The genetic architecture of type 2 diabetes

• Published in: Nature (London) Vol. 536; no. 7614; pp. 41 - 47
• Main Authors: Gaulton, Kyle J., McCarthy, Davis J., Sim, Xueling, Rayner, N. William, Cingolani, Pablo, Hartl, Christopher, Pearson, Richard D., Grarup, Niels, Chen, Yuhui, Chen, Peng, Go, Min Jin, Parker, Stephen C. J., Varga, Tibor V., Hu, Cheng, Kim, Bong-Jo, Kim, Yongkang, Kim, Young Jin, Maxwell, Taylor J., Nagai, Yoshihiko, Zhang, Weihua, Barzilai, Nir, Han, Bok-Ghee, Stančáková, Alena, Abboud, Hanna E., Boeing, Heiner, Prabhakaran, Dorairaj, Butterworth, Adam S., Lee, Heung Man, Kwak, Soo-Heon, Zhao, Wei, So, Wing Yee, Cheng, Ching-Yu, Curran, Joanne E., Freedman, Barry I., Kumar, Satish, van der Schouw, Yvonne T., Loh, Marie, Musani, Solomon K., Tan, Sian-Tsung, Taylor Jr, Herman A., Levy, Jonathan C., Mangino, Massimo, Bonnycastle, Lori L., Fadista, João, Surdulescu, Gabriela L., Herder, Christian, Groves, Christopher J., Brandslund, Ivan, Lyssenko, Valeriya, Hollensted, Mette, Jørgensen, Marit E., Ladenvall, Claes, Justesen, Johanne Marie, Linneberg, Allan, Qi, Qibin, Roden, Michael, Wood, Andrew R., Mihailov, Evelin, Maguire, Jared, Poplin, Ryan, Shakir, Khalid, Hrabé de Angelis, Martin, Jun, Goo, Murphy, Jacquelyn, Onofrio, Robert, Thorand, Barbara, Meisinger, Christa, Hu, Frank B., Peters, Annette, Rauramaa, Rainer, Salomaa, Veikko, Watanabe, Richard M., Bergman, Richard N., Bharadwaj, Dwaipayan, Chia, Kee Seng, Langenberg, Claudia, Elliott, Paul, Jablonski, Kathleen A., Ma, Ronald C. W., Tandon, Nikhil, Barroso, Inês, Zeggini, Eleftheria, Ried, Janina S., DeFronzo, Ralph A., Grallert, Harald, Banks, Eric, Trakalo, Joseph, Lind, Lars, Farjoun, Yossi, Owen, Katharine R., Gloyn, Anna L., Kooner, Jaspal Singh, Bowden, Donald W., Collins, Francis S., Atzmon, Gil, Hanis, Craig L., Seielstad, Mark, Frayling, Timothy M., Scott, Laura J., Altshuler, David
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.08.2016; Nature Publishing Group
• Subjects: 45/23; 45/43; 631/208/205/2138; 631/208/514/2254; 631/208/726/649/2219; 692/699/2743/137; allele; Alleles; Analysis; ancestry; Clinical Medicine; controlled study; Diabetes; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 2 - genetics; DNA Mutational Analysis; DNA sequencing; Endocrinology and Diabetes; Endokrinologi och diabetes; ethnology; Europe; Europe - ethnology; European; Exome; gene sequence; Genes; genetic analysis; genetic code; genetic predisposition; Genetic Predisposition to Disease; Genetic Predisposition to Disease - genetics; genetic structure; genetic variation; Genetic Variation - genetics; Genetics; genome; Genome-Wide Association Study; Genomes; Genomic structural variations; genotype; genotyping technique; Genotyping Techniques; health risk; Health risk assessment; human; Humanities and Social Sciences; Humans; Klinisk medicin; major clinical study; Medical and Health Sciences; Medicin och hälsovetenskap; multidisciplinary; non insulin dependent diabetes mellitus; Nucleotide sequencing; pathology; physiology; priority journal; Sample Size; Science; Studies; Type 2 diabetes; Europe
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature18642

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. Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease. Gene variation in type 2 diabetes Common variants at more than 80 genomic loci have been associated with susceptibility to type 2 diabetes, but together explain only a small fraction of the estimated heritability. Studies have hypothesized that rare or low-frequency genetic variation may explain a large proportion of the remaining disease risk. These authors now provide a test of this hypothesis in a large-scale sequencing study for type 2 diabetes conducted as part of the GoT2D and T2D-GENES projects. This work provides the most comprehensive view to date of the overall genomic architecture for disease risk, with the ability to examine the role for rare and low-frequency genetic variation. They find that most of the identified genetic risk variants were common and found in regions previously identified by genome-wide association studies.