[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-456070-105":3,"detail-sidebar-cat-0-en-105":85,"doc-detail-456070-en":134},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":78,"head_meta":80,"extra_data":82,"updated_unix":84},105,"en","genetic-and-causal-insights-into-white-matter-hyperintensities-across-the-brain-body-axis","Genetic and Causal Insights Into White Matter Hyperintensities Across the Brain-Body Axis","","Background: White matter hyperintensities (WMHs) appear as bright regions on T2-weighted FLAIR MRI, are common with aging, and are elevated in Alzheimer’s disease (AD). WMHs reflect axonal damage, demyelination, and edema, with vascular contributions such as endothelial dysfunction and impaired cerebrovascular autoregulation. They show substantial heritability and partially overlap with AD genetics, while brain-body systemic effects remain insufficiently characterized. Objective: quantify WMH and AD genetic contributions across the brain-body axis and assess causal links to imaging-derived phenotypes (IDPs).",{"@graph":14,"@context":77},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/genetic-and-causal-insights-into-white-matter-hyperintensities-across-the-brain-body-axis/456070/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/genetic-and-causal-insights-into-white-matter-hyperintensities-across-the-brain-body-axis/456070.png","ImageObject",300,407,{"name":42,"@type":43},"Cipher","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-07","2026-09-30",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",9,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69,73],{"name":60,"@type":61,"acceptedAnswer":62},"What are white matter hyperintensities (WMHs) and why do they matter for Alzheimer’s disease?","Question",{"text":63,"@type":64},"WMHs are bright regions on T2-weighted FLAIR MRI that increase with age and are elevated in Alzheimer’s disease. They are linked to axonal damage, demyelination, edema, and vascular mechanisms and show heritability that overlaps with AD genetics.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How did the study analyze genetic contributions across the brain-body axis?",{"text":68,"@type":64},"The study used partitioned heritability via stratified-linkage disequilibrium score regression (sLDSC) on WMH and AD GWAS summary statistics with tissue-level and continuous cell-specific annotations. It further applied MAGMA and FUSION for gene prioritization and bioinformatics integration.",{"name":70,"@type":61,"acceptedAnswer":71},"What causal connections did the researchers test between genetic findings and brain imaging phenotypes?",{"text":72,"@type":64},"They used MACAW to model causal relationships between WMH-associated SNPs and 172 imaging-derived phenotypes (IDPs), leveraging directed acyclic graphs while controlling for confounders to evaluate genetic effects on imaging measures.",{"name":74,"@type":61,"acceptedAnswer":75},"What were the main findings regarding tissues, cells, and imaging-derived phenotypes?",{"text":76,"@type":64},"Tissue enrichment showed WMH-associated SNPs enriched in CNS, liver, cardiovascular system, and kidneys, while AD-associated SNPs were enriched in CNS, connective bone, liver, and immune tissues. Cell analyses highlighted vascular endothelial cells, and MACAW linked WMH-associated SNPs to IDPs consistently affecting WM hypointensities and regional brain volumes.","https://schema.org",{"og:url":32,"og:type":79,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":81,"canonical":32},"index,follow",{"doc_id":83,"site_id":7},456070,1790925223,{"code":4,"msg":86,"data":87},"success",[88,92,96,100,105,110,114,119,123,126,130],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":97,"show_sort_weight":98,"slug":99},"Exam",70,"exam",{"id":101,"doc_module":4,"doc_module_name":25,"category_name":102,"show_sort_weight":103,"slug":104},5,"Comic",60,"comic",{"id":106,"doc_module":4,"doc_module_name":25,"category_name":107,"show_sort_weight":108,"slug":109},6,"Technology",50,"technology",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":112,"slug":113},7,40,"healthcare",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},8,"Research & Report",30,"research-report",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":121,"slug":122},"Religion & Spirituality",20,"religion-spirituality",{"id":121,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":121,"slug":125},"World Cup","world-cup",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":127,"slug":129},10,"Lifestyle","lifestyle",{"id":131,"doc_module":4,"doc_module_name":25,"category_name":132,"show_sort_weight":101,"slug":133},19,"General","general",{"code":4,"msg":86,"data":135},{"doc_id":83,"user_id":136,"nickname":42,"user_avatar":137,"doc_module":4,"category_id":111,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":138,"file_id":139,"file_url":140,"file_type":141,"file_size":142,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":30,"language":143,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":144,"faqs":145,"seo_title":146,"seo_description":12,"update_tm":147,"read_time":115,"preview_page_count":4},687208528416,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","DOI: 10. 1002/alz70856_106648  \nBIOMARKERS  \nPOSTER PRESENTATION  \nBIOMARKERS (NON-NEUROIMAGING)  \nGenetic and Causal Insights Into White Matter Hyperintensities Across the Brain-Body Axis  \nManpreet Singh1, 2, 3,4  Kimia Shafighi5  Flavie E. Detcheverry 1, 2, 3, 4  Gabrielle Dagasso6  Fanta Dabo 1, 2, 4  Ikrame Housni3, 7, 8, 9   \nSridar Narayanan 10, 11, 12  Nils D. Forkert 13  Sarah A Gagliano Taliun 14, 15 Danilo Bzdok5, 12, 16  AmanPreet Badhwar3, 7, 8, 9  \n1 University of Montreal, Montreal, QC, Canada  \n2 Centre de recherche de l’Institut universitaire de geriatrie de Montreal (CRIUGM), Montreal, QC, Canada  \n3 Institute of Biomedical Engineering, University of Montreal, Montreal, QC, Canada  \n4 Multiomics Investigation of Neurodegenerative Diseases (MIND) Laboratory, Montreal, QC, Canada  \n5 McGill University, Montreal, QC, Canada  \n6 University of Calgary, Calgary, AB, Canada  \n7 Université de Montréal, Montréal, QC, Canada  \n8 Centre de recherche de l’Institut universitaire de gériatrie de Montréal (CRIUGM), Montréal, QC, Canada  \n9 Multiomics Investigation of Neurodegenerative Diseases (MIND) Laboratory, Montréal, QC, Canada  \n10 Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada  \n11 Neurology and Neurosurgery, McGill University, Montreal, QC, Canada  \n12 McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada  \n13 Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada  \n14 Montreal Heart Institute, Montreal, QC, Canada  \n15 Université de Montréal, Montreal, QC, Canada  \nAbstract  \nBackground: White matter hyperintensities (WMHs), visible as bright regions on T2-weighted FLAIR MRI, are frequent with age and elevated in Alzheimer’s disease (AD). Representing axonal damage, demyelination, and edema, WMHs are driven by vascular mechanisms, including endothelial dysfunction and impaired cerebrovascular autoregulation. WMHs also exhibit strong heritability (55–73%), with overlapping genetic pathways shared with AD. Emerging evidence suggests systemic factors across the brain-body axis influence WMHs, yet these contributions and their genetic overlap with AD remain underexplored. Our study investigated genetic underpinnings specific to WMHs and those shared with AD by assessing partitioned heritability of WMHs and AD across the brain-body axis with SNP level tissue- and cell-specific annotations; identifying genes associated with WMHs and AD through integration of gene expression data, establishing causal links between SNP-level findings and imaging-derived phenotypes (IDPs), particularly structural variations in regional brain volumes.  \nMethod: Partitioned heritability was assessed using stratified-linkage disequilibrium score regression (sLDSC) on GWAS summary statistics (N = 3 WMH studies; N = 6 AD studies) using human A1) tissue level annotations (N = 10) and A2) continuous cell-specific annotations (N = 64). MAGMA and FUSION analyses highlighted genes associated with WMH and AD for further bioinformatics analysis (using human protein atlas (HPA) and STRING database). MACAW (Vigneshwaran et al, 2024) modeled causal relationships between WMH-associated SNPs (from FUMA analysis) and IDPs (N = 172), leveraging directed acyclic graphs to evaluate genetic effects while controlling for confounders (Figure 2).  \nThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \n© 2025 The Alzheimer’s Association. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.  \nAlzheimer’s Dement. 2025;21(Suppl. 2):e106648.  \n[https://doi.org/10.1002/alz70856_106648](https://doi.org/10.1002/alz70856_106648)  \nwi[leyonlinelibrary.com/journal/alz](leyonlinelibrary.com/journal/alz)  \n1of3  \n16 Mila-Quebec Aritificial Intelligence Institute, Montreal, QC, Canada  \nCor","cbCaicvqZK4f0IjD","https://ap.wps.com/l/cbCaicvqZK4f0IjD","pdf",1255731,"English","# Abstract\n## Background\n## Method\n## Results\n## Conclusion","[{\"question\":\"What are white matter hyperintensities (WMHs) and why do they matter for Alzheimer’s disease?\",\"answer\":\"WMHs are bright regions on T2-weighted FLAIR MRI that increase with age and are elevated in Alzheimer’s disease. They are linked to axonal damage, demyelination, edema, and vascular mechanisms and show heritability that overlaps with AD genetics.\"},{\"question\":\"How did the study analyze genetic contributions across the brain-body axis?\",\"answer\":\"The study used partitioned heritability via stratified-linkage disequilibrium score regression (sLDSC) on WMH and AD GWAS summary statistics with tissue-level and continuous cell-specific annotations. It further applied MAGMA and FUSION for gene prioritization and bioinformatics integration.\"},{\"question\":\"What causal connections did the researchers test between genetic findings and brain imaging phenotypes?\",\"answer\":\"They used MACAW to model causal relationships between WMH-associated SNPs and 172 imaging-derived phenotypes (IDPs), leveraging directed acyclic graphs while controlling for confounders to evaluate genetic effects on imaging measures.\"},{\"question\":\"What were the main findings regarding tissues, cells, and imaging-derived phenotypes?\",\"answer\":\"Tissue enrichment showed WMH-associated SNPs enriched in CNS, liver, cardiovascular system, and kidneys, while AD-associated SNPs were enriched in CNS, connective bone, liver, and immune tissues. Cell analyses highlighted vascular endothelial cells, and MACAW linked WMH-associated SNPs to IDPs consistently affecting WM hypointensities and regional brain volumes.\"}]","Genetic and Causal Insights Into White Matter Hyperintensities Across the Brain-Body Axis | PDF",1790745050]