Multi-ancestry Polygenic Mechanisms of Type 2 Diabetes Elucidate Disease Processes and Clinical Heterogeneity
Abstract We identified genetic subtypes of type 2 diabetes (T2D) by analyzing genetic data from diverse groups, including non-European populations. We implemented soft clustering with 650 T2D-associated genetic variants, capturing known and novel T2D subtypes with distinct cardiometabolic trait associations. The twelve genetic clusters were distinctively enriched for single-cell regulatory regions. Polygenic scores derived from the clusters differed in distribution between ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a BMI of 30 kg/m2in the European subpopulation and 24.2 (22.9- 25.5) kg/m2in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg/m2in the East Asian group, explaining about 75% of the difference in BMI thresholds. Thus, these multi-ancestry T2D genetic subtypes encompass a broader range of biological mechanisms and help explain ancestry-associated differences in T2D risk profiles..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 03. Okt. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Smith, Kirk [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.09.28.23296294 |
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| PPN (Katalog-ID): |
XBI040988724 |
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| 520 | |a Abstract We identified genetic subtypes of type 2 diabetes (T2D) by analyzing genetic data from diverse groups, including non-European populations. We implemented soft clustering with 650 T2D-associated genetic variants, capturing known and novel T2D subtypes with distinct cardiometabolic trait associations. The twelve genetic clusters were distinctively enriched for single-cell regulatory regions. Polygenic scores derived from the clusters differed in distribution between ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a BMI of 30 kg/m2in the European subpopulation and 24.2 (22.9- 25.5) kg/m2in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg/m2in the East Asian group, explaining about 75% of the difference in BMI thresholds. Thus, these multi-ancestry T2D genetic subtypes encompass a broader range of biological mechanisms and help explain ancestry-associated differences in T2D risk profiles. | ||
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