title: Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia.
abstract: Homozygous mutations in exon 2 of TREM2, a gene involved in Nasu-Hakola disease, can cause frontotemporal dementia (FTD). Moreover, a rare TREM2 exon 2 variant (p.R47H) was reported to increase the risk of Alzheimer's disease (AD) with an odds ratio as strong as that for APOEε4. We systematically screened the TREM2 coding region within a Belgian study on neurodegenerative brain diseases (1216 AD patients, 357 FTD patients, and 1094 controls). We observed an enrichment of rare variants across TREM2 in both AD and FTD patients compared to controls, most notably in the extracellular IgV-set domain (relative risk = 3.84 [95% confidence interval = 1.29-11.44]; p = 0.009 for AD; relative risk = 6.19 [95% confidence interval = 1.86-20.61]; p = 0.0007 for FTD). None of the rare variants individually reached significant association, but the frequency of p.R47H was increased ~ 3-fold in both AD and FTD patients compared to controls, in line with previous reports. Meta-analysis including 11 previously screened AD cohorts confirmed the association of p.R47H with AD (p = 2.93×10(-17)). Our data corroborate and extend previous findings to include an increased frequency of rare heterozygous TREM2 variations in AD and FTD, and show that TREM2 variants may play a role in neurodegenerative diseases in general.
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Elise
authors.initials: E
authors.lastname: Cuyvers
authors.forename: Karolien
authors.initials: K
authors.lastname: Bettens
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Philtjens
authors.forename: Tim
authors.initials: T
authors.lastname: Van Langenhove
authors.forename: Ilse
authors.initials: I
authors.lastname: Gijselinck
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vandenbulcke
authors.forename: Jasper
authors.initials: J
authors.lastname: Van Dongen
authors.forename: Nathalie
authors.initials: N
authors.lastname: Geerts
authors.forename: Githa
authors.initials: G
authors.lastname: Maes
authors.forename: Maria
authors.initials: M
authors.lastname: Mattheijssens
authors.forename: Karin
authors.initials: K
authors.lastname: Peeters
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D001530:Belgium / Q000453:epidemiology; D015331:Cohort Studies; D005260:Female; D057180:Frontotemporal Dementia / Q000453:epidemiology / Q000235:genetics*; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D011446:Prospective Studies; D011971:Receptors, Immunologic / Q000235:genetics*
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer's disease; Frontotemporal dementia; IgV-set domain; Meta-analysis; Rare variants; TREM2