Wunderlich P, Glebov K, Kemmerling N, Tien NT, Neumann H, Walter J. Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) by ectodomain shedding and γ-secretase dependent intramembranous cleavage. J Biol Chem. 2013 Nov 15;288(46):33027-36. PubMed.
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Third Rock Ventures
As far as it goes, this paper is quite provocative. The main limitations are that the experiments were done in artificial cell lines and used transfected molecular components. It should be possible, based on these findings, to demonstrate abnormalities of signaling in myeloid cells from individuals (or mice) harboring presenilin 1 mutations. Gamma secretase inhibition should also impair DAP12 signaling in primary myeloid cells. In summary, this study represents an excellent "discovery" exercise that generates important testable hypotheses.
Icahn School of Medicine at Mount Sinai
I think the most important take-home message from these papers is that each finds evidence that the TREM2 locus is a risk factor for AD and AD-related traits. It would not be surprising for the odds ratio to be slightly lower than reported in the original manuscripts because of the “winner's curse.” However, the meta-analysis of published studies shows the odds ratio still remains above 3, suggesting that carriers of the R47H risk variant have a threefold increase in risk, which is much higher than any of the GWAS hits and similar to carriers of one APOE4 allele. A big difference between the TREM2 variant and APOE4 is the relatively low frequency of the former in the general population; thus, the total number of AD cases attributable to TREM2 will be much lower. The most important aspect of the identification of the TREM2 locus as a risk factor for AD is not the number of cases explained by R47H, or any other variant in TREM2, but the mechanism by which it influences risk for disease. This association highlights the importance of microglia in AD and strongly suggests that lower TREM2 function contributes to AD risk, perhaps through decreased clearance of Aß or regulation of inflammation in the brain.
The paper from Cruchaga et al. hints that R47H may play a role in other neurodegenerative diseases. Papers published in other journals since January have also suggested this possibility, although given the rarity of this and other variants, large meta-analyses will be needed to confirm whether TREM2 variants increase risk for multiple neurodegenerative diseases or whether this risk is specific to AD.
References:
Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM, Benitez BA, Jeng AT, Skorupa T, Carrell D, Bertelsen S, Bailey M, McKean D, Shulman JM, De Jager PL, Chibnik L, Bennett DA, Arnold SE, Harold D, Sims R, Gerrish A, Williams J, Van Deerlin VM, Lee VM, Shaw LM, Trojanowski JQ, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD, Peskind ER, Galasko D, Fagan AM, Holtzman DM, Morris JC, GERAD Consortium, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Alzheimer Disease Genetic Consortium (ADGC), Goate AM. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron. 2013 Apr 24;78(2):256-68. Epub 2013 Apr 4 PubMed.
View all comments by Alison Goate�
In general, the frequency of common alleles (i.e., those with frequency greater than 1 to 5 percent) does not differ significantly across populations, but this scenario changes for rare alleles because most of them are population-specific. Furthermore, most of the genetic variants in modern human genomes occur at low frequencies, and consequently the total number of rare alleles vastly outstrips the number of common ones. Importantly, rare variants are more prone to have functional consequences than common variants, and the role of rare variants in disease susceptibility is being established for many traits. However, because rare variants are typically population-specific, population stratification will be an important issue to consider in case-control studies. That is, subtle differences in population structure will result in false-positive and false-negative conclusions.
Next-generation sequencing technologies will allow us to explore the contribution of rare genetic variants to disease risk. However, we are just at the beginning, and I suspect that the way we analyze this data will change somewhat in the near future. First, we will have to make a great effort to use homogeneous populations because, more than ever, subtle differences in population structure will result in false-positive and false-negative conclusions. Second, because rare variants are usually geographically clustered or even limited to specific populations, we will have to build genetic catalogs of rare variants across the globe. Third, we will have to use large sample sizes with accurately classified phenotypes (i.e., using biomarkers, pathologically confirmed diagnosed, and well-defined controls, etc.). Finally, we will have to develop (and use) more sophisticated statistical strategies to evaluate the contribution of rare variants in a particular gene to a common disorder.
TREM2 is a good example of population diversity in the frequency of its risk allele R47H. Even within populations with European ancestry you will see subtle regional differences. For example, the percentage of people carrying the variant are: 0.6 in Iceland; 0.5 in France; 0.54 in Ireland; 0.45 in the United States; 0.15 in several central European countries; 0.1 in Spain. What about Asia and Africa? According to genetic databases such as 1000 Genomes or Exome Variant Server, it is possible that this variant is absent in populations from these regions. This does not mean that this gene is not relevant in these populations, but it could be that other specific, rare variants within TREM2 play a role in non-European populations.
View all comments by Jordi ClarimonWashington University School of Medicine
In the recent correspondence to the NEJM about the initial TREM2 findings, Bruno Benitez and I reported an association between the TREM2 R47H variant and Parkinson's disease risk. However it looks like neither Dr. Guerreiro nor Dr. Jonsson found the same association in their analysis. An interesting finding reported in these letters is the supplementary table provided by Dr. Hardy, including the R47H minor allele frequency (MAF) for the control populations for all the published reports.
We have since reanalyzed the association of R47H with PD risk using data for that table and including all control datasets in which the R47H variant was directly genotyped or sequenced. In this new analysis our original association remained significant: MAF for R47H in PD cases vs. controls was 0.79 percent vs. 0.38 percent; odds ratio (OR)=2.08, p= 0.03. If we include the data from Rayaprolu et al., in which an additional 1,493 PD samples were genotyped for the R47H variant, then the OR increases to 2.49 with a p=2.31×10-4.
In the reply to our correspondence, Dr. Jonsson indicated that they analyzed 2,730 PD cases and 73,710 controls, and found an OR of 1.24. We supposed that the MAF of the R47H in controls was 0.46 percent based on their original NEJM paper (Jonsson et al., 2013 and performed a meta-analysis including this dataset and the data from our reanalysis as outlined in the paragraph above. In this scenario the R47H variant remained significant, with an OR of 1.32 and p=0.03. Based on the information published by Dr. Jonsson in his reply, it is not clear whether the R47H variant was genotyped or imputed in those 73,710 controls, and what defined controls for this dataset. As they originally published, the MAF of the R47H is quite different in elderly individuals vs. cognitively normal individuals. Therefore, their estimation of the risk associated with the R47H variant in PD may be underestimated.
In summary, based on these analyses we feel confident about the association of the TREM2 R47H variant with PD risk. However, if both Drs. Guerreiro and Jonsson would publish or share their data, a more rigorous meta-analysis could be performed.
References:
Rayaprolu S, Mullen B, Baker M, Lynch T, Finger E, Seeley WW, Hatanpaa KJ, Lomen-Hoerth C, Kertesz A, Bigio EH, Lippa C, Josephs KA, Knopman DS, White CL 3rd, Caselli R, Mackenzie IR, Miller BL, Boczarska-Jedynak M, Opala G, Krygowska-Wajs A, Barcikowska M, Younkin SG, Petersen RC, Ertekin-Taner N, Uitti RJ, Meschia JF, Boylan KB, Boeve BF, Graff-Radford NR, Wszolek ZK, Dickson DW, Rademakers R, Ross OA. TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. Mol Neurodegener. 2013 Jun 21;8:19. PubMed.
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):107-16. Epub 2012 Nov 14 PubMed.
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