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

Area of Science:

• Genetics
• Neuroscience
• Genomics

Background:

• Early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD) are debilitating neurodegenerative disorders with complex genetic underpinnings.
• Identifying rare genetic variants is crucial for understanding disease mechanisms and developing targeted therapies.

Purpose of the Study:

• To investigate the role of rare genetic variations in the etiology of EOAD and FTD.
• To identify specific genes and variant types associated with increased risk for these conditions.

Main Methods:

• Genome sequencing was performed on cases and controls of European ancestry.
• Burden testing was applied to rare variants using filters for rarity, deleteriousness (CADD), and molecular function (loss-of-function, coding, non-coding regulatory).
• Replication analysis was conducted on a large independent cohort.

Main Results:

• Rare variants in the TET2 gene were significantly enriched in discovery cohorts of EOAD and FTD (p = 4.6 × 10^-8).
• This enrichment was replicated across independent Alzheimer's disease (AD) and FTD cohorts (replication p = 0.0029).
• TET2 variants, particularly loss-of-function and non-coding regulatory variants, showed significant odds ratios for disease risk (OR=2.3 for AD/FTD, OR=3.7 for non-coding, OR=3.1 for LoF).

Conclusions:

• Rare TET2 variation is a significant risk factor for EOAD and FTD.
• TET2, involved in DNA demethylation, may contribute to neurodegeneration by affecting aging-related processes.
• The study underscores the importance of considering non-coding and rare variants in complex disease genetics.