Middle aged man with type 2 diabetes using blood sugar measurement device to monitor type 2 diabetes
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An international group of researchers has carried out a large genome-wide association study (GWAS), including over 2.5 million individuals, to study the genetics of type 2 diabetes.

As reported in the journal Nature, the team found 1,289 genetic variants linked with type 2 diabetes, mapping to 611 different positions in the genome. Of these, 145 had not been seen before.

Type 2 diabetes is a common condition estimated to affect more than 36 million Americans.  It is a multifactorial condition characterized by impaired insulin secretion and resistance, and a number of different factors contribute to its onset including lifestyle, body mass index, genetics, and ancestry.

“This etiological heterogeneity leads to substantial variability in patient phenotypes, including age at disease onset, manifestation of disease complications and response to management strategies,” write the authors.

“Although environment and lifestyle are well-established risk factors for type 2 diabetes, heritability has been estimated to be 69% amongst individuals of 35–60 years of age.”

Many genetic variants linked to the condition have already been discovered, but this study sought to discover more. It was part of the Type 2 Diabetes Global Genomics Initiative and included data from 2,535,601 individuals, of whom 428,452 had type 2 diabetes. Researchers from around the world contributed to the study including those from Germany, the U.K., Japan and the U.S.

Type 2 diabetes is known to vary considerably in prevalence and genetics between people of different ancestries. To try and allow for this, the individuals included in this study were from diverse ancestry groups. Overall, around 60% of the group were European, 20% East Asian, 10.5% mixed West African and European ancestry, 6% mixed Hispanic, West African and European ancestry, 3.3% South Asian, and 0.2% South African ancestry.

In addition to finding new variants linked to the condition, the researchers also found that different sets of variants were linked with different risk factors for type 2 diabetes, which may help drive a more precision medicine focused approach for this condition in the future.

“We found eight clusters of type 2 diabetes-associated variants that have also been associated with other diabetes risk factors—such as obesity and liver-lipid metabolism— suggesting the mechanisms for how the variants may be acting to cause diabetes,” said co-author Cassandra Spracklen, assistant professor of biostatistics and epidemiology in the School of Public Health and Health Sciences, in a press statement.

Using data from these clusters, the researchers built polygenic risk scores and tested them in another diverse ancestry group of more than 200,000 people to test their accuracy. They found they were able to predict outcomes linked to the condition such as vascular disease and end-stage diabetic nephropathy.

“Improved understanding of the varied pathophysiological processes that link type 2 diabetes to vascular outcomes could offer a route to genetically informed diabetes care and global opportunities for the clinical translation of findings from type 2 diabetes GWASs,” conclude the authors.

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