Researchers Explore the Genetics of Diabetes and Obesity with $7.8 Million NIH Award

What makes people genetically prone to diabetes and obesity?

That is the central question of a new $7.8 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH).

The funding supports a multidisciplinary study called HERITAGE (Harnessing TandEm Repeats in Multi-Ancestry meTAbolic Gene-phenotype rElationships), co-led by Wei Li, PhD, Grace B. Bell Endowed Chair and professor of biological chemistry at UC Irvine, and Tamer Sallam, MD, PhD, professor of medicine at UCLA.

“The project will use population-scale genomics to investigate tandem repeats, an important but historically understudied class of human genetic variation,” says Li. “The goal is to determine how they contribute to diabetes, obesity, and other metabolic traits and diseases across diverse populations.”

This work will help address what is known as the missing heritability problem — that is, the gap between genetics accounting for up to 80% of an individual’s susceptibility to diabetes and obesity, even though most of what makes people genetically prone to these diseases is still unknown.

“Part of the missing heritability of diabetes and obesity may lie in places we haven’t looked closely,” says Sallam. “Tandem repeats are present in these datasets, but they have been difficult to analyze with existing tools. HERITAGE is designed to help make that variation easier to study.”

The HERITAGE study builds directly on recent work of the Wei Li Lab — in particular, a study published in Cell and another in Nature Genetics that establish the genomic and computational foundation for studying tandem repeats at population scale.

“The Cell study established a population-scale map of tandem repeat variation in more than 338,000 individuals, while the Nature Genetics study extended this work into functional and multi-omic genomics,” says Li. “HERITAGE is a natural next step, moving from mapping and functional characterization of tandem repeats toward understanding their contribution to metabolic disease.”

The award also reflects a long-standing collaboration between the Li Lab and the UC Irvine Diabetes Center. The director of the center, Qin Yang, MD, PhD, is a co-investigator of the HERITAGE study, bringing expertise in diabetes, obesity and metabolic biology. Another co-investigator, Ya Cui, PhD, an assistant professor in the Department of Pathology & Laboratory Medicine at UC Irvine, has played a major role in developing the tandem-repeat genomics work underlying the proposal, including the Cell and Nature Genetics studies.

“Our discussions and collaborations over the years helped connect the tandem-repeat genomics work with important biological and clinical questions in metabolic disease,” says Li. “This helped shape the scientific direction of HERITAGE.”