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GWAS Meta-Analysis of East Asian Individuals Link 60 New Loci to Diabetes Risk

NEW YORK – Researchers have linked more than 60 new loci with type 2 diabetes risk in a meta-analysis of genome-wide association studies of East Asian individuals.

More than 240 loci have been linked to type 2 diabetes risk, but most of those loci were uncovered in studies that relied on individuals of European ancestry. But people of East Asian ancestry are at greater risk of developing the condition than people of European ancestry with similar body-mass indices or waist circumference. 

An international team of researchers combined data from the Asian Genetic Epidemiology Network (AGEN) and the Diabetes Meta-Analysis of Trans-Ethnic (DIAMANTE) research consortia to conduct a large meta-analysis of more than 433,500 individuals of East Asian ancestry. As they reported in Nature this week, the researchers uncovered 301 different genetic signals at 183 loci associated with diabetes risk, including a number of novel loci. The new loci implicated genes involved in muscle and adipose differentiation.

"We know diabetes is caused by a complex set of risk factors, such as BMI, that have varying effects on the disease across ancestries," co-senior author Xueling Sim from the National University of Singapore said in a statement. "These findings expand the number of genetic variants associated with diabetes and highlight the importance of studying different ancestries." 

In their analysis of 77,418 people with type 2 diabetes and 256,122 healthy controls, the researchers homed in on 301 distinct association signals that met a locus-wide significance and 228 signals that reached genome-wide significance. 

After accounting for BMI in a subset of their cohort, the researchers tied an additional six loci to type 2 diabetes risk. These loci in particular were associated with genes involved in lipodystrophy-like traits, such as FGFR2 and NID2. This finding, the researchers noted, bolsters the notion that factors other than BMI such as visceral adiposity or lipodystrophy may influence type 2 diabetes risk among East Asians. 

Of the loci the researchers uncovered in their meta-analysis, 61 had never before been tied to type 2 diabetes risk, including ones near the genes GDAP1, PTF1A, SIX3, and ALDH2 and a microRNA cluster.

A number of the loci the researchers uncovered connected muscle and adipose differentiation as well as pancreatic function to type 2 diabetes risk. GDAP1, for instance, encodes a protein that regulates mitochondrial proteins and metabolic flux in skeletal muscle, while PTF1A encodes a transcription factor needed for pancreatic acinar cell development. Other loci are in linkage disequilibrium with cis-eQTLs involving a pancreatic islet transcription factor that's needed for the development of pancreatic alpha and beta cells or membrane proteins that affect glucose uptake in skeletal muscle. 

These findings suggested to the researchers that insulin resistance has a key role in diabetes pathogenesis among East Asians through its effects in skeletal muscle, adipose, and liver development.

The researchers also compared the effect sizes at the alleles they identified within East Asians and alleles identified in European. Overall, they found the per-allele effect sizes for the 332 variants they could assess in both datasets were moderately correlated. Variants that did show large differences in effect sizes across the ancestry groups were typically rare among Europeans and common or low-frequency among East Asians — a loci near ZNF257 has only been reported twice in non-Finnish Europeans. 

"For many years, these studies have been done primarily in white European populations," co-first author Cassandra Spracklen from the University of Massachusetts Amherst said in a statement. "There are DNA variants that are seen in some populations and not in others. Learning about the additional variants can help identify additional genes that influence a person's risk for developing type 2 diabetes."