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Frontotemporal dementia and its subtypes: a genome-wide association study
Raffaele Ferrari1, Dena G Hernandez2, Michael A Nalls3
1Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas, USA; Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
The Lancet. Neurology
|June 20, 2014
Summary
This study identified new genetic risk loci for frontotemporal dementia (FTD). Findings suggest immune system and lysosomal pathways may play a role in FTD development.
Area of Science:
- Genetics
- Neuroscience
- Immunology
Background:
- Frontotemporal dementia (FTD) is a complex neurodegenerative disorder with diverse clinical, pathological, and genetic features.
- Known genetic causes of FTD include mutations in MAPT, GRN, and C9orf72 genes.
- Identifying novel genetic risk factors is crucial for understanding FTD pathogenesis.
Purpose of the Study:
- To identify novel genetic risk loci associated with frontotemporal dementia (FTD).
- To investigate the genetic underpinnings of FTD subtypes.
- To explore the potential biological pathways implicated in FTD through genetic associations.
Main Methods:
- A two-stage genome-wide association study (GWAS) was conducted involving 3526 FTD patients and 9402 healthy controls of European ancestry.
- Association analyses were performed for FTD subtypes, followed by meta-analysis and replication in independent cohorts.
- Expression and methylation quantitative trait loci (eQTL/mQTL) analyses were performed for significant single-nucleotide polymorphisms (SNPs).
Main Results:
- Genome-wide significant associations were found at the 6p21.3 HLA locus (immune system) for SNPs rs9268877, rs9268856, and rs1980493.
- A suggestive novel locus at 11q14, near RAB38/CTSC (lysosomal biology), was identified for the behavioral variant FTD subtype (rs302668).
- eQTL and mQTL analyses indicated that these loci may influence gene expression and methylation in cis.
Conclusions:
- The study implicates immune system processes (6p21.3) and potentially lysosomal and autophagy pathways (11q14) in FTD.
- These findings highlight potential novel biological mechanisms contributing to FTD.
- Further replication studies are needed to confirm these associations and elucidate the pathomechanisms involved in FTD.
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