학술논문
Deep Resequencing of the 1q22 Locus in Non-Lobar Intracerebral Hemorrhage.
Document Type
Academic Journal
Author
Parodi L; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.; Comeau ME; Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.; Center for Precision Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.; Georgakis MK; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.; Mayerhofer E; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Chung J; Department of Medicine, Boston University School of Medicine, Boston, MA, USA.; Falcone GJ; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.; Malik R; Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.; Demel SL; Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.; Worrall BB; Department of Neurology, University of Virginia, Charlottesville, VA, USA.; Koch S; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.; Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.; Testai FD; Department of Neurology & Neurorehabilitation, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.; Kittner SJ; Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.; McCauley JL; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.; Hall CE; Department of Neurology, University of Texas Southwestern, Dallas, TX, USA.; Mayson DJ; Division of Stroke, Medstar Georgetown University Hospital, Washington, DC, USA.; Elkind MSV; Department of Neurology, Vagelos College of Physicians and Surgeons and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.; James ML; Department of Neurology, Duke University, Durham, NC, USA.; Woo D; Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.; Rosand J; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Langefeld CD; Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.; Center for Precision Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.; Anderson CD; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Source
Publisher: Wiley-Liss Country of Publication: United States NLM ID: 7707449 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1531-8249 (Electronic) Linking ISSN: 03645134 NLM ISO Abbreviation: Ann Neurol Subsets: MEDLINE
Subject
Language
English
Abstract
Objective: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases, including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study, we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.
Methods: A total of 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44, and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) 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-C, chromatin immunoprecipitation followed by sequencing, and chromatin interaction analysis with paired-end tag databases. Multivariable Mendelian randomization assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk.
Results: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 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-end tag data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. Multivariable Mendelian randomization analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk.
Interpretation: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and cerebral small vessel disease. ANN NEUROL 2024;95:325-337.
(© 2023 American Neurological Association.)
Methods: A total of 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44, and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) 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-C, chromatin immunoprecipitation followed by sequencing, and chromatin interaction analysis with paired-end tag databases. Multivariable Mendelian randomization assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk.
Results: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 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-end tag data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. Multivariable Mendelian randomization analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk.
Interpretation: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and cerebral small vessel disease. ANN NEUROL 2024;95:325-337.
(© 2023 American Neurological Association.)