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Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease.

ABSTRACT: Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.

SUBMITTER: Dalmasso MC

PROVIDER: S-EPMC6355764 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease.

Dalmasso Maria Carolina MC Brusco Luis Ignacio LI Olivar Natividad N Muchnik Carolina C Hanses Claudia C Milz Esther E Becker Julian J Heilmann-Heimbach Stefanie S Hoffmann Per P Prestia Federico A FA Galeano Pablo P Avalos Mariana Soledad Sanchez MSS Martinez Luis Eduardo LE Carulla Mariana Estela ME Azurmendi Pablo Javier PJ Liberczuk Cynthia C Fezza Cristina C Sampaño Marcelo M Fierens Maria M Jemar Guillermo G Solis Patricia P Medel Nancy N Lisso Julieta J Sevillano Zulma Z Bosco Paolo P Bossù Paola P Spalletta Gianfranco G Galimberti Daniela D Mancuso Michelangelo M Nacmias Benedetta B Sorbi Sandro S Mecocci Patrizia P Pilotto Alberto A Caffarra Paolo P Panza Francesco F Bullido Maria M Clarimon Jordi J Sánchez-Juan Pascual P Coto Eliecer E Sanchez-Garcia Florentino F Graff Caroline C Ingelsson Martin M Bellenguez Céline C Castaño Eduardo Miguel EM Kairiyama Claudia C Politis Daniel Gustavo DG Kochen Silvia S Scaro Horacio H Maier Wolfgang W Jessen Frank F Mangone Carlos Alberto CA Lambert Jean-Charles JC Morelli Laura L Ramirez Alfredo A

Translational psychiatry 20190131 1

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genoty ...[more]

PMID: 30705288

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Project description: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.

Project description:Missense variants ABI3_rs616338-T and PLCG2_rs72824905-G were previously associated with elevated or reduced risk of Alzheimer's disease (AD), respectively. Despite reports of associations with other neurodegenerative diseases, there are few studies of these variants in purely neuropathologically diagnosed cohorts. Further, the effect of these mutations on neurodegenerative disease pathologies is unknown. In this study, we tested the effects of ABI3_rs616338-T and PLCG2_rs72824905-G on disease risk in autopsy cohorts comprised of 973 patients diagnosed neuropathologically with Lewy body disease (LBD-NP) and 1040 with progressive supranuclear palsy (PSP), compared to 3351 controls. LBD-NP patients were further categorized as high, intermediate and low likelihood of clinical dementia with Lewy bodies (DLB-CL) based on DLB Consortium criteria. We also tested for association with both Braak neurofibrillary tau tangle (nTotal?=?2008, nPSP?=?1037, nLBD-NP?=?971) and Thal phase amyloid plaque scores (nTotal?=?1786, nPSP?=?1018, nLBD-NP?=?768). Additionally, 841 PSP patients had quantitative tau neuropathology measures that were assessed for genetic associations. There was no statistically significant association with disease risk for either LBD-NP or PSP in our study. LBD intermediate category disease risk was significantly associated with ABI3_rs616338-T (OR?=?2.65, 95% CI 1.46-4.83, p?=?0.001). PLCG2_rs72824905-G was associated with lower Braak stage (ß?=?-?0.822, 95% CI -?1.439 to -?0.204, p?=?0.009). This effect was more pronounced in the PSP (ß?=?-?0.995, 95% CI -?1.773 to -?0.218, p?=?0.012) than LBD-NP patients (ß?=?-?0.292, 95% CI -?1.283 to 0.698, p?=?0.563). PLCG2_rs72824905-G also showed association with reduced quantitative tau pathology for each lesion type and overall tau burden in PSP (ß?=?-?0.638, 95% CI -?1.139 to -?0.136, p?=?0.013). These findings support a role for PLCG2_rs72824905-G in suppressing tau neuropathology. ABI3_rs616338-T may influence disease risk specifically in the LBD-NP intermediate category comprised of patients with diffuse neocortical or limbic LB, concurrently with moderate or high AD neuropathology, respectively. Our study provides a potential mechanism of action for the missense PLCG2 variant and suggests a differential disease risk effect for ABI3 in a distinct LBD-NP neuropathologic category.

Dataset Information

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease.

Publications

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease.

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