{"doi":"10.2337/figshare.17099780","title":"Recessive Genome-wide Meta-analysis Illuminates Genetic Architecture of Type 2 Diabetes","abstract":"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. 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 identified 51 loci associated with type 2 diabetes, including five variants 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 in homozygous carriers. Using two additional cohorts, FinnGen and a Danish cohort, 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, <i>P</i>=1´10<sup>-16</sup>) and a stronger effect in men than in women (interaction <i>P</i>=7´10<sup>-7</sup>). The signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL and a 20% increase in triglycerides, and colocalization analysis linked this signal to reduced expression of the nearby <i>PELO</i> gene. These 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.","journal":null,"year":2021,"id":228753,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9488,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":707669,"name":"Philip Schroeder","orcid":"0000-0002-9885-7787","position":1,"is_corresponding":false},{"id":614898,"name":"Alicia Huerta‐Chagoya","orcid":"0000-0001-6218-3904","position":2,"is_corresponding":false},{"id":708262,"name":"Paula Cortés-Sánchez","orcid":null,"position":3,"is_corresponding":false},{"id":556042,"name":"Sílvia Bonàs‐Guarch","orcid":"0000-0002-2085-7488","position":4,"is_corresponding":false},{"id":499619,"name":"Marta Guindo-Martínez","orcid":"0000-0002-8099-9170","position":5,"is_corresponding":false},{"id":5013,"name":"Joanne B. 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Rundsten","orcid":null,"position":12,"is_corresponding":false},{"id":16755,"name":"Oluf Pedersen","orcid":"0000-0002-3321-3972","position":13,"is_corresponding":false},{"id":90117,"name":"Ivan Brandslund","orcid":"0000-0002-4203-5442","position":14,"is_corresponding":false},{"id":38875,"name":"Allan Linneberg","orcid":"0000-0002-0994-0184","position":15,"is_corresponding":false},{"id":11251,"name":"Torben Hansen","orcid":"0000-0001-8748-3831","position":16,"is_corresponding":false},{"id":263594,"name":"Aaron Leong","orcid":"0000-0002-3248-9547","position":17,"is_corresponding":false},{"id":1150,"name":"José C. Florez","orcid":"0000-0002-1730-9325","position":18,"is_corresponding":false},{"id":253982,"name":"Josep M. Mercader","orcid":"0000-0001-8494-3660","position":19,"is_corresponding":false},{"id":707668,"name":"Mark J. 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