Genome-wide association study of brain arteriolosclerosis

Lincoln M.P. Shade, Yuriko Katsumata, Timothy J. Hohman, Kwangsik Nho, Andrew J. Saykin, Shubhabrata Mukherjee, Kevin L. Boehme, John S.K. Kauwe, Lindsay A. Farrer, Gerard D. Schellenberg, Jonathan L. Haines, Richard P. Mayeux, Julie A. Schneider, Peter T. Nelson, David W. Fardo

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Brain arteriolosclerosis (B-ASC) is characterized by pathologically altered brain parenchymal arterioles. B-ASC is associated with cognitive impairment and increased likelihood of clinical dementia. To date, no study has been conducted on genome-wide genetic risk of autopsy-proven B-ASC. We performed a genome-wide association study (GWAS) of the B-ASC phenotype using multiple independent aged neuropathologic cohorts. Included in the study were participants with B-ASC autopsy and genotype data available from the NACC, ROSMAP, ADNI, and ACT data sets. Initial Stage 1 GWAS (n = 3382) and Stage 2 mega-analysis (n = 4569) were performed using data from the two largest cohorts (NACC and ROSMAP). Replication of top variants and additional Stage 3 mega-analysis were performed incorporating two smaller cohorts (ADNI and ACT). Lead variants in the top two loci in the Stage 2 mega-analysis (rs7902929, p = (Formula presented.) ; rs2603462, p = (Formula presented.)) were significant in the ADNI cohort (rs7902929, p = (Formula presented.) ; rs2603462, p = (Formula presented.)). The rs2603462 lead variant colocalized with ELOVL4 expression in the cerebellum (posterior probability = 90.1%). Suggestive associations were also found near SORCS1 and SORCS3. We thus identified putative loci associated with B-ASC risk, but additional replication is needed.

Original languageEnglish
Pages (from-to)1437-1450
Number of pages14
JournalJournal of Cerebral Blood Flow and Metabolism
Volume42
Issue number8
DOIs
StatePublished - Aug 2022

Bibliographical note

Publisher Copyright:
© The Author(s) 2022.

Keywords

  • SVD
  • VCID
  • aging
  • arteriosclerosis
  • dementia
  • neuropathology

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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