medwireNews: Researchers have used exome-wide sequencing to identify several rare variants within four genes that are significantly associated with type 2 diabetes.
The analysis included 20,791 individuals with type 2 diabetes and 24,440 nondiabetic controls of Hispanic/Latino, European, African–American, East Asian, or South Asian ancestry, and produced a dataset of 6.33 million variants.
This accounted for “more than twice the number of variants” previously reported in a type 2 diabetes exome-sequencing study, with 93.5% of those identified in the current study classed as rare (minor allele frequency [MAFs] <0.5%), according to Jason Flannick (Broad Institute, Cambridge, Massachusetts, USA) and colleagues.
Further analysis revealed gene-level associations of exome-wide significance for rare variants in genes encoding the melanocortin 4 receptor (MC4R), solute carrier family 30 member 8 (SLC30A8), and peptidylglycine alpha-amidating monooxygenase (PAM), with combined MAFs of 0.8%, 1.4%, and 4.9%, respectively.
These rare exome-wide significant gene-level signals explained an estimated 0.11%, 0.072%, and 0.092%, respectively, of genetic variance in type 2 diabetes, which was approximately 10-fold lower than that explained by the strongest independent common-variant associations.
Such findings “argue against a large contribution to [type 2 diabetes] heritability from even the strongest gene level signals,” Flannick and team remark.
The researchers report in Nature, that while the diabetes associations with MC4R and PAM were primarily driven by individual variants, the association with SLC30A8 was driven by 90 missense mutations.
They say that although SLC30A8 has been linked to type 2 diabetes for more than 10 years, the mechanism through which it acts remains unclear. However, the authors believe that “[t]he protective allelic series from our analysis argues that decreased [type 2 diabetes] risk is the typical effect of SLC30A8 missense variation–that is, it is not unique to haploinsufficiency–and provides many additional alleles that can be characterized to gain mechanistic insights.”
Flannick et al confirmed the associations in a meta-analysis of more than 70,000 individuals with and without type 2 diabetes. This analysis also identified the gene encoding ubiquitin conjugating enzyme E2N-like (UBE2NL) as having exome-wide significance in type 2 diabetes. The investigators note that this gene “has few prior links” to type 2 diabetes and further replication of their findings will be required to establish its relevance in type 2 diabetes.
The investigators also analyzed 16 gene sets connected to type 2 diabetes that did not achieve exome-wide significance. Of these, 12 achieved “set-level” significance and included type 2 diabetes drug targets, genes previously reported in mouse models of non-insulin dependent diabetes or impaired glucose tolerance, and genes implicated in maturity onset diabetes of the young.
“Collectively, these results suggest that association strength at the gene level can be used as a potential metric to prioritize candidate genes relevant to [type 2 diabetes],” they say.
Nonetheless, the team points out that even though there was agreement between genetic and therapeutic directions of effect for seven out of eight type 2 diabetes drug targets tested, 75,000–185,000 sequenced cases were required to achieve exome-wide significance.
“Thus, for biological discovery in many complex traits, such as [type 2 diabetes], exome sequencing and array-based GWAS [genome-wide association studies] seem complementary: locus discovery and fine mapping are achieved most efficiently using larger array-based GWAS, whereas rare coding variant allelic series–that could aid experimental gene characterization or provide confidence in disease-gene identification–are best discoverable through sequencing,” the researchers conclude.
By Laura Cowen
medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group
Nature 2019; doi:10.1038/s41586-019-1231-2
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