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.
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Accession codes
Data deposits
Whole-genome sequence data from the GoT2D project are available by application to the European Genome-Phenome Archive (https://www.ebi.ac.uk/ega/home) under accession number EGAS00001001459 and from dbGAP (http://www.ncbi.nlm.nih.gov/gap) under accession number phs000840.v1.p1. Whole-exome sequence data from the T2D-GENES project are available from the European Genome-Phenome Archive (https://www.ebi.ac.uk/ega/home) under accession number EGAS00001001460 and from dbGAP (http://www.ncbi.nlm.nih.gov/gap) under accession numbers phs000847.v1.p1, phs001093.v1.p1, phs001095.v1.p1, phs001096.v1.p1, phs001097.v1.p1, phs001098.v1.p1, phs001099.v1.p1, phs001100.v1.p1 and phs001102.v1.p1. Summary-level data from the exome array component of this project (and from the exome and genome sequences) can be freely accessed at the Accelerating Medicines Partnership T2D portal (http://www.type2diabetesgenetics.org), and similar data from the GoT2D-imputed data at http://www.diagram-consortium.org.
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Acknowledgements
Grant support and acknowledgments are listed in the Supplementary Information.