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 - 11 Jul 2016 |
Keywords
- Alleles
- DNA Mutational Analysis
- Diabetes Mellitus, Type 2
- Europe
- Exome
- Genetic Predisposition to Disease
- Genetic Variation
- Genome-Wide Association Study
- Genotyping Techniques
- Humans
- Sample Size
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
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The genetic architecture of type 2 diabetes. / Fuchsberger, Christian; Flannick, Jason; Teslovich, Tanya M et al.
In: Nature, Vol. 536, No. 7614, 11.07.2016, p. 41-47.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The genetic architecture of type 2 diabetes
AU - Fuchsberger, Christian
AU - Flannick, Jason
AU - Teslovich, Tanya M
AU - Mahajan, Anubha
AU - Agarwala, Vineeta
AU - Gaulton, Kyle J
AU - Ma, Clement
AU - Fontanillas, Pierre
AU - Moutsianas, Loukas
AU - McCarthy, Davis J
AU - Rivas, Manuel A
AU - Perry, John R B
AU - Sim, Xueling
AU - Blackwell, Thomas W
AU - Robertson, Neil R
AU - Rayner, N William
AU - Cingolani, Pablo
AU - Locke, Adam E
AU - Fernandez Tajes, Juan
AU - Highland, Heather M
AU - Dupuis, Josee
AU - Chines, Peter S
AU - Lindgren, Cecilia M
AU - Hartl, Christopher
AU - Jackson, Anne U
AU - Chen, Han
AU - Huyghe, Jeroen R
AU - van de Bunt, Martijn
AU - Pearson, Richard D
AU - Kumar, Ashish
AU - Müller-Nurasyid, Martina
AU - Grarup, Niels
AU - Stringham, Heather M
AU - Gamazon, Eric R
AU - Lee, Jaehoon
AU - Chen, Yuhui
AU - Scott, Robert A
AU - Below, Jennifer E
AU - Chen, Peng
AU - Huang, Jinyan
AU - Go, Min Jin
AU - Stitzel, Michael L
AU - Pasko, Dorota
AU - Parker, Stephen C J
AU - Varga, Tibor V
AU - Green, Todd
AU - Beer, Nicola L
AU - Day-Williams, Aaron G
AU - Ferreira, Teresa
AU - Fingerlin, Tasha
AU - Horikoshi, Momoko
AU - Hu, Cheng
AU - Huh, Iksoo
AU - Ikram, Mohammad Kamran
AU - Kim, Bong-Jo
AU - Kim, Yongkang
AU - Kim, Young Jin
AU - Kwon, Min-Seok
AU - Lee, Juyoung
AU - Lee, Selyeong
AU - Lin, Keng-Han
AU - Maxwell, Taylor J
AU - Nagai, Yoshihiko
AU - Wang, Xu
AU - Welch, Ryan P
AU - Yoon, Joon
AU - Zhang, Weihua
AU - Barzilai, Nir
AU - Voight, Benjamin F
AU - Han, Bok-Ghee
AU - Jenkinson, Christopher P
AU - Kuulasmaa, Teemu
AU - Kuusisto, Johanna
AU - Manning, Alisa
AU - Ng, Maggie C Y
AU - Palmer, Nicholette D
AU - Balkau, Beverley
AU - Stancáková, Alena
AU - Abboud, Hanna E
AU - Boeing, Heiner
AU - Giedraitis, Vilmantas
AU - Prabhakaran, Dorairaj
AU - Gottesman, Omri
AU - Scott, James
AU - Carey, Jason
AU - Kwan, Phoenix
AU - Grant, George
AU - Smith, Joshua D
AU - Neale, Benjamin M
AU - Purcell, Shaun
AU - Butterworth, Adam S
AU - Howson, Joanna M M
AU - Lee, Heung Man
AU - Lu, Yingchang
AU - Kwak, Soo-Heon
AU - Zhao, Wei
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
AU - Chan, Edmund
AU - Navarro, Carmen
AU - Cheng, Ching-Yu
AU - Palli, Domenico
AU - Correa, Adolfo
AU - Curran, Joanne E
AU - Rybin, Denis
AU - Farook, Vidya S
AU - Fowler, Sharon P
AU - Freedman, Barry I
AU - Griswold, Michael
AU - Hale, Daniel Esten
AU - Hicks, Pamela J
AU - Khor, Chiea-Chuen
AU - Kumar, Satish
AU - Lehne, Benjamin
AU - Thuillier, Dorothée
AU - Lim, Wei Yen
AU - Liu, Jianjun
AU - van der Schouw, Yvonne T
AU - Loh, Marie
AU - Musani, Solomon K
AU - Puppala, Sobha
AU - Scott, William R
AU - Yengo, Loïc
AU - Tan, Sian-Tsung
AU - Taylor, Herman A
AU - Thameem, Farook
AU - Wilson, Gregory
AU - Wong, Tien Yin
AU - Njølstad, Pål Rasmus
AU - Levy, Jonathan C
AU - Mangino, Massimo
AU - Bonnycastle, Lori L
AU - Schwarzmayr, Thomas
AU - Fadista, João
AU - Surdulescu, Gabriela L
AU - Herder, Christian
AU - Groves, Christopher J
AU - Wieland, Thomas
AU - Bork-Jensen, Jette
AU - Brandslund, Ivan
AU - Christensen, Cramer
AU - Koistinen, Heikki A
AU - Doney, Alex S F
AU - Kinnunen, Leena
AU - Esko, Tõnu
AU - Farmer, Andrew J
AU - Hakaste, Liisa
AU - Hodgkiss, Dylan
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
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
AU - Chandak, Giriraj R
AU - Chan, Juliana C N
AU - Chia, Kee Seng
AU - Daly, Mark J
AU - Ebrahim, Shah B
AU - Langenberg, Claudia
AU - Elliott, Paul
AU - Jablonski, Kathleen A
AU - Lehman, Donna M
AU - Jia, Weiping
AU - Ma, Ronald C W
AU - Pollin, Toni I
AU - Sandhu, Manjinder
AU - Tandon, Nikhil
AU - Froguel, Philippe
AU - Barroso, Inês
AU - Teo, Yik Ying
AU - Zeggini, Eleftheria
AU - Loos, Ruth J F
AU - Small, Kerrin S
AU - Ried, Janina S
AU - DeFronzo, Ralph A
AU - Grallert, Harald
AU - Glaser, Benjamin
AU - Metspalu, Andres
AU - Wareham, Nicholas J
AU - Walker, Mark
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
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.
KW - Alleles
KW - DNA Mutational Analysis
KW - Diabetes Mellitus, Type 2
KW - Europe
KW - Exome
KW - Genetic Predisposition to Disease
KW - Genetic Variation
KW - Genome-Wide Association Study
KW - Genotyping Techniques
KW - Humans
KW - Sample Size
KW - Journal Article
KW - Research Support, N.I.H., Extramural
KW - Research Support, Non-U.S. Gov't
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 -