{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T13:27:12Z","timestamp":1791466032335,"version":"4.3.4"},"reference-count":38,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T00:00:00Z","timestamp":1625529600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Metabolism Res"],"published-print":{"date-parts":[[2022,1]]},"abstract":"Abstract<\/jats:title>\n \n Aims<\/jats:title>\n The study aimed to elucidate the effects of rare genetic variants on the risk of type 2 diabetes (T2D).<\/jats:p>\n <\/jats:sec>\n \n Materials and methods<\/jats:title>\n Weighted burden analysis of rare variants was applied to a sample of 200,000 exome\u2010sequenced participants in the UK Biobank project, of whom over 13,000 were identified as having T2D. Variant weights were allocated based on allele frequency and predicted effect, as informed by a previous analysis of hyperlipidaemia.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n There was an exome\u2010wide significant increased burden of rare, functional variants in three genes,\n GCK<\/jats:italic>\n ,\n HNF4A<\/jats:italic>\n and\n GIGYF1<\/jats:italic>\n .\n GIGYF1<\/jats:italic>\n has not previously been identified as a diabetes risk gene and its product appears to be involved in the modification of insulin signalling. A number of other genes did not attain exome\u2010wide significance but were highly ranked and potentially of interest, including\n ALAD<\/jats:italic>\n ,\n PPARG<\/jats:italic>\n ,\n GYG1<\/jats:italic>\n and\n GHRL<\/jats:italic>\n . Loss of function (LOF) variants were associated with T2D in\n GCK<\/jats:italic>\n and\n GIGYF1<\/jats:italic>\n whereas nonsynonymous variants annotated as probably damaging were associated in\n GCK<\/jats:italic>\n and\n HNF4A<\/jats:italic>\n . Overall, fewer than 1% of T2D cases carried one of these variants. In\n HNF1A<\/jats:italic>\n and\n HNF1B<\/jats:italic>\n there was an excess of LOF variants among cases but the small numbers of these fell short of statistical significance.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Rare genetic variants make an identifiable contribution to T2D in a small number of cases but these may provide valuable insights into disease mechanisms. As larger samples become available it is likely that additional genetic factors will be identified.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/dmrr.3482","type":"journal-article","created":{"date-parts":[[2021,7,3]],"date-time":"2021-07-03T04:20:18Z","timestamp":1625286018000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Analysis of rare coding variants in 200,000 exome\u2010sequenced subjects reveals novel genetic risk factors for type 2 diabetes"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4089-9183","authenticated-orcid":false,"given":"David","family":"Curtis","sequence":"first","affiliation":[{"name":"UCL Genetics Institute University College London London UK"},{"name":"Centre for Psychiatry Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,7,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04951-w"},{"key":"e_1_2_10_3_1","first-page":"3","article-title":"Genomic risk score provides predictive performance for type 2 diabetes in the UK biobank","volume":"1","author":"Chen X","year":"2021","journal-title":"Acta Diabetol"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncpendmet0778"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.2337\/db17-1236"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2010-0020"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature18642"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1231-2"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-00294-3"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2882"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0173-1"},{"key":"e_1_2_10_12_1","first-page":"2020","volume-title":"Advancing Human Genetics Research and Drug Discovery through Exome Sequencing of the UK Biobank","author":"Szustakowski JD","year":"2020"},{"key":"e_1_2_10_13_1","article-title":"Analysis of 200,000 exome\u2010sequenced UK Biobank subjects illustrates the contribution of rare genetic variants to hyperlipidaemia","author":"Curtis D.","year":"2021","journal-title":"medRxiv"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4"},{"key":"e_1_2_10_15_1","first-page":"20","article-title":"Predicting functional effect of human missense mutations using PolyPhen\u20102","volume":"7","author":"Adzhubei I","year":"2013","journal-title":"Curr Protoc Hum Genet"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.86"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13742-015-0047-8"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.12.022"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1159\/000512576"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-018-0272-6"},{"key":"e_1_2_10_21_1","first-page":"1","article-title":"A rapid method for combined analysis of common and rare variants at the level of a region, gene, or pathway","volume":"5","author":"Curtis D.","year":"2012","journal-title":"Adv Appl Bioinform Chem"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/YPG.0000000000000132"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_10_24_1","volume-title":"A Language and Environment for Statistical Computing","author":"R Core Team. 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