Dataset Information

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

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.

SUBMITTER: Nag A

PROVIDER: S-EPMC9668288 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Nag Abhishek A Dhindsa Ryan S RS Mitchell Jonathan J Vasavda Chirag C Harper Andrew R AR Vitsios Dimitrios D Ahnmark Andrea A Bilican Bilada B Madeyski-Bengtson Katja K Zarrouki Bader B Zoghbi Anthony W AW Wang Quanli Q Smith Katherine R KR Alegre-Díaz Jesus J Kuri-Morales Pablo P Berumen Jaime J Tapia-Conyer Roberto R Emberson Jonathan J Torres Jason M JM Collins Rory R Smith David M DM Challis Benjamin B Paul Dirk S DS Bohlooly-Y Mohammad M Snowden Mike M Baker David D Fritsche-Danielson Regina R Pangalos Menelas N MN Petrovski Slavé S

Science advances 20221116 46

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 replicat ...[more]

PMID: 36383675

Similar Datasets

Project description:Type 2 diabetes mellitus (T2D) and obesity already represent 2 of the most prominent risk factors for cardiovascular disease, and are destined to increase in importance given the global changes in lifestyle. Ten years have passed since the first round of genome-wide association studies for T2D and obesity. During this decade, we have witnessed remarkable developments in human genetics. We have graduated from the despair of candidate gene-based studies that generated few consistently replicated genotype-phenotype associations, to the excitement of an exponential harvest of loci robustly associated with medical outcomes through ever larger genome-wide association study meta-analyses. As well as discovering hundreds of loci, genome-wide association studies have provided transformative insights into the genetic architecture of T2D and other complex traits, highlighting the extent of polygenicity and the tiny effect sizes of many common risk alleles. Genome-wide association studies have also provided a critical starting point for discovering new biology relevant to these traits. Expectations are high that these discoveries will foster development of more effective strategies for intervention, through optimization of precision medicine approaches. In this article, we review current knowledge and provide suggestions for the next steps in genetic research for T2D and obesity. We focus on four areas relevant to precision medicine: genetic architecture, pharmacogenetics and other gene-environment interactions, mechanistic inference, and drug development. As we describe, the genetic architecture of complex traits has major implications for the prospects of precision medicine, rendering some anticipated approaches decidedly unrealistic. We highlight obstacles to the translation of human genetic findings into mechanism inference but are optimistic that, as these are overcome, there is untapped potential for novel drugs and more effective strategies for treating and preventing T2D and obesity.

Dataset Information

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

Publications

Human genetics uncovers <i>MAP3K15</i> as an obesity-independent therapeutic target for diabetes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Publications

Human genetics uncovers &lt;i&gt;MAP3K15&lt;/i&gt; as an obesity-independent therapeutic target for diabetes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Human genetics uncovers <i>MAP3K15</i> as an obesity-independent therapeutic target for diabetes.