Genome-Wide Association Meta-Analysis Using a Recessive Model Illuminates Genetic Architecture of Type 2 Diabetes

ABSTRACT Objective Most genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered. Research Design and Methods We conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 cases and 279,507 controls from seven European-ancestry cohorts including the UK Biobank. We then used two additional cohorts, FinnGen and a Danish cohort, for replication. For the most significant recessive signal, we conducted a phenome-wide association study across hundreds of traits to make inferences about the pathophysiology underlying the increased risk seen in homozygous carriers. Results We identified 51 loci associated with type 2 diabetes, including five variants with recessive effects undetected by prior additive analyses. Two of the five had minor allele frequency less than 5% and were each associated with more than doubled risk. We replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19, P =1×10 −16 ) and a stronger effect in men than in women (interaction P =7×10 −7 ). Colocalization analysis linked this signal to reduced expression of the nearby PELO gene, and the signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL and a 20% increase in triglycerides. Conclusions Our results demonstrate that recessive models, when compared to GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes.