|(C;C)||0||common in clinvar|
|(C;T)||3||risk of Alzheimer's disease|
|(T;T)||3.5||risk of Alzheimer's disease|
rs75932628(T), a SNP in the TREM2 gene on chromosome 6 resulting in an R47H substitution, was found to confer a significantly higher risk of late-onset Alzheimer's disease based on two articles published together in 2013 in the New Engl. J. of Med.
In one study, the odds ratio for rs75932628(T) was 2.9 (CI: 2.09 to 4.09, P=3.42×10−10). The mutation had a frequency of 0.46% in controls 85 years of age or older. The authors also observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10−12 in combined discovery and replication samples), and found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P=0.003).[PMID 23150908]
In the other study, analysis of the rs75932628(T) in a series that included 1887 patients with Alzheimer's disease showed a strong, highly significant association (odds ratio, 5.05, CI: 2.77 to 9.16; P=9.0×10−9). Four other TREM2 gene variants (D87N, T66M, Y38C, and Q33X) were also associated with higher risk for a frontotemporal dementia–like syndrome when homozygous.[PMID 23150934]
Notably, a 2018 study has raised the possibility that in TREM2 R47H mutation carriers, an APOE4 allele may be required for Alzheimer's to develop.[PMID 29411406]
Other studies confirming (or in some cases, refuting) an association between R47H and Alzheimer's include:
[PMID 25936935] Data shows that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (OR 2.71, p = 4.67 × 10e-25).
[PMID 25160042] Based on a study of ~1,000 Alzheimer patients, the R47H mutation does appear to be a risk factor for AD (OR = 2.19, CI:1.04-4.51, p = .03). Individuals with p.R47H associated AD (n = 12) had significantly earlier symptom onset than individuals with no TREM2 variants (n = 551) (55.2 years vs. 61.7 years (p = .02).
[PMID 26058841] Based on a Caucasian population comprising ~1,600 late-onset Alzheimer cases, carriers of the R47H variant are at increased risk (OR 7.40, p = 3.66e-06).
[PMID 25260849] A study of 474 AD patients from the northwest region of the UK showed a significant association of the R47H mutation with AD (OR 11.08, CI: 2.55-48.09, and Yates' corrected p value = 0.000146).
[PMID 25186855] Meta-analysis of 2 family-based and 5 case-control cohorts yielded an overall summary estimate (using case-control data only) for an odds ratio of 1.67 (CI: 0.95-2.92) for the association between the TREM2 R47H and increased AD risk; so while this study replicates the association, it finds a weaker effect than have other studies.
[PMID 24041969] A study of ~3,000 AD patients from Spain did see the R47H association with AD (OR 4.12, CI: 1.21-14.00, p = 0.014). A meta-analysis comprising 32,598 subjects from 4 previous studies demonstrated the large effect of the p.R47H variant in AD risk (OR 4.11, CI: 2.99-5.68, p = 5.27×10e-18).
[PMID 24762945] No association was seen between R47H and AD in a study of ~2,000 Japanese patients with late-onset AD.
Additional studies include:
[PMID 23391427] TREM2 is associated with the risk of Alzheimer's disease in Spanish population
[PMID 23800361] TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease
[PMID 24041969] Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia
[PMID 24602511] Triggering receptor expressed on myeloid cells 2 variants are rare in Parkinson's disease in a Han Chinese cohort [PMID 23380991] TREM2 R47H variant as a risk factor for early-onset Alzheimer's disease.
[PMID 23510020] Have we learnt all we need to know from genetic studies - is genetics over in Alzheimer's disease?
[PMID 23855982] Assessment of TREM2 rs75932628 association with Alzheimer's disease in a population-based sample: the Cache County Study.
[PMID 25027412] Frontobasal gray matter loss is associated with the TREM2 p.R47H variant
[PMID 25852195] Lack of Genetic Association Between TREM2 and Alzheimer's Disease in East Asian Population: A Systematic Review and Meta-Analysis
[PMID 26021840] Association Study of the TREM2 Gene and Identification of a Novel Variant in Exon 2 in Iranian Patients with Late-Onset Alzheimer's Disease
[PMID 26026943] Assessment of TREM2 rs75932628 association with amyotrophic lateral sclerosis in a Chinese population
[PMID 26058955] Assessment of TREM2 rs75932628 association with Parkinson's disease and multiple system atrophy in a Chinese population
[PMID 26058841] More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer's disease risk