TY - JOUR

T1 - Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes

AU - Lohmueller, Kirk E.

AU - Sparsø, Thomas Hempel

AU - Li, Qibin

AU - Galijatovic, Ehm Astrid Andersson

AU - Korneliussen, Thorfinn Sand

AU - Albrechtsen, Anders

AU - Banasik, Karina

AU - Grarup, Niels

AU - Hallgrimsdottir, Ingileif

AU - Kiil, Kristoffer

AU - Oskari Kilpeläinen, Tuomas

AU - Krarup, Nikolaj Thure

AU - Pers, Tune Hannes

AU - Sanchez, Gaston

AU - Hu, Youna

AU - DeGiorgio, Michael

AU - Jørgensen, Torben

AU - Sandbæk, Annelli

AU - Lauritzen, Torsten

AU - Brunak, Søren

AU - Kristiansen, Karsten

AU - Li, Yingrui

AU - Hansen, Torben

AU - Wang, Jun

AU - Nielsen, Rasmus

AU - Pedersen, Oluf Borbye

N1 - Erratum: Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes DOI: 10.1016/j.ajhg.2014.02.002

PY - 2013/12/5

Y1 - 2013/12/5

N2 - 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.

AB - 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.

UR - http://10.1016/j.ajhg.2014.02.002

U2 - 10.1016/j.ajhg.2013.11.005

DO - 10.1016/j.ajhg.2013.11.005

M3 - Journal article

C2 - 24290377

VL - 93

SP - 1072

EP - 1086

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -