According to a massive new study published on 22 May in Nature, four genes with rare variants may affect type 2 diabetes risk (1). The new findings provide an updated view of the role of rare gene variants in type 2 diabetes.
Diabetes affects over 400 million people worldwide, according to the World Health Organisation (WHO), and is estimated to be the seventh leading cause of death. Lifestyle and environmental factors play significant roles in the development type 2 diabetes, however, biological factors may also come into play.
Therefore, it is important to understand the genetic mechanisms behind the disease in order to reduce the global risk. Furthermore, the discovery of genes and the proteins they encode for could provide potential targets for new medicines to treat or prevent diabetes. Moreover, they contribute to our overall understanding of the fundamental processes underlying disease.
The international team of scientists, led by the Broad Institute, the University of Michigan, and the University of Oxford, analysed the genomes of nearly 46,000 people — 20,791 individuals with type 2 diabetes and 24,440 nondiabetic controls — of European, African American, Hispanic/Latino, East Asian, and South Asian descent.
Most large population studies focus on individuals of European ancestry, which makes it difficult to apply the results on a global scale. Moreover, the resulting dataset contained over six million variants – more than twice the number of variants previously reported in any type 2 diabetes exome-sequencing study.
Based on their initial analyses, the researchers were able to narrow in on 16 gene sets characterised by rare variants with links to type 2 diabetes. These variants were further analysed in subsequent gene prioritization analyses.
The team only sequenced the so-called exome, which includes regions of the genome that encode for proteins. This approach differs from genome-wide association studies or GWAS, which analyse the entire genome but can often miss subtle variations in the exome. This is important as some variants associated with diseases are so rare that they cannot be detected by GWAS. However, GWAS and exome sequencing are often complementary.
According to the authors, 93.5 per cent of the variants identified in the study are classed as rare. But it’s crucial to bear in mind that although a certain gene variant, rare or otherwise, may be associated with a disease that doesn’t necessarily mean someone with the variant will develop the disease. The gene is simply correlated and under the right conditions, the disease could arise.
The sequencing study is the largest of its kind, to date. Even so, the authors suggest sample sizes ranging between 75,000 and 185,000 cases are still needed to identify even rare variants with the largest influence – large sample sizes are needed to focus in on rare variants
Results of the study are publicly available online via the Type 2 Diabetes Knowledge Portal, which will allow other researchers to use the information. The portal was established through the Accelerating Medicines Partnership (AMP) public-private partnership between the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), multiple biopharmaceutical and life science companies, and non-profits with the aim of developing novel diagnostics and treatments for disease.
(1) Flannick et al. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature, 2019; DOI: 10.1038/s41586-019-1231-2