| Title: | Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes |
| Journal: | Science Advances |
| Published: | 16 Nov 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36383675/ |
| DOI: | https://doi.org/10.1126/sciadv.add5430 |
| URL: | https://www.science.org/doi/pdf/10.1126/sciadv.add5430?download=true |
Publication 10693
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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.</p>
29 Authors
- Abhishek Nag
- Ryan S Dhindsa
- Jonathan Mitchell
- Chirag Vasavda
- Andrew R Harper
- Dimitrios Vitsios
- Andrea Ahnmark
- Bilada Bilican
- Katja Madeyski-Bengtson
- Bader Zarrouki
- Anthony W Zoghbi
- Quanli Wang
- Katherine R Smith
- Jesus Alegre-Díaz
- Pablo Kuri-Morales
- Jaime Berumen
- Roberto Tapia-Conyer
- Jonathan Emberson
- Jason M Torres
- Rory Collins
- David M Smith
- Benjamin Challis
- Dirk S Paul
- Mohammad Bohlooly-Y
- Mike Snowden
- David Baker
- Regina Fritsche-Danielson
- Menelas N Pangalos
- Slavé Petrovski
1 Application
| Application ID | Title |
|---|---|
| 26041 | Large-Scale Sequencing in the UK Biobank to Facilitate Gene Discovery, Genome Sciences, and Precision Medicine |
Enabling scientific discoveries that improve human health