01 May 2020
Rare but powerful gene variants help scientists understand how disease develops, but they are hard to find. By pooling data on people with different early onset dementias to get cohorts of a workable size, researchers pulled out an association between mutations in the DNA demethylase ten-eleven translocation 2 (TET2) and elevated risk for Alzheimers disease, frontotemporal dementia, and amyotrophic lateral sclerosis. In the May 7 American Journal of Human Genetics, Jennifer Yokoyama at the University of California, San Francisco, and Richard Myers at the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, and colleagues report that both coding and noncoding TET2 variants nearly doubled a persons risk, and also meant faster decline in people who already had mild cognitive impairment.
The findings strengthen the idea that certain epigenetic changes can lead to neurodegeneration. The data also suggest that noncoding variants can have a powerful effect, and may indeed be the source of much of the still-unexplained heritability of these diseases, Yokoyama said.
Julie van der Zee at the VIB-University of Antwerp, Belgium, believes this last point is important. 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, she wrote to Alzforum (full comment below).
Accelerated Decline. Extrapolations predict that TET2 carriers will worsen faster on the CDR-SB than noncarriers. [Courtesy of Cochran et al., American Journal of Human Genetics.]
Geneticists search for rare disease variants in familial and early onset cohorts, but these are small, making it difficult to know whether a hit is statistically significant (Aug 2017 news). Or they sift through exome sequences, but these leave out noncoding variants.
Instead, Yokoyama and colleagues looked for variants linked to two different forms of early onset dementia. They capitalized on pleiotropy, or the ability of one gene to contribute to multiple diseases. The authors pooled data from clinically diagnosed AD and FTD patients seen at the UCSF Memory and Aging Center and the University of Alabama at Birmingham. The AD patients ranged from 45 to 84 years old, with an average age of 59, hence were enriched for early onset cases. Healthy age-matched controls came from UCSF, UAB, and a National Institute of Mental Health healthy aging cohort. People with known genetic mutations, or those who were related to each other, were excluded. The authors also excluded people with non-European ancestry, hoping to make the sample more homogeneous. They ended up with 671 controls and 435 cases, 227 of whom had EOAD and 208 FTD.
First author Nicholas Cochran at HudsonAlpha analyzed cases versus controls to find rare genetic variants enriched in the former. Cochran weeded out any that were predicted to be harmless. To do that, he used Combined Annotation Dependent Depletion (CADD) scores, a metric for assessing how likely a variant is to be pathogenic. The authors considered only variants with CADD scores above 10.
TET2 was the only gene that came up as significant across the whole cohort. Putative deleterious TET2 variants cropped up in 11 people with EOAD, eight with FTD, and one control. Two of them harbored the same variant, for a total of 19 different variants. Intriguingly, nine were in coding regions, 10 in noncoding regions.
Although the variants were equally enriched among participants with EOAD and FTD, the association with disease did not reach statistical significance in either of these smaller groups alone. This suggests that the strategy of pooling across diseases helped uncover the association.
To see if the finding held up, the authors turned to the much larger, late-onset AD cohorts of the Alzheimers Disease Sequencing Project (ADSP) and the Accelerating Medicines Partnership (AMP-AD), as well as early onset AD participants of non-European ancestry in the UCSF cohort. Together, this dataset comprised 2,849 EOAD, LOAD, and FTD cases, and 2,457 controls. Again, TET2 variants associated with disease in the whole cohort, at p=0.003, but missed statistical significance among AD or FTD patients alone.
The authors also saw an enrichment of TET2 mutations in an ALS cohort, Project MinE, suggesting the gene may contribute to this disease, as well. ALS and FTD form part of a biologically related disease spectrum (Sep 2011 news;Apr 2018 news).
The strength of the disease association varied widely across cohorts, with the greatest effect on early onset disease. In the original UCSF and UAB EOAD cohorts, TET2 mutations gave an odds ratio of 29 for developing early onset AD/FTD, while in the smaller, non-European ancestry UCSF cohort, variants increased the likelihood of early onset AD/FTD by 6.4-fold. In the other replication cohorts, which consisted of mostly late-onset AD cases, the odds ratio was less than two. Across all cohorts, this averaged to an odds ratio of 2.3. Rita Guerreiro at the Van Andel Institute in Grand Rapids, Michigan, noted that because of these group differences, it will be important to replicate the TET2 findings in additional cohorts (see comment below).
Do TET2 variants predict how fast a patient will deteriorate? Among 786 ADNI participants who have LOAD, TET2 mutation carriers worsened faster than noncarriers on the CDR-SB. This was particularly pronounced among people with mild cognitive impairment. In the MCI group, carriers declined by an additional 0.64 points per year on the CDR-SB compared with noncarriers. Extrapolated over 12 years for the whole cohort, this comes out to a 10-point decline for carriers, versus two points for noncarriers (see image above). TET2 mutation carriers with MCI also slid 0.43 points per year faster on the MMSE than did noncarriers. However, this cognition finding did not replicate in the UCSF cohort, which has less longitudinal follow-up.
How might TET2 affect disease risk? Seven of the nine coding variants were predicted to result in a loss of function, suggesting the protein is normally protective. As a group, these coding variants tripled a persons risk of developing AD, FTD, or ALS.
The noncoding variants were even more powerful, with an odds ratio of 3.7. We were quite surprised by that finding, Yokoyama said. It suggests that noncoding variants might nearly abolish expression of the gene, resulting in haploinsufficiency, she noted. The authors are now expressing each variant in cultured cells to determine their effects on gene expression. They will also try to identify which genes TET2 demethylates. Typically, demethylation releases gene repression, allowing more transcription of its targets.
Curiously, global brain methylation drops in aging and AD. This would seem to be at odds with a protective effect for the TET2 demethylase (Jun 2010 conference news). But the effect of a specific demethylase depends on its targets; for example, demethylation boosts expression of reelin, which aids memory formation (Mar 2007 news).TET2 mutations have been found to pop up with high frequency in somatic cells in AD and PD blood and brain (Oct 2018 news). In a mouse model of amyloidosis, loss of TET2 accelerated plaque formation and memory problems (Li et al., 2020).
Recently, TET2 was reported to promote a proinflammatory response in microglia, and to be elevated in microglia surrounding amyloid plaques in mouse models and AD brain (Carrillo-Jimenez et al., 2019). The question remains if TET2 in plaque-associated microglia plays a deleterious or beneficial role in AD, noted Miguel Burguillos, University of Seville, Spain, the senior author of that study, in an email to Alzforum (see comment below). Further studies using conditional TET2 knockout mice crossed with an AD model may answer this. Burguillos believes the varying levels of TET2 in neurons and microglia in mouse models hint that the gene could have multiple effects in AD brain.Madolyn Bowman Rogers
See the original post:
Mutations in Epigenetic Gene Linked to Neurodegeneration - Alzforum
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