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

Dalmasso, Carolina; Brusco, Luis I.; Olivar, Natividad; Muchnik, Carolina; Hanses, Claudia; Milz, Esther; Becker, J.; Heilmann‐Heimbach, Stefanie; Hoffmann, Per; Prestia, Federico Ariel; Galeano, Pablo; Avalos, Mariana Soledad Sanchez; Martínez, Luis Eduardo; Carulla, Mariana Estela; Azurmendi, Pablo Javier; Liberczuk, Cynthia; Fezza, Cristina; Sampaño, Marcelo; Fierens, Maria; Jemar, Guillermo; Solís, Patricia; Medel, Nancy; Lisso, Julieta; Sevillano, Zulma; Bosco, Paolo; Bossù, Paola; Spalletta, Gianfranco; Galimberti, Daniela; Mancuso, Michelangelo; Nacmias, Benedetta; Sorbi, Sandro; Mecocci, Patrizia; Pilotto, Alberto; Caffarra, Paolo; Panza, Francesco; Bullido, María J.; Clarimón, Jordi; Sánchez‐Juan, Pascual; Coto, Eliécer; Sánchez-García, Florentino; Graff, Caroline; Ingelsson, Martin; Bellenguez, Céline; Castaño, Eduardo M.; Kairiyama, Claudia; Politis, Daniel Gustavo; Kochen, Silvia; Scaro, Horacio; Maier, Wolfgang; Jessen, Frank; Mangone, Carlos A.; Lambert, Jean‐Charles; Morelli, Laura; Ramı́rez, Alfredo

doi:10.1038/s41398-019-0394-9

Cited by 38 publications

(42 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Deacetylation of FOXO3A has been shown to possess a neuroprotective role in Huntington’s disease models (Jiang et al, 2011). Besides TREM2 , the expression of ABI3 also increased in TBI according to the present analysis, which has been considered to modulate the susceptibility to AD in recent years (Dalmasso et al, 2019). Both of them are highly expressed in microglia, providing evidence for the role of a microglia-mediated innate immune response in the development of AD (Sims et al, 2017).…”

Section: Discussionsupporting

confidence: 61%

Identification of target genes in neuroinflammation and neurodegeneration after traumatic brain injury in rats

Zhao

Cao

et al. 2019

PeerJ

View full text Add to dashboard Cite

BackgroundTraumatic brain injury (TBI) is a common neurological emergency observed in hospitals. A considerable number of patients suffer from long-term disabilities after TBI. This study aimed to identify altered gene expression signatures and mechanisms related to TBI-induced chronic neuroinflammation and neurodegeneration.MethodsAn integrated analysis was performed using published RNA-sequencing studies to determine TBI-induced differentially expressed genes (DEGs). Based on the DEG data, functional annotation, signal-net, and transcription factor analyses were conducted to understand the mechanism of chronic neuroinflammation and neurodegeneration induced after TBI.ResultsTwo datasets were obtained using the Gene Expression Omnibus database, of which, 6,513 DEGs were identified (6,464 upregulated and 49 downregulated). Positive regulation of biological process, positive regulation of cellular process, nucleus, and heterocyclic compound binding were Gene Ontology terms significantly enriched in post-TBI rat models. Leukocyte transendothelial migration, chemokine signaling pathway, neurotrophin signaling pathway, and longevity-regulating pathway were significantly enriched after TBI. With regard to the signal-net analysis, FOXO3, DGKZ and ILK were considered the most critical genes derived using high–betweenness centrality calculation. A total of 44 TFs, including FOXO1, SRY and KLF4, were predicted to play an important role in the upregulation of gene expression. Using integrated bioinformatics analysis, TBI was found to be associated with a significant inflammatory response and neurodegeneration. FOXO3, apolipoprotein (APOE), microtubule-associated protein tau (MAPT), and TREM2 were probably associated with the TBI pathological process. The mitochondrial electron transport chain may be associated with neurodegeneration in patients with TBI, serving as a potential therapeutic target.

show abstract

Section: Discussionsupporting

confidence: 61%

Identification of target genes in neuroinflammation and neurodegeneration after traumatic brain injury in rats

Zhao

Cao

et al. 2019

PeerJ

View full text Add to dashboard Cite

show abstract

“…In 2017, we and others identified a specific rare nonsynonymous coding variant (rs72824905, p.P522R) in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that confers protection against the susceptibility to AD [68]. This association has been replicated in multiple independent samples from different populations [10,13,78]. PLCG2 is an enzyme mainly expressed in immune cells including microglia which are involved in innate immunity [47,78].…”

Section: Introductionmentioning

confidence: 93%

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment

Kleineidam¹,

Chouraki²,

Próchnicki³

et al. 2020

Acta Neuropathol

Self Cite

View full text Add to dashboard Cite

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau 181 , total tau, and Aβ 1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau 181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau 181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ 1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade Agustin Ruiz and Alfredo Ramirez have contributed equally to this work. The members of the Alzheimer's Disease Neuroimaging Initiative (ADNI) group are listed in Acknowledgements section. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc. edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report.

show abstract

“…Thus it is expected that different levels of genetic risk may selectively affect the prevalence of dementia in this region. For instance, the impact of rare variants ( TREM2 , PLCG2 , and ABI3 ) on the Argentinian population highlights different features of LAC admixed populations 62 . At the environmental level, socioeconomic status (SES) and social determinants of health (SDH), which signficantly influence the prevalence of dementia, 63 reveal larger inequalities in LACs than in HICs.…”

Section: Knowledge Creationmentioning

confidence: 99%

Dementia in Latin America: Paving the way toward a regional action plan

Parra¹,

Báez²,

Sedeño³

et al. 2020

Alzheimer's & Dementia

Self Cite

121

View full text Add to dashboard Cite

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC‐CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence‐based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.

show abstract

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

Cited by 38 publications

References 21 publications

Identification of target genes in neuroinflammation and neurodegeneration after traumatic brain injury in rats

Identification of target genes in neuroinflammation and neurodegeneration after traumatic brain injury in rats

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment

Dementia in Latin America: Paving the way toward a regional action plan

Contact Info

Product

Resources

About