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Cited by 36Genetic Associations and EpidemiologyDiabetes and associated disordersGenomics and Rare Diseases

Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes

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Nag, Abhishek, Dhindsa, Ryan S., Mitchell, Jonathan, Vasavda, Chirag, Harper, Andrew R., Vitsios, Dimitrios, Ahnmark, Andrea, Bilican, Bilada +21 more·2022·Science Advances
DOI 10.1126/sciadv.add5430PMC PMC9668288
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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.

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  • Identifying allelic series can help prioritize candidate drug targets.

    “Identifying allelic series, in which multiple variants in a gene associate with a phenotype with varying effect sizes, can help prioritize candidate drug targets13,14.”

    From Rare variant associations with plasma protein levels in the UK Biobank (2023) · cites this paper as [14]

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Authors
Nag, A., Dhindsa, R. S., Mitchell, J., Vasavda, C., Harper, A. R., Vitsios, D., Ahnmark, A., Bilican, B., Madeyski-Bengtson, K., Zarrouki, B., Zoghbi, A. W., Wang, Q., Smith, K. R., Alegre-Díaz, J., Kuri-Morales, P., Berumen, J., Tapia-Conyer, R., Emberson, J., Torres, J. M., Collins, R., Smith, D. M., Challis, B., Paul, D. S., Bohlooly-Y, M., Snowden, M., Baker, D., Fritsche-Danielson, R., Pangalos, M. N., & Petrovski, S.
Affiliations
  • AstraZeneca (United Kingdom) (GB)
  • AstraZeneca (United States) (US)
  • AstraZeneca (Sweden) (SE)
  • Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Coyoacán, 4360 Ciudad de México, Mexico.
  • Universidad Nacional Autónoma de México (MX)
  • University of Oxford (GB)
  • Discovery Biology, Discovery Sciences, BioPharmaceuticals R&amp;D, AstraZeneca, Gothenburg, Sweden.
  • Early CVRM, BioPharmaceuticals R&amp;D, AstraZeneca, Gothenburg, Sweden.
Corresponding author
  • Nag, Abhishek
  • Dhindsa, Ryan S.
  • Petrovski, Slavé
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-11-16
Volume
8
Issue
46
Pages
eadd5430-eadd5430
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.add5430
PMC
PMC9668288
OpenAlex
W4309323599
Cited by
36
References
6
Citations by year
2026: 6 · 2025: 10 · 2024: 13 · 2023: 7
FWCI
4.52
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
  • Wellcome Trust (058299)
  • British Heart Foundation (RG/18/13/33946, CH/1996001/9454, CH/12/2/29428, RG/13/13/30194)
  • Medical Research Council (MC_UU_00017/2, MC_PC_12029, MC_PC_12027, MC_UU_00017/3, MC_PC_12028, MC_EX_G0801669)
  • National Institute of Mental Health (T32MH018870)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
diabetes mellitus, type 1 diabetes, type 2 diabetes, insulin resistance, obesity, non-synonymous mutations, truncating mutations, HbA1c, therapeutic target, exome sequencing, gene-environment interaction
MeSH terms
Diabetes Mellitus, Type 2, Humans, Obesity, Prospective Studies, Genetic Predisposition to Disease, MAP Kinase Kinase Kinases, Monocarboxylic Acid Transporters

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