Multi-ancestry Polygenic Mechanisms of Type 2 Diabetes Elucidate Disease Processes and Clinical Heterogeneity
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/m2 in the European subpopulation and 24.2 (22.9-25.5) kg/m2 in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg/m2 in 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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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
medRxiv : the preprint server for health sciences - (2023) vom: 29. Sept. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Smith, Kirk [VerfasserIn] |
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| Anmerkungen: |
Date Revised 19.04.2024 published: Electronic UpdateIn: Nat Med. 2024 Mar 5;:. - PMID 38443691 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2023.09.28.23296294 |
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| funding: |
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| PPN (Katalog-ID): |
NLM363019308 |
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| 500 | |a UpdateIn: Nat Med. 2024 Mar 5;:. - PMID 38443691 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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/m2 in the European subpopulation and 24.2 (22.9-25.5) kg/m2 in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg/m2 in 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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| 700 | 1 | |a Deutsch, Aaron J |e verfasserin |4 aut | |
| 700 | 1 | |a McGrail, Carolyn |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Hyunkyung |e verfasserin |4 aut | |
| 700 | 1 | |a Hsu, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Mandla, Ravi |e verfasserin |4 aut | |
| 700 | 1 | |a Schroeder, Philip H |e verfasserin |4 aut | |
| 700 | 1 | |a Westerman, Kenneth E |e verfasserin |4 aut | |
| 700 | 1 | |a Szczerbinski, Lukasz |e verfasserin |4 aut | |
| 700 | 1 | |a Majarian, Timothy D |e verfasserin |4 aut | |
| 700 | 1 | |a Kaur, Varinderpal |e verfasserin |4 aut | |
| 700 | 1 | |a Williamson, Alice |e verfasserin |4 aut | |
| 700 | 1 | |a Claussnitzer, Melina |e verfasserin |4 aut | |
| 700 | 1 | |a Florez, Jose C |e verfasserin |4 aut | |
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| 700 | 1 | |a Mercader, Josep M |e verfasserin |4 aut | |
| 700 | 1 | |a Gaulton, Kyle J |e verfasserin |4 aut | |
| 700 | 1 | |a Udler, Miriam S |e verfasserin |4 aut | |
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