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Like gene expression, DNA methylation is an important biological process and, being under genetic regulation, may be imputable from SNP genotypes. Here, we investigate prediction of CpG methylation levels from SNP genotype data to help elucidate relationships between methylation, gene expression and complex traits. We start by examining how well CpG methylation can be predicted from SNP genotypes, comparing three penalised regression approaches and examining whether changing the window size improves prediction accuracy. Although methylation at most CpG sites cannot be accurately predicted from SNP genotypes, for a subset it can be predicted well. We next apply our methylation prediction models (trained using the optimal method and window size) to carry out a methylome\u2010wide association study (MWAS) of primary biliary cholangitis. We intersect the regions identified via MWAS with those identified via TWAS, providing insight into the interplay between CpG methylation, gene expression and disease status. We conclude that MWAS has the potential to improve understanding of biological mechanisms in complex traits.<\/jats:p>","DOI":"10.1002\/gepi.22496","type":"journal-article","created":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T17:40:17Z","timestamp":1659721217000},"page":"629-643","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Investigating the prediction of CpG methylation levels from SNP genotype data to help elucidate relationships between methylation, gene expression and complex traits"],"prefix":"10.1002","volume":"46","author":[{"given":"James J.","family":"Fryett","sequence":"first","affiliation":[{"name":"Population Health Sciences Institute, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Morris","sequence":"additional","affiliation":[{"name":"Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1879-5572","authenticated-orcid":false,"given":"Heather J.","family":"Cordell","sequence":"additional","affiliation":[{"name":"Population Health Sciences Institute, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004663"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03621-1"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002629"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2005.07.002"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dys064"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.10.026"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.04.055"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwy025"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11115"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dys066"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v033.i01"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.22290"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.04.002"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3367"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0926-z"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty147"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.10.004"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3506"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.00523"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.09.007"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007544"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.04.013"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.2307\/1271436"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009811"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008198"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06149-6"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0126-8"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-020-3443-8"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-018-0519-4"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat6806"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1133"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06302-1"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1222794"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2019.00261"},{"key":"e_1_2_9_36_1","doi-asserted-by":"crossref","unstructured":"Min J. 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