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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.    Electronic supplementary material  The online version of this article (10.1186/s13024-018-0289-x) contains supplementary material, which is available to authorized users.

ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans