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 |
|---|---|
| Journal | Nature |
| Volume | 536 |
| Issue number | 7614 |
| Pages (from-to) | 41-47 |
| Number of pages | 7 |
| ISSN | 0028-0836 |
| DOIs | |
| Publication status | Published - 2016 |
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In: Nature, Vol. 536, No. 7614, 2016, p. 41-47.
Research output: Contribution to journal › Journal article › Research › peer-review
TY - JOUR
T1 - The genetic architecture of type 2 diabetes
AU - Fuchsberger, Christian
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AU - Zhang, Weihua
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AU - Saleheen, Danish
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AU - Tam, Claudia H T
AU - Afzal, Uzma
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AU - Schwarzmayr, Thomas
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AU - Christensen, Cramer
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AU - Esko, Tõnu
AU - Farmer, Andrew J
AU - Hakaste, Liisa
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AU - Kravic, Jasmina
AU - Lyssenko, Valeriya
AU - Hollensted, Mette
AU - Jørgensen, Marit E
AU - Jørgensen, Torben
AU - Ladenvall, Claes
AU - Justesen, Johanne Marie
AU - Käräjämäki, Annemari
AU - Kriebel, Jennifer
AU - Rathmann, Wolfgang
AU - Lannfelt, Lars
AU - Lauritzen, Torsten
AU - Narisu, Narisu
AU - Linneberg, Allan
AU - Melander, Olle
AU - Milani, Lili
AU - Neville, Matt
AU - Orho-Melander, Marju
AU - Qi, Lu
AU - Qi, Qibin
AU - Roden, Michael
AU - Rolandsson, Olov
AU - Swift, Amy
AU - Rosengren, Anders H
AU - Stirrups, Kathleen
AU - Wood, Andrew R
AU - Mihailov, Evelin
AU - Blancher, Christine
AU - Carneiro, Mauricio O
AU - Maguire, Jared
AU - Poplin, Ryan
AU - Shakir, Khalid
AU - Fennell, Timothy
AU - DePristo, Mark
AU - Hrabé de Angelis, Martin
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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
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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 - Chan, Juliana C N
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AU - Jablonski, Kathleen A
AU - Lehman, Donna M
AU - Jia, Weiping
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AU - Sandhu, Manjinder
AU - Tandon, Nikhil
AU - Froguel, Philippe
AU - Barroso, Inês
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AU - Loos, Ruth J F
AU - Small, Kerrin S
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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
PY - 2016
Y1 - 2016
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.
U2 - 10.1038/nature18642
DO - 10.1038/nature18642
M3 - Journal article
C2 - 27398621
SN - 0028-0836
VL - 536
SP - 41
EP - 47
JO - Nature
JF - Nature
IS - 7614
ER -