ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans 11 Medical and Health Sciences 1109 Neurosciences 06 Biological Sciences 0604 Genetics

Olivia J. Conway, Minerva M. Carrasquillo, Xue Wang, Jenny M. Bredenberg, Joseph S. Reddy, Samantha L. Strickland, Curtis S. Younkin, Jeremy D. Burgess, Mariet Allen, Sarah J. Lincoln, Thuy Nguyen, Kimberly G. Malphrus, Alexandra I. Soto, Ronald L. Walton, Bradley F. Boeve, Ronald C. Petersen, John A. Lucas, Tanis J. Ferman, William Polk Jr. Cheshire, Jay A. Van GerpenRyan J Uitti, Zbigniew K. Wszolek, Owen A. Ross, Dennis W. Dickson, Neill R. Graff-Radford, Nilüfer Ertekin-Taner

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Background: Rare coding variants ABI3-rs616338-T and PLCG2-rs72824905-G were identified as risk or protective factors, respectively, for Alzheimer's disease (AD). Methods: We tested the association of these variants with five neurodegenerative diseases in Caucasian case-control cohorts: 2742 AD, 231 progressive supranuclear palsy (PSP), 838 Parkinson's disease (PD), 306 dementia with Lewy bodies (DLB) and 150 multiple system atrophy (MSA) vs. 3351 controls; and in an African-American AD case-control cohort (181 AD, 331 controls). 1479 AD and 1491 controls were non-overlapping with a prior report. Results: Using Fisher's exact test, there was significant association of both ABI3-rs616338-T (OR = 1.41, p = 0.044) and PLCG2-rs72824905-G (OR = 0.56, p = 0.008) with AD. These OR estimates were maintained in the non-overlapping replication AD-control analysis, albeit at reduced significance (ABI3-rs616338-T OR = 1.44, p = 0.12; PLCG2-rs72824905-G OR = 0.66, p = 0.19). None of the other cohorts showed significant associations that were concordant with those for AD, although the DLB cohort had suggestive findings (Fisher's test: ABI3-rs616338-T OR = 1.79, p = 0.097; PLCG2-rs72824905-G OR = 0.32, p = 0.124). PLCG2-rs72824905-G showed suggestive association with pathologically-confirmed MSA (OR = 2.39, p = 0.050) and PSP (OR = 1.97, p = 0.061), although in the opposite direction of that for AD. We assessed RNA sequencing data from 238 temporal cortex (TCX) and 224 cerebellum (CER) samples from AD, PSP and control patients and identified co-expression networks, enriched in microglial genes and immune response GO terms, and which harbor PLCG2 and/or ABI3. These networks had higher expression in AD, but not in PSP TCX, compared to controls. This expression association did not survive adjustment for brain cell type population changes. Conclusions: We validated the associations previously reported with ABI3-rs616338-T and PLCG2-rs72824905-G in a Caucasian AD case-control cohort, and observed a similar direction of effect in DLB. Conversely, PLCG2-rs72824905-G showed suggestive associations with PSP and MSA in the opposite direction. We identified microglial gene-enriched co-expression networks with significantly higher levels in AD TCX, but not in PSP, a primary tauopathy. This co-expression network association appears to be driven by microglial cell population changes in a brain region affected by AD pathology. Although these findings require replication in larger cohorts, they suggest distinct effects of the microglial genes, ABI3 and PLCG2 in neurodegenerative diseases that harbor significant vs. low/no amyloid ß pathology.

Original languageEnglish (US)
Article number53
JournalMolecular neurodegeneration
Volume13
Issue number1
DOIs
StatePublished - Oct 11 2018

Keywords

  • ABI3
  • African-American
  • Alzheimer's disease (AD)
  • Dementia with Lewy bodies (DLB)
  • Expression
  • Genetic association
  • Multiple system atrophy (MSA)
  • PLCG2
  • Parkinson's disease (PD)
  • Progressive supranuclear palsy (PSP)

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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