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 world’s 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. ### Competing Interest Statement All authors are current or former employees of 23andMe, Inc., and hold stock and/or stock options in 23andMe. J.J.B. is an option holder at Variant Bio. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Participants provided informed consent and volunteered to participate in the research online under a protocol approved by the external AAHRPP-accredited Salus IRB (). All research was performed in accordance with relevant guidelines/regulations, including the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Given restrictions to the availability of 23andMe individual-level data owing to 23andMe consent and privacy/IRB guidelines, data sharing is limited to aggregate statistics that are necessary for reproducibility. Broader data sharing pertaining to the data/samples supporting the findings of this study may be made available upon reasonable request or collaboration, to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants, in accordance with individual consent and additional requirements within the scope of our IRB approval.