{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T18:56:03Z","timestamp":1769108163252,"version":"3.49.0"},"posted":{"date-parts":[[2024,10,6]]},"group-title":"Neurology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,6]],"date-time":"2024-10-06T00:00:00Z","timestamp":1728172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,10,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>Genetic research on Alzheimer\u2019s disease (AD) has primarily focused on amyloid-\u03b2 (A\u03b2) pathogenesis, with fewer studies exploring tau pathology. Elucidating the genetic basis of tau pathology could identify novel pathways in AD.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>\n                    We conducted a genome-wide association study of tau standard uptake value ratios (SUVRs) from\n                    <jats:sup>[18]<\/jats:sup>\n                    F-flortaucipir positron emission tomography (PET) images to identify genetic variants underlying Tau pathology. Genetic data and tau-SUVRs from\n                    <jats:sup>[18]<\/jats:sup>\n                    F-flortaucipir PET images were acquired from the A4 (311 with preclinical AD) and ADNI (280 cognitively normal, 76 with mild cognitive impairment, and 19 AD patients) studies. Circulating plasma proteins in UK Biobank Pharma Proteomics Project (UKBPPP, N=54,129) were used to validate genetic findings. SNP genotypes were tested for association with Tau-SUVR levels adjusting for age, sex and population substructure variables. AD association of polygenic risk scores (PRS) of tau and amyloid-SUVRs were assessed. Causal effect of plasma protein levels on Tau pathology were tested using Mendelian randomization analyses.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>\n                    GWAS of tau-SUVR revealed two significant loci: rs78636169 (\n                    <jats:italic>P<\/jats:italic>\n                    =5.76\u00d710\n                    <jats:sup>-10<\/jats:sup>\n                    ) in\n                    <jats:italic>JARID2<\/jats:italic>\n                    and rs7292124 (\n                    <jats:italic>P<\/jats:italic>\n                    =2.20\u00d710\n                    <jats:sup>-8<\/jats:sup>\n                    ) near\n                    <jats:italic>ISX<\/jats:italic>\n                    . Gene-based analysis of tau deposition highlighted\n                    <jats:italic>APOE<\/jats:italic>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    =2.55\u00d710\n                    <jats:sup>-6<\/jats:sup>\n                    ),\n                    <jats:italic>CTNNA3<\/jats:italic>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    =2.86\u00d710\n                    <jats:sup>-6<\/jats:sup>\n                    ) and\n                    <jats:italic>JARID2<\/jats:italic>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    =1.23\u00d710\n                    <jats:sup>-4<\/jats:sup>\n                    ), a component of the\n                    <jats:italic>PRC2<\/jats:italic>\n                    multi-protein complex which regulates gene expression. Mendelian randomization analysis of available circulating plasma proteins in the UK Biobank Pharma Proteomics Project (UKBPPP) identified LRRFIP1, a protein that binds with\n                    <jats:italic>PRC2<\/jats:italic>\n                    multi-protein complex, as potentially causally linked to tau pathology. Genes associated with both amyloid and tau pathologies were enriched in endocytosis and signal transduction pathways. AD polygenic risk score (PRS) was associated with amyloid-SUVR but not with tau-SUVR. Amyloid-SUVR PRS had a notable association with AD clinical status, particularly in younger\n                    <jats:italic>APOE<\/jats:italic>\n                    -\u03b54 carriers, whereas tau-SUVR PRS showed a stronger association in older carriers.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSION<\/jats:title>\n                  <jats:p>\n                    We identified a novel potential therapeutic target,\n                    <jats:italic>JARID2<\/jats:italic>\n                    in the\n                    <jats:italic>PRC2<\/jats:italic>\n                    multi-protein complex, for tau pathology. Furthermore, gene pathway analysis clarified the distinct roles of A\u03b2 and tau in AD progression, underscoring the complexity of genetic influences across different stages of the disease.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.10.04.24314853","type":"posted-content","created":{"date-parts":[[2024,10,6]],"date-time":"2024-10-06T23:10:12Z","timestamp":1728256212000},"source":"Crossref","is-referenced-by-count":3,"title":["Genome-wide scan of Flortaucipir PET levels finds\n                  <i>JARID2<\/i>\n                  associated with cerebral tau deposition"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8639-5060","authenticated-orcid":false,"given":"Tamil Iniyan","family":"Gunasekaran","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devendra","family":"Meena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annie J","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siwei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Logan","family":"Dumitrescu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reisa","family":"Sperling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3377-7014","authenticated-orcid":false,"given":"Timothy J","family":"Hohman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Alzheimer\u2019s Disease Neuroimaging Initiative and the A4 Study","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingxian","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6403-016X","authenticated-orcid":false,"given":"Abbas","family":"Dehghan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4275-9328","authenticated-orcid":false,"given":"Ioanna","family":"Tzoulaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6519-9696","authenticated-orcid":false,"given":"Richard","family":"Mayeux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Badri","family":"Vardarajan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"4","key":"2024101008351174000_2024.10.04.24314853v2.1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1001\/jamaneurol.2013.5847","article-title":"Amyloid-\u03b2 and Tau: The Trigger and Bullet in Alzheimer Disease Pathogenesis","volume":"71","year":"2014","journal-title":"JAMA Neurology"},{"key":"2024101008351174000_2024.10.04.24314853v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.09.001"},{"issue":"1","key":"2024101008351174000_2024.10.04.24314853v2.3","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s40478-023-01563-4","article-title":"Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease","volume":"11","year":"2023","journal-title":"Acta Neuropathologica Communications"},{"key":"2024101008351174000_2024.10.04.24314853v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2013.19"},{"key":"2024101008351174000_2024.10.04.24314853v2.5","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv231"},{"issue":"10","key":"2024101008351174000_2024.10.04.24314853v2.6","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1001\/jamaneurol.2020.1760","article-title":"Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease","volume":"77","year":"2020","journal-title":"JAMA Neurology"},{"key":"2024101008351174000_2024.10.04.24314853v2.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2017.03.002"},{"issue":"1","key":"2024101008351174000_2024.10.04.24314853v2.8","doi-asserted-by":"crossref","first-page":"e222441","DOI":"10.1148\/radiol.222441","article-title":"MRI-based Deep Learning Assessment of Amyloid, Tau, and Neurodegeneration Biomarker Status across the Alzheimer Disease Spectrum","volume":"309","year":"2023","journal-title":"Radiology"},{"key":"2024101008351174000_2024.10.04.24314853v2.9","doi-asserted-by":"crossref","unstructured":"Chen X , Toueg TN , Harrison TM , Baker SL , Jagust WJ . 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