Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia

Ruiz, Agustín; Dols‐Icardo, Oriol; Bullido, María J.; Pástor, Pau; Rodríguez-Rodríguez, Eloy; Munáin, Adolfo López de; Pancorbo, Marian M. de; Pérez-Tur, Jordi; Álvarez, Victoria; Antonell, Anna; López‐Arrieta, Jesús; Hernández, Isabel; Tárraga, Lluís; Boada, Merçé; Lleó, Alberto; Blesa, Rafael; Frank-García, Ana; Sastre, Isabel; Razquín, Cristina; Ortega‐Cubero, Sara; Lorenzo, Elena; Sánchez‐Juan, Pascual; Combarros, Onofre; Moreno, Fermín; Gorostidi, Ana; Elcoroaristizabal, Xabier; Baquero, Miquel; Coto, Eliécer; Sánchez‐Valle, Raquel; Clarimón, Jordi

doi:10.1016/j.neurobiolaging.2013.08.011

Cited by 106 publications

(87 citation statements)

References 15 publications

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“…Our group also found an enrichment of the p.R47H variant in 726 EOAD cases compared to 783 controls (OR = 4.07; 95% CI = 1.29-16.89; p = 0.009) [60] , and other studies reported comparable results [61][62][63][64][65][66][67][68] .…”

Section: The Trem2 Genesupporting

confidence: 81%

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

Nicolas

Charbonnier²,

Campion³

2016

Hum Hered

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Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Aβ peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Aβ production/secretion, aggregation, clearance, or toxicity. Among them, the APOE ε4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at-risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is still limited. An alternative approach is to consider the de novo paradigm, stating that de novo variants may contribute to AD genetics in sporadic patients. Here, we critically review AD genetics reports with a special focus on rare variants.

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Section: The Trem2 Genesupporting

confidence: 81%

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

Nicolas

Charbonnier²,

Campion³

2016

Hum Hered

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“…However, associations of rs75932628 with FTD have not been replicated in different populations. In a large cohort of AD and FTD patients from Spanish origin, the rs75932628 variant contributed to the risk of AD, but was not harbored by any of the FTD patients [12]. Moreover, this variant was not identified in patients with early-onset FTD in the French population [21].…”

Section: Discussionmentioning

confidence: 93%

“…This association was confirmed in a French [8] and a Spanish [9] population including both LOAD and early-onset AD (EOAD) patients, and a similar trend was also observed in a population originating from United States, United Kingdom, and Europe [10]. However, there is no agreement on the degree to which carrying TREM2 rs75932628 increases AD risk, and the range fluctuates from a low of 1.7-fold to a high of 4.1-fold [8,11,12].…”

Section: Introductionmentioning

confidence: 79%

Assessment of TREM2 rs75932628 association with amyotrophic lateral sclerosis in a Chinese population

Chen¹,

Chen²,

Wei

et al. 2015

Journal of the Neurological Sciences

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“…Heterozygous expression of TREM2 variants has also been linked to cases of FTD, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) [79][80][81][82]. However, other studies have not found any TREM2 association with these neurodegenerative diseases, and it remains unclear whether TREM2 variants in the heterozygous state contribute to risk of neurodegenerative diseases other than AD [62,[83][84][85].…”

Section: Box 1 Plaque-associated Myeloid Cells: Identity and Impactmentioning

confidence: 99%