title: Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes.
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/m(2) 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.
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Kirk E
authors.initials: KE
authors.lastname: Lohmueller
authors.forename: Thomas
authors.initials: T
authors.lastname: Sparsø
authors.forename: Qibin
authors.initials: Q
authors.lastname: Li
authors.forename: Ehm
authors.initials: E
authors.lastname: Andersson
authors.forename: Thorfinn
authors.initials: T
authors.lastname: Korneliussen
authors.forename: Anders
authors.initials: A
authors.lastname: Albrechtsen
authors.forename: Karina
authors.initials: K
authors.lastname: Banasik
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.forename: Ingileif
authors.initials: I
authors.lastname: Hallgrimsdottir
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Kiil
authors.forename: Tuomas O
authors.initials: TO
authors.lastname: Kilpeläinen
authors.forename: Nikolaj T
authors.initials: NT
authors.lastname: Krarup
authors.forename: Tune H
authors.initials: TH
authors.lastname: Pers
authors.forename: Gaston
authors.initials: G
authors.lastname: Sanchez
authors.forename: Youna
authors.initials: Y
authors.lastname: Hu
authors.forename: Michael
authors.initials: M
authors.lastname: Degiorgio
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.forename: Annelli
authors.initials: A
authors.lastname: Sandbæk
authors.forename: Torsten
authors.initials: T
authors.lastname: Lauritzen
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
authors.forename: Yingrui
authors.initials: Y
authors.lastname: Li
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Rasmus
authors.initials: R
authors.lastname: Nielsen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D019295:Computational Biology; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D059472:Exome; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015233:Models, Statistical; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D044465:White People