public Health, Section for General Practice, Aarhus University, 8000 Aarhus, Denmark
14 Faculty of Health Sciences, University of Southern Denmark, 5230 Odense M, Denmark
15 Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA
16 Institute of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
17 Faculty of Health Sciences, Aarhus University, 8000 Aarhus, Denmark
Corresponding author
Corresponding author
18 These authors contributed equally to this work
19 Present address: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
20 Present address: Department of Biology, Pennsylvania State University, 502 Wartik Laboratory, University Park, PA 16802, USA
Abstract
It has been hypothesized that, in aggregate, rare variants in coding regions of genes explain a substantial fraction of the heritability of common diseases. We sequenced the exomes of 1,000 Danish cases with common forms of type 2 diabetes (including body mass index > 27.5 kg/m2 and hypertension) and 1,000 healthy controls to an average depth of 56×. Our simulations suggest that our study had the statistical power to detect at least one causal gene (a gene containing causal mutations) if the heritability of these common diseases was explained by rare variants in the coding regions of a limited number of genes. We applied a series of gene-based tests to detect such susceptibility genes. However, no gene showed a significant association with disease risk after we corrected for the number of genes analyzed. Thus, we could reject a model for the genetic architecture of type 2 diabetes where rare nonsynonymous variants clustered in a modest number of genes (fewer than 20) are responsible for the majority of disease risk.