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

Kirk E. Lohmueller; Thomas Hempel Sparsø; Qibin Li; Ehm Astrid Andersson Galijatovic; Thorfinn Sand Korneliussen; Anders Albrechtsen; Karina Banasik; Niels Grarup; Ingileif Hallgrimsdottir; Kristoffer Kiil; Tuomas Oskari Kilpeläinen; Nikolaj Thure Krarup; Tune Hannes Pers; Gaston Sanchez; Youna Hu; Michael DeGiorgio; Torben Jørgensen; Annelli Sandbæk; Torsten  Lauritzen; Søren Brunak; Karsten Kristiansen; Yingrui Li; Torben Hansen; Jun Wang; Rasmus Nielsen; Oluf Borbye Pedersen

doi:10.1016/j.ajhg.2013.11.005

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

Kirk E. Lohmueller, Thomas Hempel Sparsø, Qibin Li, Ehm Astrid Andersson Galijatovic, Thorfinn Sand Korneliussen, Anders Albrechtsen, Karina Banasik, Niels Grarup, Ingileif Hallgrimsdottir, Kristoffer Kiil, Tuomas Oskari Kilpeläinen, Nikolaj Thure Krarup, Tune Hannes Pers, Gaston Sanchez, Youna Hu, Michael DeGiorgio, Torben Jørgensen, Annelli Sandbæk, Torsten Lauritzen, Søren BrunakKarsten Kristiansen, Yingrui Li, Torben Hansen, Jun Wang, Rasmus Nielsen, Oluf Borbye Pedersen

98 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	American Journal of Human Genetics
Vol/bind	93
Udgave nummer	6
Sider (fra-til)	1072-1086
Antal sider	15
ISSN	0002-9297
DOI	https://doi.org/10.1016/j.ajhg.2013.11.005
Status	Udgivet - 5 dec. 2013

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

10.1016/j.ajhg.2013.11.005

http://www.cell.com/article/S000292971300520X/pdf

Andre filer og links

Erratum

Citationsformater

Lohmueller, K. E., Sparsø, T. H., Li, Q., Galijatovic, E. A. A., Korneliussen, T. S., Albrechtsen, A., Banasik, K., Grarup, N., Hallgrimsdottir, I., Kiil, K., Oskari Kilpeläinen, T., Krarup, N. T., Pers, T. H., Sanchez, G., Hu, Y., DeGiorgio, M., Jørgensen, T., Sandbæk, A., Lauritzen, T., ... Pedersen, O. B. (2013). Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes. American Journal of Human Genetics, 93(6), 1072-1086. https://doi.org/10.1016/j.ajhg.2013.11.005

Lohmueller, KE, Sparsø, TH, Li, Q, Galijatovic, EAA, Korneliussen, TS , Albrechtsen, A , Banasik, K , Grarup, N, Hallgrimsdottir, I, Kiil, K, Oskari Kilpeläinen, T, Krarup, NT, Pers, TH, Sanchez, G, Hu, Y, DeGiorgio, M, Jørgensen, T, Sandbæk, A, Lauritzen, T, Brunak, S, Kristiansen, K, Li, Y, Hansen, T, Wang, J, Nielsen, R & Pedersen, OB 2013, 'Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes', American Journal of Human Genetics, bind 93, nr. 6, s. 1072-1086. https://doi.org/10.1016/j.ajhg.2013.11.005

@article{4aea19c28e81438e8e5fe05ac34fff6f,

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.",

author = "Lohmueller, {Kirk E.} and Spars{\o}, {Thomas Hempel} and Qibin Li and Galijatovic, {Ehm Astrid Andersson} and Korneliussen, {Thorfinn Sand} and Anders Albrechtsen and Karina Banasik and Niels Grarup and Ingileif Hallgrimsdottir and Kristoffer Kiil and {Oskari Kilpel{\"a}inen}, Tuomas and Krarup, {Nikolaj Thure} and Pers, {Tune Hannes} and Gaston Sanchez and Youna Hu and Michael DeGiorgio and Torben J{\o}rgensen and Annelli Sandb{\ae}k and Torsten Lauritzen and S{\o}ren Brunak and Karsten Kristiansen and Yingrui Li and Torben Hansen and Jun Wang and Rasmus Nielsen and Pedersen, {Oluf Borbye}",

note = "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",

year = "2013",

month = dec,

day = "5",

doi = "10.1016/j.ajhg.2013.11.005",

language = "English",

volume = "93",

pages = "1072--1086",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "6",

}

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

SN - 0002-9297

VL - 93

SP - 1072

EP - 1086

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

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

Abstract

FN’s Verdensmål

Adgang til dokumentet

Andre filer og links

Fingeraftryk

Citationsformater