Identifying risk loci for FTD and shared genetic component with ALS: A large-scale multitrait association analysis

Area of Science:

• Neurogenetics
• Genomics
• Neurodegenerative Diseases

Background:

• Genome-wide association studies (GWAS) for frontotemporal dementia (FTD) are limited by sample size.
• The shared genetic underpinnings between FTD and amyotrophic lateral sclerosis (ALS) remain largely unknown.

Purpose of the Study:

• To investigate the genetic correlation between FTD and ALS using the largest available summary statistics.
• To identify novel genetic variants and genes associated with FTD and potentially shared with ALS.

Main Methods:

• Utilized large-scale GWAS summary statistics for FTD (3,526 cases, 9,402 controls) and ALS (27,205 cases, 110,881 controls).
• Performed genetic correlation analysis and identified FTD-associated variants and loci.
• Conducted SNP- and gene-level analyses to discover causal variants and associated genes.

Main Results:

• A significant genetic correlation (r_g = 0.637, P = 0.032) was found between FTD and ALS.
• Identified 190 FTD-related variants within 5 loci, with causal variants for both diseases at 9p21.2 and 19p13.11.
• Discovered 15 FTD-associated genes, including 10 novel genes, enriched in cardiac and renal tissues, as well as brain regions.

Conclusions:

• This study provides crucial insights into the genetic architecture of FTD.
• Identified shared genetic etiology between FTD and ALS, highlighting potential common biological pathways.
• The findings pave the way for future research into the genetic determinants of these devastating neurodegenerative conditions.