Non-Coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>We conducted genome sequencing to search for rare variation contributing to early onset Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 493 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than 1 in 10,000 or private), computational prediction of deleteriousness (CADD 10 or 15 thresholds), and molecular function (protein loss-of-function only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions).</jats:p><jats:p>Replication analysis was conducted on 16,871 independent cases and 15,941 independent controls. Rare variants in <jats:italic>TET2</jats:italic> were enriched in the discovery combined EOAD and FTD cohort (<jats:italic>p</jats:italic>=6.5×10<jats:sup>−8</jats:sup>, genome-wide corrected <jats:italic>p</jats:italic>=0.0037). Most of these variants were canonical loss-of-function or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of AD and FTD (replication only <jats:italic>p</jats:italic>=0.0071). The combined analysis odds ratio was 2.2 (95% CI 1.5–3.2) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 2.1 (95% CI 1.2–3.9). For loss-of-function variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.2 (95% CI 2.0–5.3). TET2 catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in <jats:italic>TET2</jats:italic> may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.</jats:p>

Microglia: Agents of the CNS Pro-Inflammatory Response

“…Notably, the relevance of TET2 in neurodegenerative diseases has come to attention in a recent paper published by Cochran and colleagues [ 268 ]. In this paper, the authors established an association between TET2 mutations and an increased disease risk for AD, frontotemporal dementia, and ALS using genome sequencing.…”

TSC1loss-of-function increases risk for tauopathy by inducing tau acetylation and preventing autophagy-mediated tau clearance

“…We have previously demonstrated a link between FTLD and pathogenic variants in TSC1 ( 11, 15 ). To better understand the relationship between TSC1 and risk of tauopathies, we examined the frequency of rare TSC1 variants in a cohort of individuals diagnosed with early-onset Alzheimer’s disease (EOAD) ( 16 ), which has a stronger contribution of tau pathology than its more common, late-onset counterpart. The EOAD cohort showed an enrichment of the rare variant in TSC1 rs2234980 dupTGC (also known as rs118203743), relative to controls from the Genome Aggregation Database (gnomAD v2.1.1) (minor allele frequency, MAF EOAD = 0.0066 vs MAF gnomAD = 0.00006).…”

Genome-wide association study of cognitive function in diverse Hispanics/Latinos: results from the Hispanic Community Health Study/Study of Latinos

“…Only two out of 148 previously identified loci met the criteria for replication in our study. These include a locus on chromosome 4q24, which encompasses TET2, a gene encoding a DNA demethylase with known roles in the microglial inflammatory response and neurodegenerative diseases; 77,78 and a locus on chromosome 13q31.2, which encompasses LINC00433 but no protein-coding gene. Taken together, these results further illustrate the need for larger samples of diverse Hispanics/Latinos and the potentially unique genetic architecture of cognitive function in this population.…”