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Multi-ancestry polygenic mechanisms of type 2 diabetes
Kirk Smith1,2,3, Aaron J Deutsch1,2,3,4, Carolyn McGrail5
1Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Nature Medicine
|March 5, 2024
Summary
This study identified 12 genetic clusters for type 2 diabetes (T2D) across diverse ancestries. These clusters reveal distinct biological mechanisms and explain ancestry-related differences in T2D risk profiles.
Area of Science:
- Genetics
- Metabolic Diseases
- Population Health
Background:
- Type 2 diabetes (T2D) is a complex disease with significant genetic influences, but its underlying biological mechanisms remain incompletely understood.
- Genetic risk factors for T2D vary across different ancestral populations, contributing to disparities in disease prevalence and presentation.
Purpose of the Study:
- To identify distinct genetic clusters associated with type 2 diabetes (T2D) across multiple ancestries.
- To investigate the cardiometabolic trait associations and biological mechanisms underlying these T2D genetic clusters.
- To explore how these genetic clusters contribute to ancestry-specific differences in T2D risk.
Main Methods:
- Analysis of genetic data from over 1.4 million individuals across 37 T2D genome-wide association studies.
- Implementation of soft clustering using 650 T2D-associated genetic variants and 110 T2D-related traits.
- Examination of genetic clusters in independent biobanks representing African, Admixed American, East Asian, European, and South Asian populations.
Main Results:
- Identification of 12 multi-ancestry T2D genetic clusters, enriched for specific single-cell regulatory regions.
- Discovery of distinct cardiometabolic trait associations for each cluster across diverse ancestral groups.
- Observation of differential distribution of polygenic scores among ancestry groups, including higher lipodystrophy risk in East Asians.
- Demonstration that equivalent T2D risk occurs at lower BMI thresholds in East Asians, with adjustments for genetic risk altering these thresholds.
Conclusions:
- The identified T2D genetic clusters represent a broader spectrum of biological mechanisms than previously recognized.
- These clusters provide insights into the genetic basis for ancestry-associated differences in T2D risk and presentation.
- Further research into these genetic clusters can refine our understanding of T2D pathogenesis and inform personalized risk assessment.
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