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As Mendelian randomisation (MR) avoids many limitations of conventional observational studies, this two-sample bidirectional MR analysis was conducted to determine the following: (i) whether genetically predicted 25-hydroxyvitamin D [25(OH)D] levels are a risk factor for NAFLD, and (ii) whether genetic risk for NAFLD influences 25(OH)D levels. Single-nucleotide polymorphisms (SNPs) associated with serum 25(OH)D levels were obtained from the European ancestry-derived SUNLIGHT consortium. SNPs associated with NAFLD or NASH (p-value &lt; 1 \u00d7 10\u22125) were extracted from previous studies and supplemented by genome-wide association studies (GWASs) performed in the UK Biobank. These GWASs were done both without (primary analysis) and with (sensitivity analysis) the population-level exclusion of other liver diseases (e.g., alcoholic liver diseases, toxic liver diseases, viral hepatitis, etc.). Subsequently, MR analyses were performed to obtain effect estimates using inverse variance weighted (IVW) random effect models. Cochran\u2019s Q statistic, MR-Egger regression intercept, MR pleiotropy residual sum and outlier (MR-PRESSO) analyses were used to assess pleiotropy. No causal association of genetically predicted serum 25(OH)D (per standard deviation increase) with risk of NAFLD was identified in either the primary analysis: n = 2757 cases, n = 460,161 controls, odds ratio (95% confidence interval): 0.95 (0.76, \u22121.18), p = 0.614; or the sensitivity analysis. Reciprocally, no causal association was identified between the genetic risk of NAFLD and serum 25(OH)D levels, OR = 1.00 (0.99, 1.02, p = 0.665). In conclusion, this MR analysis found no evidence of an association between serum 25(OH)D levels and NAFLD in a large European cohort.<\/jats:p>","DOI":"10.3390\/nu15061442","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T02:29:59Z","timestamp":1679020199000},"page":"1442","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Non-Alcoholic Fatty Liver Disease and Vitamin D in the UK Biobank: A Two-Sample Bidirectional Mendelian Randomisation Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3446-0772","authenticated-orcid":false,"given":"Zixuan","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Food Science & Nutrition, University of Leeds, Leeds LS2 9JT, UK"},{"name":"Department of Medicine, National University of Singapore, Singapore 117549, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberley","family":"Burrows","sequence":"additional","affiliation":[{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8381-519X","authenticated-orcid":false,"given":"Harriett","family":"Fuller","sequence":"additional","affiliation":[{"name":"School of Food Science & Nutrition, University of Leeds, Leeds LS2 9JT, UK"},{"name":"Public Health Science Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth K.","family":"Speliotes","sequence":"additional","affiliation":[{"name":"Divisions of Gastroenterology, Computational Medicine and Bioinformatics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kushala W. M.","family":"Abeysekera","sequence":"additional","affiliation":[{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3037-8528","authenticated-orcid":false,"given":"James L.","family":"Thorne","sequence":"additional","affiliation":[{"name":"School of Food Science & Nutrition, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4311-6890","authenticated-orcid":false,"given":"Sarah J.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4944-5521","authenticated-orcid":false,"given":"Michael A.","family":"Zulyniak","sequence":"additional","affiliation":[{"name":"School of Food Science & Nutrition, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4750-1550","authenticated-orcid":false,"given":"J. Bernadette","family":"Moore","sequence":"additional","affiliation":[{"name":"School of Food Science & Nutrition, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrgastro.2017.109","article-title":"Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention","volume":"15","author":"Younossi","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101143","DOI":"10.1016\/j.molmet.2020.101143","article-title":"Metabolic drivers of non-alcoholic fatty liver disease","volume":"50","author":"Bence","year":"2021","journal-title":"Mol. 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