medwireNews: The effect of common genetic variants on the risk of type 2 diabetes is significantly greater in adolescent diseases than in adults, researchers report.
And the team also identified four rare variants with large individual effects on diabetes risk in young people, although this was still outweighed by the cumulative effects of several more common variants, Soo Heon Kwak (Seoul National University, Republic of Korea) told participants in the virtual ADA 81. Scientific Sessions.
The results are based on a sequence analysis of the entire exome of 3005 people from the TODAY and SEARCH studies with type 2 diabetes diagnosed before the age of 20 and 9777 adults of matching ancestry without diabetes.
Two of the rare variants identified had genome-wide significance and both were associated with an increased risk of diabetes in adolescence; the other two were exome-wide and one was associated with an increased risk and the other was associated with a decreased risk.
The researchers found that the effect sizes of these variants were greater than normally seen in genetic studies of type 2 diabetes, and then examined 16 common, previously identified variants that have also been associated with adolescent diabetes. They found that the effect size of these variants in juvenile diabetes was on average 11.8% stronger than in adults.
At the gene level, three genes were significantly associated with diabetes in adolescence. Two of these genes were HNF1A, the defects of which can lead to monogenic diabetes, and those encoding the melanocortin-4 receptor, the disruption of which can lead to hyperphagia and severe obesity.
The third gene identified was ATXN2L, which Kwak said was a new finding.
Looking at other diabetes-related genes, the researchers “were surprised to find large effect sizes for genes related to obesity and beta cell function,” he said.
Many of the associations concerned genes with a recognized role in monogenic diabetes, such as GCK and RFX6, which Kwak said support a model in which diabetes onset in adolescents is “enriched with variants of known monogenic diabetes genes.”
In fact, the effect sizes of variants in almost all of these genes were greater for diabetes onset in adolescence than for diabetes in adulthood. It is noteworthy, however, that the association between variants in these genes and diabetes in adolescence remained significant even after excluding variants that definitely or probably cause monogenic diabetes. For example, the odds ratio related to GCK variants decreased from 7.7 to 2.8, but remained highly significant.
The speaker emphasized that the cumulative contribution of rare gene variants to the risk of diabetes in adolescence is around 20–30% of the proportion of common single nucleotide variants; however, their contribution to adolescent diabetes risk was 1.7 times greater than their contribution to adult diabetes risk.
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Scientific meetings of the ADA; 25-29 June 2021
