Gene-level analysis of rare variants in 363,977 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes

Sequencing of large cohorts offers an unprecedented opportunity to identify rare genetic variants and to find novel contributors to human disease. We used gene-based collapsing tests to identify genes associated with glucose, HbA1c and type 2 diabetes (T2D) diagnosis in 363,977 exome-sequenced participants in the UK Biobank. We identified associations for variants in GCK, HNF1A and PDX1 , which are known to be involved in Mendelian forms of diabetes. Notably, we uncovered novel associations for GIGYF1 , a gene not previously implicated by human genetics, in diabetes. GIGYF1 predicted loss of function (pLOF) variants associated with increased levels of glucose (0.77 mmol/L increase, p = 4.42 × 10-12) and HbA1c (4.33 mmol/mol, p = 1.28 × 10-14) as well as T2D diagnosis (OR = 4.15, p= 6.14 ×10-11). Multiple rare variants contributed to these associations, including singleton variants. GIGYF1 pLOF also associated with decreased cholesterol levels as well as an increased risk of hypothyroidism. The association of GIGYF1 pLOF with T2D diagnosis replicated in an independent cohort from the Geisinger Health System. In addition, a common variant association for glucose and T2D was identified at the GIGYF1 locus. Our results highlight the role of GIGYF1 in regulating insulin signaling and protecting from diabetes. Author Summary Genetic studies focused on high impact variants in protein-coding regions of the genome can provide valuable insight into the biology of human disease. As these variants tend to be rare, studying them requires large cohort sizes and methods to aggregate variants that are likely to have a similar biological impact. We studied how rare genetic variants contribute to type 2 diabetes (T2D) using sequencing data from 363,977 participants in the UK Biobank, employing methods to aggregate variants at the level of individual genes. As well as identifying genes known to be involved in inherited forms of diabetes, we uncovered a novel association for GIGYF1. GIGYF1 loss of function associated with increased risk of T2D and increased levels of the diabetes biomarkers glucose and HbA1c. This association was also seen in an independent dataset. GIGYF1 encodes a protein that binds a negative regulator of the insulin receptor that has not been well-characterized in the literature. By highlighting the importance of GIGYF1 in modulating insulin signaling these results may lead to new therapeutic approaches for diabetes as well as a new appreciation for GIGYF1 loss of function as a genetic risk factor for T2D. ### Competing Interest Statement A.D, L.W., M.P., A.F.C., L.B., G.H. and P.N. are employees and stockholders of Alnylam Pharmaceuticals. P.A., L.L. and A.B. are employees and stockholders of Regeneron Pharmaceuticals. ### Funding Statement This study was funded by Alnylam Pharmaceuticals and Regeneron Pharmaceuticals. No external funding was received. ### 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: Advarra IRB determined that the primary research project involving UK Biobank, FinnGen and Biobank Japan does not meet the Department of Health and Human Services definition of human subjects research under 45 CFR 46 and, therefore, does not require IRB oversight. The project used de-identified data from UK Biobank as well as summary statistics from FinnGen and Biobank Japan. Details on ethical approval and oversight for these individual projects is as follows. UK Biobank's scientific protocol and operational procedures have been reviewed and approved by the North West NHS research ethics committee. The UK Biobank resource is an approved Research Tissue Bank and is registered with the Human Tissue Authority, which means that researchers who wish to use it do not need to seek separate ethics approval (unless re-contact with participants is required). FinnGen was evaluated by the Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District. The research project complies with existing legislation (in particular, the Biobank Law and the Personal Data Act) and will conform to any new laws. The Biobank Japan Project was approved by the research ethics committees at the Institute of Medical Science, the University of Tokyo, the RIKEN Yokohama Institute, and the 12 cooperating hospitals. All participants gave written consent to participate in the study. Replication analysis performed in Geisinger Health system received separate ethical approval. This study was approved by Geisinger Health IRB, approval number 2006-0258. All participants gave written consent to participate in the study. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data used in this study were obtained from the UKBB through application 26041. All phenotypic data and array genotypes are accessible through application to UK Biobank. Currently, exome sequencing data for ∼200,000 participants is available; the remainder of the exome data is scheduled for public release in 2021.