Cochran JN, Geier EG, Bonham LW, Newberry JS, Amaral MD, Thompson ML, Lasseigne BN, Karydas AM, Roberson ED, Cooper GM, Rabinovici GD, Miller BL, Myers RM, Yokoyama JS, Alzheimer’s Disease Neuroimaging Initiative. Non-coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases. Am J Hum Genet. 2020 May 7;106(5):632-645. Epub 2020 Apr 23 PubMed.

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  1. It is nice to see that large-scale genome-sequencing projects are starting to deliver new risk factors for the rarer, early onset dementia phenotypes like FTD and EOAD. In contrast to whole-genome sequencing, we can now zoom in to the impact of rare variants, with moderate to high penetrance and study how they impact one's genetic risk profile.

    An added value of their study design is that they demonstrate that one can have sufficient power to associate disease risk with noncoding regulatory variants.

    View all comments by Julie van der Zee

  2. This paper by Cochran et al. reports on the potential role of TET2 variants in neurodegenerative diseases. The authors search for variants that contribute to disease via haploinsufficiency by focusing on loss-of-function variants or rare coding and noncoding variants after filtering conditions. Their approach builds upon the pleiotropy known to be part of the genetic architecture of dementias and neurodegenerative diseases by using a discovery cohort including EOAD and FTD and replication cohorts including LOAD, FTD, and ALS.

    The only significant association identified was between filtered TET2 variants and EOAD and FTD combined, compared to controls. TET2 is the type of gene one would expect to see associated with different forms of neurodegenerative disease given its known role in DNA methylation. However, the differences seen in the association across cohorts suggest that independent follow-up studies are needed to definitively establish TET2 as a gene associated with neurodegenerative disease risk. In fact, there is a wide range of odds ratios seen in the different cohorts, from very strong effects (OR=29) in the UCSF discovery series to completely null (OR=1) in the AMP-AD series, and when assessing risk association only in the larger cohorts (ADSP and AMP-AD), the results are not as significant.

    Important factors that may have contributed to biasing the results include the young age of the controls in the discovery set, the small size of the discovery cohort, and the impossibility of validating variants identified in non-UCSF samples. Still, if confirmed, the association of TET2 gene variants with AD and FTD suggests a possible role for epigenetic age clock signatures in neurodegenerative diseases.

    View all comments by Rita Guerreiro

  3. Using genome sequencing, the authors identified deleterious variations in TET2, with predicted loss-of-function outcomes, as a risk factor for multiple neurodegenerative disorders, including EOAD, LOAD, FTD, and ALS. This is an interesting paper where Cochran and colleagues hypothesized that non-functional TET2 enzymatic activity in neurons could explain the difference between normal physiological aging and neurodegenerative disease based on studies where increased expression of TET2 promoted neurogenesis (Li et al., 2017) and in a 2xTg AD mouse model where there is a decreased expression of Tet2 in the hippocampus (Li et al., 2020). 

    A common feature of neurodegenerative diseases is the presence of a chronic inflammatory response, which in many cases is considered to be detrimental for the surrounding neuronal population. Within the last five years, several studies have highlighted the role played by TET2 in the control of the inflammatory response from either the lymphoid (Ichiyama et al., 2015) or myeloid (Zhang et al., 2015) lineage, including our group's recent publication in microglia cells (Carrillo-Jimenez et al., 2019), where TET2 was necessary for the full proinflammatory response upon TLR-4 agonist treatment. In this context, TET2 is known to be able to regulate the inflammatory response dependent on (in the case of T-cells) or independently of (peripheral macrophages and microglia) its enzymatic activity. For instance, in our study of microglia cells, and in peripheral macrophages, TET2 plays an important activity-independent role upon TLR4 activation (Carrillo-Jimenez et al., 2019; Zhang et al., 2015). In our study, we also describe high protein expression of TET2 in microglia surrounding the amyloid plaque in a 5xFAD AD mouse model, but the function of TET2 in these microglia is yet to be elucidated. Therefore, the question remains if TET2 in plaque-associated microglia plays a deleterious or beneficial role in AD, and furthermore if the enzymatic activity of TET2 is required.

    To address the latter question, more in-depth studies of TET2 post-translational modifications could shed light on the role that TET2 has under different disease conditions. For instance, TET2 acetylation by P300 increases its enzymatic activity (Zhang et al., 2016). Regarding whether microglial TET2 plays a beneficial or deleterious role in AD, further studies using conditional TET2 KO mice crossed with an AD mouse model may answer this.

    In summary, the varying levels of TET2 expression in neurons versus microglia in AD disease models suggest multiple roles for TET2 in neurodegenerative disease (i.e., aging in neurons and modulation of microglia reactivity) where a loss-of-function variant of TET2 could be considered a risk factor for neurodegenerative diseases, including AD.

    References:

    Li X, Yao B, Chen L, Kang Y, Li Y, Cheng Y, Li L, Lin L, Wang Z, Wang M, Pan F, Dai Q, Zhang W, Wu H, Shu Q, Qin Z, He C, Xu M, Jin P. Ten-eleven translocation 2 interacts with forkhead box O3 and regulates adult neurogenesis. Nat Commun. 2017 Jun 29;8:15903. PubMed.

    Li L, Qiu Y, Miao M, Liu Z, Li W, Zhu Y, Wang Q. Reduction of Tet2 exacerbates early stage Alzheimer's pathology and cognitive impairments in 2 × Tg-ad mice. Hum Mol Genet. 2020 Jan 15; PubMed.

    Ichiyama K, Chen T, Wang X, Yan X, Kim BS, Tanaka S, Ndiaye-Lobry D, Deng Y, Zou Y, Zheng P, Tian Q, Aifantis I, Wei L, Dong C. The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity. 2015 Apr 21;42(4):613-26. Epub 2015 Apr 7 PubMed.

    Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, Zhao D, Liu Y, Wang C, Zhang X, Su X, Liu J, Ge W, Levine RL, Li N, Cao X. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature. 2015 Sep 17;525(7569):389-393. Epub 2015 Aug 19 PubMed.

    Carrillo-Jimenez A, Deniz Ö, Niklison-Chirou MV, Ruiz R, Bezerra-Salomão K, Stratoulias V, Amouroux R, Yip PK, Vilalta A, Cheray M, Scott-Egerton AM, Rivas E, Tayara K, García-Domínguez I, Garcia-Revilla J, Fernandez-Martin JC, Espinosa-Oliva AM, Shen X, St George-Hyslop P, Brown GC, Hajkova P, Joseph B, Venero JL, Branco MR, Burguillos MA. TET2 Regulates the Neuroinflammatory Response in Microglia. Cell Rep. 2019 Oct 15;29(3):697-713.e8. PubMed.

    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.

    Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, Zhao D, Liu Y, Wang C, Zhang X, Su X, Liu J, Ge W, Levine RL, Li N, Cao X. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature. 2015 Sep 17;525(7569):389-393. Epub 2015 Aug 19 PubMed.

    Zhang YW, Wang Z, Xie W, Cai Y, Xia L, Easwaran H, Luo J, Yen RC, Li Y, Baylin SB. Acetylation Enhances TET2 Function in Protecting against Abnormal DNA Methylation during Oxidative Stress. Mol Cell. 2017 Jan 19;65(2):323-335. PubMed.

    View all comments by Miguel Burguillos

  4. With great interest have we read this article by Cochran et al., who used peripheral blood cells as a resource for the germline genome. Recent developments in the field of hematology have shown that somatic mutations in the TET2 gene have been found to drive age-related clonal hematopoiesis (ARCH). Therefore, it may be possible that the effect observed by Cochran et al. is an age-related effect, and not an AD-related effect.

    Recent reports have shown that while humans age, our blood cells become more and more clonal (Genovese et al., 2014; Jaiswal et al., 2014; Xie et al., 2014). When we are young, our blood cells are generated by several thousands of hematopoietic stem cells (HSCs), which each produce offspring that contribute to the multiple hematopoietic lineages that constitute our peripheral blood, i.e., all myeloid and lymphoid cells.

    However, as we age, many of these HSCs die or become inactive, while a few survive and gain a competitive advantage over other HSCs. This competitive advantage is driven by the accumulation of somatic mutations in several genes, of which somatic mutations in the TET2 and DNMT3A genes are most common (Busque et al., 2012; Genovese et al., 2014; Jaiswal et al., 2017). Both genes are associated with epigenetic regulation, i.e., DNA-methylation and -demethylation processes.

    As we age, the HSC clone will expand and contribute to an increasing fraction of cells in our peripheral blood. This process has been coined “age-related clonal hematopoiesis,” ARCH (Shlush, 2018; Steensma et al., 2015). The somatic mutations accumulated by the stem cell over the course of a lifetime effectively “tag” each individual stem cell with a unique genetic “barcode” (Zink et al., 2017). 

    Acquired somatic mutations are heterozygous in the clone, and because the clone contributes to only a fraction of the total peripheral blood cells, these mutations can be recognized by their allele balance (between alternate allele and reference allele), which will be consistently lower than the 1:1 ratio observed for germline heterozygous mutations. With age, all somatic mutations accumulated in the HSC during aging will become more and more prevalent in the blood cells, and more and more detectable by genetic sequencing.

    In 2014, we reported that ~70 percent of the peripheral blood cells in a 115-year-old woman were generated by one hematopoietic stem cell “clone” and its subclones (Holstege et al., 2014). Recently, we found that one clone contributed to 75 percent of the peripheral blood cells in a 111-year-old woman, and that the clone generated almost all myeloid cells (van den Akker et al., 2020). Note that neither of these women suffered from hematopoietic malignancies.

    In the discovery analysis of this paper, the authors compared older AD and FTD cases with young controls. They find that mutations in the TET2 gene associated with a 29-fold increased risk of AD/FTD (OR: 28.9, 95%CI 4.5–1200, p= 4.9E-7; AD cases: N=227, median age 59, 23% >65; FTD cases: N=208, median age 65 year, 49% > 65; controls N=671; median age 40 years, 9% >65). However, in a replication analysis, in which controls were more age-matched with the cases (although still slightly younger), the authors found that the TET2 mutations associated with a 1.7-fold increased AD/FTD risk and with lower significance (OR= 1.7, 95%CI 1.2–2.6, p= 6.1-3; AD cases: N=2,530, median age 79, 90% >65; FTD cases: N=319, median age 76 year, 78% > 65; controls N=2,457; median age 74 years, 84% >65). This indicates an age relation in the burden of TET2 mutations in the samples, that is independent of the case-control association.

    A current debate in the hematology field is whether ARCH causes age-related disease or is a consequence of aging, and thereby indirectly associated with age-related diseases. Indeed, ARCH was previously associated with several age-related hematological diseases such as myeloid dysplasia or malignancies (Genovese et al., 2014; Jaiswal et al., 2014), and large prospective epidemiological studies have also established associations between ARCH and prevalent Type 2 diabetes, prevalent chronic obstructive pulmonary disease, incident cardiovascular disease, and vascular or all-cause mortality (Bonnefond et al., 2013; Genovese et al., 2014; Jaiswal et al., 2014; Jaiswal et al., 2017; Zink et al., 2017). However, ARCH has also been observed in many individuals with no apparent disease (van den Akker et al., 2016). 

    To confirm that germline variants in the TET2 gene are Alzheimer’s disease risk variants, the authors would need to separate the somatic signal from the germline signal. This could be done by investigating whether the allele balance of the heterozygous TET2 mutations is consistently lower than the allele frequency of heterozygous germline (common) variants. Moreover, the authors might investigate whether, in these datasets, a similar signal can be observed for somatic mutations in the DNMT3A gene and/or other ARCH-related genes (Jaiswal et al., 2017). 

    We encourage the authors to perform these follow-up analyses to confirm that the variants are germline, somatic, or a mix of both. The results might lead to confirmation of the conclusions in the paper, or they may provide evidence that AD should be included in the list of age-related diseases associated with carrying a TET2 mutation, i.e. ARCH. Alternatively, the results may indicate that somatic TET2 mutations lead to ARCH, but not to an increased risk of AD.

    References:

    Bonnefond A, Skrobek B, Lobbens S, Eury E, Thuillier D, Cauchi S, Lantieri O, Balkau B, Riboli E, Marre M, Charpentier G, Yengo L, Froguel P. Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications. Nat Genet. 2013 Sep;45(9):1040-3. Epub 2013 Jul 14 PubMed.

    Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, Mollica L, Li J, Viale A, Heguy A, Hassimi M, Socci N, Bhatt PK, Gonen M, Mason CE, Melnick A, Godley LA, Brennan CW, Abdel-Wahab O, Levine RL. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012 Nov;44(11):1179-81. Epub 2012 Sep 23 PubMed.

    Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, Chambert K, Mick E, Neale BM, Fromer M, Purcell SM, Svantesson O, Landén M, Höglund M, Lehmann S, Gabriel SB, Moran JL, Lander ES, Sullivan PF, Sklar P, Grönberg H, Hultman CM, McCarroll SA. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014 Dec 25;371(26):2477-87. Epub 2014 Nov 26 PubMed.

    Holstege H, Pfeiffer W, Sie D, Hulsman M, Nicholas TJ, Lee CC, Ross T, Lin J, Miller MA, Ylstra B, Meijers-Heijboer H, Brugman MH, Staal FJ, Holstege G, Reinders MJ, Harkins TT, Levy S, Sistermans EA. Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis. Genome Res. 2014 May;24(5):733-42. Epub 2014 Apr 23 PubMed.

    Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, Higgins JM, Moltchanov V, Kuo FC, Kluk MJ, Henderson B, Kinnunen L, Koistinen HA, Ladenvall C, Getz G, Correa A, Banahan BF, Gabriel S, Kathiresan S, Stringham HM, McCarthy MI, Boehnke M, Tuomilehto J, Haiman C, Groop L, Atzmon G, Wilson JG, Neuberg D, Altshuler D, Ebert BL. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014 Dec 25;371(26):2488-98. Epub 2014 Nov 26 PubMed.

    Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, McConkey M, Gupta N, Gabriel S, Ardissino D, Baber U, Mehran R, Fuster V, Danesh J, Frossard P, Saleheen D, Melander O, Sukhova GK, Neuberg D, Libby P, Kathiresan S, Ebert BL. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med. 2017 Jul 13;377(2):111-121. Epub 2017 Jun 21 PubMed.

    Shlush LI. Age-related clonal hematopoiesis. Blood. 2018 Feb 1;131(5):496-504. Epub 2017 Nov 15 PubMed.

    Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, Ebert BL. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015 Jul 2;126(1):9-16. Epub 2015 Apr 30 PubMed.

    van den Akker EB, Pitts SJ, Deelen J, Moed MH, Potluri S, van Rooij J, Suchiman HE, Lakenberg N, de Dijcker WJ, Uitterlinden AG, Kraaij R, Hofman A, de Craen AJ, Houwing-Duistermaat JJ, van Ommen GJ, Genome of The Netherlands Consortium, Cox DR, van Meurs JB, Beekman M, Reinders MJ, Slagboom PE. Uncompromised 10-year survival of oldest old carrying somatic mutations in DNMT3A and TET2. Blood. 2016 Mar 17;127(11):1512-5. Epub 2016 Jan 29 PubMed.

    Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, McMichael JF, Schmidt HK, Yellapantula V, Miller CA, Ozenberger BA, Welch JS, Link DC, Walter MJ, Mardis ER, Dipersio JF, Chen F, Wilson RK, Ley TJ, Ding L. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014 Dec;20(12):1472-8. Epub 2014 Oct 19 PubMed.

    Zink F, Stacey SN, Norddahl GL, Frigge ML, Magnusson OT, Jonsdottir I, Thorgeirsson TE, Sigurdsson A, Gudjonsson SA, Gudmundsson J, Jonasson JG, Tryggvadottir L, Jonsson T, Helgason A, Gylfason A, Sulem P, Rafnar T, Thorsteinsdottir U, Gudbjartsson DF, Masson G, Kong A, Stefansson K. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood. 2017 Aug 10;130(6):742-752. Epub 2017 May 8 PubMed.

    View all comments by Erik van den Akker

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  1. Mutations in Epigenetic Gene Linked to Neurodegeneration