Abstract
The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
Original language | English |
---|---|
Pages (from-to) | 41-47 |
Number of pages | 7 |
Journal | Nature |
Volume | 536 |
Issue number | 7614 |
DOIs | |
State | Published - 11 Jul 2016 |
Bibliographical note
Publisher Copyright:© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
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In: Nature, Vol. 536, No. 7614, 11.07.2016, p. 41-47.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - The genetic architecture of type 2 diabetes
AU - Fuchsberger, Christian
AU - Flannick, Jason
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AU - Mahajan, Anubha
AU - Agarwala, Vineeta
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AU - Wang, Xu
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AU - Zhang, Weihua
AU - Barzilai, Nir
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AU - Carey, Jason
AU - Kwan, Phoenix
AU - Grant, George
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AU - Lee, Heung Man
AU - Lu, Yingchang
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AU - Danesh, John
AU - Lam, Vincent K.L.
AU - Park, Kyong Soo
AU - Saleheen, Danish
AU - So, Wing Yee
AU - Tam, Claudia H.T.
AU - Afzal, Uzma
AU - Aguilar, David
AU - Arya, Rector
AU - Aung, Tin
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AU - Correa, Adolfo
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AU - Schwarzmayr, Thomas
AU - Fadista, Joao
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AU - Herder, Christian
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AU - Bork-Jensen, Jette
AU - Brandslund, Ivan
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AU - Kinnunen, Leena
AU - Esko, Tonu
AU - Farmer, Andrew J.
AU - Hakaste, Liisa
AU - Hodgkiss, Dylan
AU - Kravic, Jasmina
AU - Lyssenko, Valeriya
AU - Hollensted, Mette
AU - Jorgensen, Marit E.
AU - Jorgensen, Torben
AU - Ladenvall, Claes
AU - Justesen, Johanne Marie
AU - Käräjämäki, Annemari
AU - Kriebel, Jennifer
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AU - Lauritzen, Torsten
AU - Narisu, Narisu
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AU - Melander, Olle
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AU - Orho-Melander, Marju
AU - Qi, Lu
AU - Qi, Qibin
AU - Roden, Michael
AU - Rolandsson, Olov
AU - Swift, Amy
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AU - Stirrups, Kathleen
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AU - Mihailov, Evelin
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AU - DePristo, Mark
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AU - Deloukas, Panos
AU - Gjesing, Anette P.
AU - Jun, Goo
AU - Nilsson, Peter
AU - Murphy, Jacquelyn
AU - Onofrio, Robert
AU - Thorand, Barbara
AU - Hansen, Torben
AU - Meisinger, Christa
AU - Hu, Frank B.
AU - Isomaa, Bo
AU - Karpe, Fredrik
AU - Liang, Liming
AU - Peters, Annette
AU - Huth, Cornelia
AU - O'Rahilly, Stephen P.
AU - Palmer, Colin N.A.
AU - Pedersen, Oluf
AU - Rauramaa, Rainer
AU - Tuomilehto, Jaakko
AU - Salomaa, Veikko
AU - Watanabe, Richard M.
AU - Syvänen, Ann Christine
AU - Bergman, Richard N.
AU - Bharadwaj, Dwaipayan
AU - Bottinger, Erwin P.
AU - Cho, Yoon Shin
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AU - Banks, Eric
AU - Gieger, Christian
AU - Ingelsson, Erik
AU - Im, Hae Kyung
AU - Illig, Thomas
AU - Franks, Paul W.
AU - Buck, Gemma
AU - Trakalo, Joseph
AU - Buck, David
AU - Prokopenko, Inga
AU - Mägi, Reedik
AU - Lind, Lars
AU - Farjoun, Yossi
AU - Owen, Katharine R.
AU - Gloyn, Anna L.
AU - Strauch, Konstantin
AU - Tuomi, Tiinamaija
AU - Kooner, Jaspal Singh
AU - Lee, Jong Young
AU - Park, Taesung
AU - Donnelly, Peter
AU - Morris, Andrew D.
AU - Hattersley, Andrew T.
AU - Bowden, Donald W.
AU - Collins, Francis S.
AU - Atzmon, Gil
AU - Chambers, John C.
AU - Spector, Timothy D.
AU - Laakso, Markku
AU - Strom, Tim M.
AU - Bell, Graeme I.
AU - Blangero, John
AU - Duggirala, Ravindranath
AU - Tai, E. Shyong
AU - McVean, Gilean
AU - Hanis, Craig L.
AU - Wilson, James G.
AU - Seielstad, Mark
AU - Frayling, Timothy M.
AU - Meigs, James B.
AU - Cox, Nancy J.
AU - Sladek, Rob
AU - Lander, Eric S.
AU - Gabriel, Stacey
AU - Burtt, Noël P.
AU - Mohlke, Karen L.
AU - Meitinger, Thomas
AU - Groop, Leif
AU - Abecasis, Goncalo
AU - Florez, Jose C.
AU - Scott, Laura J.
AU - Morris, Andrew P.
AU - Kang, Hyun Min
AU - Boehnke, Michael
AU - Altshuler, David
AU - McCarthy, Mark I.
N1 - Publisher Copyright: © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2016/7/11
Y1 - 2016/7/11
N2 - The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
AB - The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
UR - http://www.scopus.com/inward/record.url?scp=84978128486&partnerID=8YFLogxK
U2 - 10.1038/nature18642
DO - 10.1038/nature18642
M3 - Article
C2 - 27398621
AN - SCOPUS:84978128486
SN - 0028-0836
VL - 536
SP - 41
EP - 47
JO - Nature
JF - Nature
IS - 7614
ER -