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Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225\u2009195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage using Cox regression analysis. Statins were prescribed at least once to 75\u2009973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean low-density lipoprotein decreased by 3.45\u2005mg\/dl per year [95% confidence interval (CI): (\u22123.47, \u22123.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein levels [\u22120.05\u2005mg\/dl per year, (\u22120.07, \u22120.02)], showed concordant lipidomic effects on other lipid traits as statin use and was associated with a lower risk for incident myocardial infarction [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P\u2009=\u20090.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage.<\/jats:p>","DOI":"10.1093\/brain\/awac186","type":"journal-article","created":{"date-parts":[[2022,5,22]],"date-time":"2022-05-22T09:06:25Z","timestamp":1653210385000},"page":"2677-2686","source":"Crossref","is-referenced-by-count":32,"title":["Genetically predicted on-statin LDL response is associated with higher intracerebral haemorrhage risk"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8902-4209","authenticated-orcid":false,"given":"Ernst","family":"Mayerhofer","sequence":"first","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital , Boston, MA , USA"},{"name":"Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology , Boston, MA , USA"},{"name":"Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital , Boston, MA , USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA"},{"name":"Department of Neurology and Neurophysiology, Medical Center\u2014University of Freiburg, Faculty of Medicine, University of Freiburg , Freiburg , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9212-2520","authenticated-orcid":false,"given":"Rainer","family":"Malik","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU) Munich , Munich , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Livia","family":"Parodi","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital , Boston, MA , USA"},{"name":"Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology , Boston, MA , USA"},{"name":"Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital , Boston, MA , USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5365-8760","authenticated-orcid":false,"given":"Stephen","family":"Burgess","sequence":"additional","affiliation":[{"name":"University of Cambridge, MRC Biostatistics Unit , Cambridge , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Harloff","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurophysiology, Medical Center\u2014University of Freiburg, Faculty of Medicine, University of Freiburg , Freiburg , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Dichgans","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU) Munich , Munich , Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE, Munich) , Munich , Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy) , Munich , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Rosand","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital , Boston, MA , USA"},{"name":"Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology , Boston, MA , USA"},{"name":"Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital , Boston, MA , USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0053-2002","authenticated-orcid":false,"given":"Christopher D","family":"Anderson","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital , Boston, MA , USA"},{"name":"Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology , Boston, MA , USA"},{"name":"Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital , Boston, MA , USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA"},{"name":"Department of Neurology, Brigham and Women\u2019s Hospital , Boston, MA , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3507-3659","authenticated-orcid":false,"given":"Marios 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