May 22, 2019 -- An exome sequencing study of almost 46,000 people has pinpointed four genes with rare variants that put people at risk for type 2 diabetes, a large team of international researchers led by the Broad Institute of MIT and Harvard reported in the journal Nature on May 22.
The results, which are publicly available on the Type 2 Diabetes Knowledge Portal, could be helpful for guiding drug development for type 2 diabetes in the future, and the finding of rare variations with an effect on disease might also apply to other complex conditions, the authors suggested.
The study included 20,791 people with diabetes and 24,440 healthy controls from five ancestries: European, Hispanic/Latino, East Asian, and South Asian. Prior studies identified few exome-wide significant variant associations for complex diseases like type 2 diabetes, but the "paucity of findings is in part due to the limited sample sizes of previous studies, the largest of which included less than 10,000 disease cases and fall short of the sample sizes that analytic and simulation-based calculations predict are needed to identify rare disease-associated variants under plausible disease models," Harvard professor Jason Flannick, PhD, and colleagues noted in the Nature article.
"Rare-variant gene-level signals are likely to be distributed across numerous genes; however, the vast majority of signals individually explain vanishingly small amounts of [type 2 diabetes] heritability," the authors wrote. More than 1 million samples may be needed for rare-variant signals in validated therapeutic targets to become significant exome-wide, they added.
The results suggest that a much larger study of from 75,000 to 185,000 sequenced cases will be needed to identify rare variants that make a big difference in the disease, the researchers concluded.