Common and rare variant analyses implicate JARID2 in cerebral tau deposition.

Authors

Tamil Iniyan Gunasekaran, Devendra Meena, Annie J Lee, Siwei Wu, Logan Dumitrescu, Reisa Sperling, Timothy J Hohman, Jingxian Huang, A4 Study, Alzheimer’s Disease Sequencing Project (ADSP), Abbas Dehghan, Ioanna Tzoulaki, Richard Mayeux, Badri Vardarajan

Published in

NPJ dementia. Volume 2. Issue 1. Pages 52. Epub Jul 03, 2026.

Abstract

Genetic research on Alzheimer's disease (AD) has primarily focused on amyloid-β (Aβ), with fewer studies exploring tau pathology. We performed common variant GWAS on tau-PET SUVRs from A4 (n = 311 preclinical AD) and ADNI (n = 375 across diagnostic groups) cohorts. We complemented this with locus-specific rare variant analyses in 1561 individuals across five cohorts. Genetic findings were evaluated using circulating plasma proteins from the UK Biobank Pharma Proteomics Project (n = 54,129). Polygenic risk scores (PRS) for tau and amyloid-SUVR were tested for association with AD. GWAS identified two loci: rs78636169 (P = 5.76 × 10^-10) in JARID2 and rs7292124 (P = 2.20 × 10^-8) near ISX. Rare-variant analysis in JARID2 revealed chr6:15257832:A:G (P = 7.08 × 10^-05) in harmonized analysis and chr6:15492808:C:T (P = 1.65 × 10^-09) in rare-variant meta-analysis. Pleiotropy analyses suggested limited overlap between tau- and amyloid-related genetic signals. Gene-based analysis highlighted JARID2, a component of the PRC2 multi-protein complex. Mendelian randomization analysis identified LRRFIP1, a protein that binds with PRC2, as potentially causally linked to tau pathology. Amyloid-PRS, but not tau-PRS, was associated with AD clinical status, with age-dependent effects in APOE-ε4 carriers. Leveraging both GWAS and a large rare-variant cohort, we identified JARID2 as a candidate gene associated with tau pathology and observed patterns consistent with partially distinct roles of Aβ and tau in AD progression.

PMID:
42404994
Bibliographic data and abstract were imported from PubMed on 06 Jul 2026.

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