The Metabolic Role of MAP3K15: Genetic and Phenotypic Insights from the 23andMe Research Database and Genetics-Driven Recruitment

MAP3K15 has been previously associated with protection from type 2 diabetes (T2D), prompting interest in the development of MAP3K15 inhibitors as a potential therapeutic option for diabetes. The trans-ancestry genome-wide association study (GWAS) meta-analysis and loss-of-function (LoF) burden testing methods that implicate association with T2D greatly benefit from large sample size. The direct-to-consumer genetic testing company, 23andMe, Inc., is the worlds largest research consented genetic database. We leveraged the 23andMe database to further inform the metabolic role of MAP3K15, using a variety of genetic analysis methods. We find that MAP3K15 LoF carriers show a significant delay of 4.5 years in the median age of T2D diagnosis among individuals at high polygenic risk and uncover a novel burden association of MAP3K15 LoF with protection against high cholesterol. We expanded these findings by establishing a capability to recruit consented participants on the basis of genetics unknown to them (specifically, a single LoF variant in MAP3K15, rs148312150), and obtained clinical laboratory evidence of a modest reduction in median cholesterol and LDL/HDL ratio in MAP3K15 LoF carriers. Our findings demonstrate the discovery power of the 23andMe database, including the feasibility of consented participant recruitment to inform therapeutic discovery and development.