Identifying risk loci for FTD and shared genetic component with ALS: A large-scale multitrait association analysis
Open accessAbstract
Current genome-wide association studies of frontotemporal dementia (FTD) are underpowered due to limited samples. Further, common genetic etiologies between FTD and amyotrophic lateral sclerosis (ALS) remain unknown. Using the largest summary statistics of FTD (3526 cases and 9402 controls) and ALS (27,205 cases and 110,881 controls), we found a significant genetic correlation between them (rˆ g = 0.637, P = 0.032) and identified 190 FTD-related variants within 5 loci (3p22.1, 5q35.1, 9p21.2, 19p13.11, and 20q13.13). Among these, ALS and FTD had causal variants in 9p21.2 and 19p13.11. Moreover, MOBP (3p22.1), C9orf72 (9p21.2), MOB3B (9p21.2), UNC13A (19p13.11), SLC9A8 (20q13.13), SNAI1 (20q13.13), and SPATA2 (20q13.13) were discovered by both SNP- and gene-level analyses, which together discovered 15 FTD-associated genes, with 10 not detected before (IFNK, RNF114, SLC9A8, SPATA2, SNAI1, SCFD1, POLDIP2, TMEM97, G2E3, and PIGW). Functional analyses showed these genes were enriched in heart left ventricle, kidney cortex, and some brain regions. Overall, this study provides insights into genetic determinants of FTD and shared genetic etiology underlying FTD and ALS.
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Aberrant Wnt signaling is associated with TDP43 mislocalization in cellular and animal models.
“Notably, TGF-ß is upregulated in ALS (55), and aberrant Wnt signaling is associated with TDP43 mislocalization in cellular and animal models (56).”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [56]
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TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A
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Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS
Bekier, M. E., Pinarbasi, E., Krishnan, G., Mesojedec, J. J., Hurley, M., Harikumar Sheela, H., Collins, C. A., Ghaffari, L., de Majo, M., Ullian, E. M., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci188138 · Cited by 2 · see citing works
“Targeting NLK protein levels or kinase activity could thus represent a potentially novel therapeutic approach for ALS, FTLD-TDP, and other TDP43 proteinopathies.”
Influential
- Authors
- Chen, K., Gao, T., Liu, Y., Zhu, K., Wang, T., & Zeng, P.
- Affiliations
- Xuzhou Medical College (CN)
- Corresponding author
- Zeng, Ping
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2024-02
- Volume
- 134
- Pages
- 28-39
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W4387142713
- Cited by
- 15
- References
- 8
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 3
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Aging (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Xuzhou Medical University (TD202008)
- National Natural Science Foundation of China (82173630, 81402765)
- Six Talent Peaks Project in Jiangsu Province (WSN-087)
- Ministry of Education of the People's Republic of China (18YJC910002)
- China Postdoctoral Science Foundation (2019T120465, 2018M630607)
- Natural Science Foundation of Jiangsu Province (BK20181472)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- frontotemporal dementia, amyotrophic lateral sclerosis, genetic correlation, shared genetic etiology, genetic susceptibility loci, pleiotropy, C9orf72, MOBP, UNC13A, SNAI1, Poldip2, TMEM97, RNF114, renal cortex, brain regions
- MeSH terms
- Amyotrophic Lateral Sclerosis, Humans, Mutation, Nuclear Proteins, Proteins, Pick Disease of the Brain, Genome-Wide Association Study, Frontotemporal Dementia
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