Elsevier

Neurobiology of Aging

Volume 34, Issue 6, June 2013, Pages 1711.e15-1711.e17
Neurobiology of Aging

Genetic reports abstract
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TREM2 is associated with the risk of Alzheimer's disease in Spanish population

https://doi.org/10.1016/j.neurobiolaging.2012.12.018Get rights and content

Abstract

Two recent studies have reported the association of rs75932628-T in the TREM2 gene with the risk for Alzheimer's disease (AD). Rs75932628-T is a rare nonsynonymous variant (p.R47H) that confers a high risk of AD with an effect size similar to that of the APOE ɛ4 allele. However, this association has not been replicated in any independent studies to date. The allelic frequency of rs75932628 varies according to the population from 0.02% to 0.63% among healthy controls. In an attempt to replicate the association between rs75932628-T and AD risk, we genotyped rs75932628 in a cohort of 504 AD subjects and 550 healthy controls from a Spanish population. Rs75932628-T showed a minor allele frequency of 0.3% among this cohort. Interestingly, in our study, rs75932628-T was found exclusively in 1.4% of AD cases (7/504), including 4 early-onset AD cases, and in none of the controls (n = 0/550). Here, we report the first positive replication study in a Spanish population and confirm that TREM2 rs75932628-T is associated with the risk for AD.

Introduction

Homozygous loss-of-function mutations in the triggering receptor expressed on myeloid cells 2 protein (TREM2, MIM 605086) were initially associated with an autosomal recessive form of early-onset dementia, polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL, MIM 221770), from Swedish and Norwegian families (Paloneva et al., 2003). Subsequently, mutations in the TREM2 gene were found worldwide in PLOSL patients from different countries and ethnic origins (Klunemann et al., 2005; Numasawa et al., 2011; Paloneva et al., 2003; Soragna et al., 2003). Interestingly, PLOSL patients carrying TREM2 mutations exhibit a similar clinical phenotype with respect to the neurologic and skeletal abnormalities (Klunemann et al., 2005; Numasawa et al., 2011; Paloneva et al., 2003; Soragna et al., 2003). However, the clinical spectrum associated with TREM2 mutations was broadened after the identification of 3 siblings from a Lebanese family carrying the TREM2 homozygous (c.40+3delAGG) mutation and exhibiting early-onset dementia without skeletal symptoms (bone cysts) (Chouery et al., 2008). Moreover, mutations in TREM2 (homozygous nonsense mutation p.Q33*) were also found in 3 Turkish probands with frontotemporal-like dementia without any bone-associated symptoms (Guerreiro et al., 2013b). Interestingly, patients carrying the same TREM2 mutation (p.Q33*), but from different genetic backgrounds, exhibit different clinical phenotypes. These results suggest the presence of genetic/environmental modifiers of disease expressivity.

Previous efforts to link TREM2 to Alzheimer's disease (AD) or frontotemporal lobar degeneration (FTLD) in an Italian population did not identify allelic variants in the TREM2 coding region in patients with AD (n = 100) and FTLD (n = 56) or in age-matched (n = 80) and younger control subjects (n = 60) (Fenoglio et al., 2007). However, 2 independent studies recently reported that a nonsynonymous variant in TREM2, rs75932628 (encoding R47H), is strongly associated with AD (Guerreiro et al., 2013a; Jonsson et al., 2012). Rs75932628-T is a rare variant that expresses a different minor allele frequency (MAF) across healthy individuals from different populations. For example, in Iceland, rs75932628 has an MAF of 0.63%, but in the United States, the MAF is 0.12% (Jonsson et al., 2012). In addition, it has been reported that the MAF of rs75932628-T among European or North American descent AD cases also varies among the European Alzheimer's Disease Initiative Consortium (MAF = 0.9%), the Genetic and Environmental Risk for Alzheimer's Disease Consortium (MAF = 1%), and the AddNeuroMed (MAF = 2%) (Guerreiro et al., 2013a). The exome variant server database (http://evs.gs.washington.edu/EVS/) reports that rs75932628-T exhibits wide variability in frequency presenting much higher for European Americans (MAF = 0.26%) than for African Americans (MAF = 0.02%). All together, these results suggest that the MAF of rs75932628 varies according to population.

In this study, we analyzed whether heterozygous variants in TREM2 can increase the risk of AD in Spanish population.

Section snippets

Study subjects

DNA was collected from individuals of Spanish descent recruited between 2003 and 2012 from the Memory Disorders Unit, Department of Neurology, Clínica Universidad de Navarra, School of Medicine (Pamplona, Spain). The diagnosis of probable AD was made according to National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria (McKhann et al., 1984). Before their participation, a written informed

Results

The p.R47H variant was directly genotyped in 180 patients with EOAD, 324 LOAD participants, and in 550 controls. From a total of 1054 individuals, rs75932628-T exhibits an MAF = 0.3%. Rs75932628-T was found in 1.4% (7/504) of AD cases and in none of the controls (0/550) (p = 0.009). Four p.R47H carriers were EOAD patients (AAO mean = 57.2 ± 1.3 years), and 3 were LOAD patients (AAO mean = 74 ± 3.5 years). None of EOAD and p.R47H carriers have pathogenic mutations in APP, PSEN1, PSEN2, MAPT, and

Discussion

Rs75932628-T is a rare nonsynonymous variant that confers a risk of AD with an effect size that is similar to that of the APOE ɛ4 allele (Guerreiro et al., 2013a; Jonsson et al., 2012). To date, these findings have not been independently replicated in populations beyond those already reported (Guerreiro et al., 2013a; Jonsson et al., 2012). Our replication study confirmed the association of rs75932628-T with AD in a group of Spanish AD patients, validating recent reports from independent cohort

Disclosure statement

The authors report no conflict of interest.

All participants had agreed by signed informed consent to participate in genetic studies approved by our Institutional Review Board.

Acknowledgements

This work was supported by grants from the National Institutes of Health (P30-NS069329-01) and from the Alzheimer Association (NIRG-11-200110). This work was supported by a grant to P.P. from the Department of Health of the Government of Navarra (refs. 13085 and 3/2008).

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