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Title: | Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes. | Austin Authors: | Nag, Abhishek;Dhindsa, Ryan S;Mitchell, Jonathan;Vasavda, Chirag;Harper, Andrew R;Vitsios, Dimitrios;Ahnmark, Andrea;Bilican, Bilada;Madeyski-Bengtson, Katja;Zarrouki, Bader;Zoghbi, Anthony W;Wang, Quanli;Smith, Katherine R;Alegre-Díaz, Jesus;Kuri-Morales, Pablo;Berumen, Jaime;Tapia-Conyer, Roberto;Emberson, Jonathan;Torres, Jason M;Collins, Rory;Smith, David M;Challis, Benjamin;Paul, Dirk S;Bohlooly-Y, Mohammad;Snowden, Mike;Baker, David;Fritsche-Danielson, Regina;Pangalos, Menelas N;Petrovski, Slavé | Affiliation: | Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. Bioscience Metabolism, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA. Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Coyoacán, 4360 Ciudad de México, Mexico. Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, England, UK. Emerging Innovations, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. Translational Science and Experimental Medicine, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. Bioscience Metabolism, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. Medicine (University of Melbourne) |
Issue Date: | 18-Nov-2022 | Date: | 2022 | Publication information: | Science Advances 2022; 8(46) | Abstract: | We performed collapsing analyses on 454,796 UK Biobank (UKB) exomes to detect gene-level associations with diabetes. Recessive carriers of nonsynonymous variants in MAP3K15 were 30% less likely to develop diabetes (P = 5.7 × 10-10) and had lower glycosylated hemoglobin (β = -0.14 SD units, P = 1.1 × 10-24). These associations were independent of body mass index, suggesting protection against insulin resistance even in the setting of obesity. We replicated these findings in 96,811 Admixed Americans in the Mexico City Prospective Study (P < 0.05)Moreover, the protective effect of MAP3K15 variants was stronger in individuals who did not carry the Latino-enriched SLC16A11 risk haplotype (P = 6.0 × 10-4). Separately, we identified a Finnish-enriched MAP3K15 protein-truncating variant associated with decreased odds of both type 1 and type 2 diabetes (P < 0.05) in FinnGen. No adverse phenotypes were associated with protein-truncating MAP3K15 variants in the UKB, supporting this gene as a therapeutic target for diabetes. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/31696 | DOI: | 10.1126/sciadv.add5430 | ORCID: | 0000-0002-4638-2433 0000-0002-8965-0813 0000-0003-4558-4698 0000-0002-8939-5445 0000-0001-8932-4631 0000-0002-3057-2654 0000-0002-0329-5938 0000-0001-9390-3871 0000-0002-0704-9507 0000-0001-6707-3317 0000-0003-3814-2904 0000-0001-7792-9422 0000-0002-7537-7035 0000-0001-8288-8602 0000-0001-6831-280X 0000-0002-1130-2851 0000-0002-8230-0116 0000-0002-8020-3275 0000-0003-0582-6429 0000-0001-9783-0956 0000-0002-1527-961X |
Journal: | Science Advances | Start page: | eadd5430 | PubMed URL: | 36383675 | ISSN: | 2375-2548 | Type: | Journal Article | Subjects: | Diabetes Mellitus, Type 2/genetics Monocarboxylic Acid Transporters/genetics Obesity/genetics MAP Kinase Kinase Kinases/genetics |
Appears in Collections: | Journal articles |
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