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In the present study, we performed targeted high\u2010depth sequencing of\n 1q22<\/jats:italic>\n in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n A total of 95,000 base pairs spanning\n 1q22<\/jats:italic>\n , including\n SEMA4A<\/jats:italic>\n ,\n SLC25A44<\/jats:italic>\n , and\n PMF1<\/jats:italic>\n \/\n PMF1\u2010BGLAP<\/jats:italic>\n were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non\u2010lobar) and 1,078 controls. Firth regression and Rare Variant Influential Filtering Tool analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi\u2010C, chromatin immunoprecipitation followed by sequencing, and chromatin interaction analysis with paired\u2010end tag databases. Multivariable Mendelian randomization assessed whether alterations in gene\u2010specific expression relative to regionally co\u2010expressed genes at\n 1q22<\/jats:italic>\n could be causally related to ICH risk.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Common and rare variant analyses prioritized variants in\n SEMA4A<\/jats:italic>\n 5\u2032\u2010UTR and\n PMF1<\/jats:italic>\n intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi\u2010C data analysis determined that\n 1q22<\/jats:italic>\n is spatially organized in a single chromatin loop, and that the genes therein belong to the same topologically associating domain. Chromatin immunoprecipitation followed by sequencing and chromatin interaction analysis with paired\u2010end tag data analysis highlighted the presence of long\u2010range interactions between the\n SEMA4A<\/jats:italic>\n \u2010promoter and\n PMF1<\/jats:italic>\n \u2010enhancer regions prioritized by association testing. Multivariable Mendelian randomization analyses demonstrated that\n PMF1<\/jats:italic>\n overexpression could be causally related to non\u2010lobar ICH risk.\n <\/jats:p>\n <\/jats:sec>\n \n Interpretation<\/jats:title>\n \n Altered promoter\u2013enhancer interactions leading to\n PMF1<\/jats:italic>\n overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non\u2010lobar ICH risk at\n 1q22<\/jats:italic>\n , offering a potential new target for prevention of ICH and cerebral small vessel disease. ANN NEUROL 2024;95:325\u2013337\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/ana.26814","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T04:34:25Z","timestamp":1696394065000},"page":"325-337","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Deep Resequencing of the\n 1q22<\/i>\n Locus in Non\u2010Lobar Intracerebral Hemorrhage"],"prefix":"10.1002","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0605-2381","authenticated-orcid":false,"given":"Livia","family":"Parodi","sequence":"first","affiliation":[{"name":"Center for Genomic Medicine Massachusetts General Hospital Boston MA USA"},{"name":"McCance Center for Brain Health Massachusetts General Hospital Boston MA USA"},{"name":"Broad Institute of MIT and Harvard Cambridge MA USA"},{"name":"Department of Neurology Brigham and Women's Hospital Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Comeau","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Data Science, Division of Public Health Sciences Wake Forest University School of Medicine Winston\u2010Salem NC USA"},{"name":"Center for Precision Medicine Wake Forest University School of Medicine Winston\u2010Salem NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3507-3659","authenticated-orcid":false,"given":"Marios K.","family":"Georgakis","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard Cambridge MA USA"},{"name":"Institute for Stroke and Dementia Research (ISD) University Hospital, Ludwig\u2010Maximilians\u2010University (LMU) Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernst","family":"Mayerhofer","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine Massachusetts General Hospital Boston MA USA"},{"name":"McCance Center for Brain Health Massachusetts General Hospital Boston MA USA"},{"name":"Broad Institute of MIT and Harvard Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6431-9454","authenticated-orcid":false,"given":"Jaeyoon","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Medicine Boston University School of Medicine Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6407-0302","authenticated-orcid":false,"given":"Guido J.","family":"Falcone","sequence":"additional","affiliation":[{"name":"Division of Neurocritical Care and Emergency Neurology, Department of Neurology Yale School of Medicine New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Malik","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD) University Hospital, Ludwig\u2010Maximilians\u2010University (LMU) Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacie L.","family":"Demel","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Cincinnati Cincinnati OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradford B.","family":"Worrall","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Virginia Charlottesville VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Koch","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences University of Virginia Charlottesville VA USA"},{"name":"Department of Neurology Miller School of Medicine, University of Miami Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando D.","family":"Testai","sequence":"additional","affiliation":[{"name":"Department of Neurology & Neurorehabilitation College of Medicine, University of Illinois at Chicago Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Kittner","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob L.","family":"McCauley","sequence":"additional","affiliation":[{"name":"John P. 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