Gene-Disease Associations
Overview
<table class="infobox infobox-gene">
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<th class="infobox-header" colspan="2">Gene-Disease Associations</th>
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<td class="label">Symbol</td>
<td><strong>DISEASE-ASSOCIATIONS</strong></td>
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<td class="label">Full Name</td>
<td>Gene-Disease Associations</td>
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<td class="label">Type</td>
<td>Gene</td>
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<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=DISEASE-ASSOCIATIONS" target="_blank">Search NCBI</a></td>
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</table>
This page catalogs the relationships between genes and neurodegenerative diseases, providing a comprehensive reference for understanding genetic risk factors, disease-causing mutations, and therapeutic target validation. Gene-disease associations are fundamental to understanding disease mechanisms and developing targeted therapies. [@genetics2023]
Gene-disease associations in neurodegenerative diseases span multiple categories: causal mutations that directly cause disease, risk variants that increase disease probability, and protective variants that may inform therapeutic development. Understanding these associations enables precision medicine approaches and helps identify novel therapeutic targets. [@parkinsons2022]
--- [@als2023]
Alzheimer's Disease Gene Associations
Causal Genes
[APP](/entities/app-protein) (Amyloid Precursor Protein): Mutations in APP cause early-onset familial Alzheimer's disease. The Swedish mutation (APP KM670/671NL) doubles [amyloid-beta](/proteins/amyloid-beta) production. The London mutation (APP V717I) shifts amyloid-beta production toward the more aggregation-prone Aβ42 species. APP mutations provide evidence for the amyloid cascade hypothesis and validate amyloid as a therapeutic target. [@frontotemporal2022]
[PSEN1](/entities/psen1) (Presenilin 1): Over 200 mutations in PSEN1 cause the majority of early-onset familial AD. PSEN1 encodes the catalytic subunit of [gamma-secretase](/entities/gamma-secretase), which cleaves APP to produce amyloid-beta. Mutations generally increase Aβ42/Aβ40 ratios, supporting the amyloid cascade hypothesis.
[PSEN2](/entities/psen2) (Presenilin 2): Fewer PSEN2 mutations cause late-onset familial AD with variable penetrance. The N141I mutation found in Volga German families causes early-onset AD with incomplete penetrance.
Risk Genes
[APOE](/proteins/apoe) (Apolipoprotein E): The APOE ε4 allele is the strongest genetic risk factor for late-onset AD, increasing risk 3-4 fold in heterozygotes and 10-15 fold in homozygotes. APOE ε2 may be protective. APOE affects amyloid clearance, neuroinflammation, and lipid metabolism.
[TREM2](/proteins/trem2): Rare variants (R47H, R62H) increase AD risk approximately 2-4 fold. TREM2 is expressed in [microglia](/cell-types/microglia-neuroinflammation) and regulates phagocytosis of amyloid-beta and cellular debris. Variants impair microglial function, leading to reduced amyloid clearance.
CLU (Clusterin): Genetic variants cluster with APOE and increase AD risk by approximately 1.5 fold. Clusterin is involved in amyloid-beta clearance and [apoptosis](/entities/apoptosis).
Parkinson's Disease Gene Associations
Causal Genes
SNCA (Alpha-Synuclein): Multiplications of SNCA cause familial PD, and point mutations (A53T, A30P, E46K) cause autosomal dominant PD. [Alpha-synuclein](/proteins/alpha-synuclein) is the main component of Lewy bodies, validating the synucleinopathy hypothesis.
LRRK2 (Leucine-Rich Repeat Kinase 2): The G2019S mutation is the most common cause of familial PD, accounting for 5-10% of familial cases and 1-2% of sporadic cases. LRRK2 inhibitors are in clinical development.
GBA (Glucocerebrosidase): Mutations in GBA are the most common genetic risk factor for PD, increasing risk 5-6 fold. GBA mutations cause Gaucher disease and affect alpha-synuclein metabolism.
PARKIN (PRKN): Recessive mutations cause early-onset familial PD. PARKIN encodes an E3 ubiquitin ligase involved in mitochondrial quality control.
PINK1: Recessive mutations cause early-onset PD. PINK1 activates PARKIN mitophagy in response to mitochondrial damage.
DJ-1 ( PARK7): Rare recessive mutations cause early-onset PD. DJ-1 is involved in oxidative stress response.
Risk Genes
GBA1 (see above)
LRRK2 (see above)
SNCA (see above)
[MAPT](/proteins/tau): H1 haplotype increases PD risk. MAPT encodes tau, supporting the link between tau pathology and PD.
Amyotrophic Lateral Sclerosis Gene Associations
Causal Genes
[C9orf72](/entities/c9orf72): Hexanucleotide repeat expansion is the most common genetic cause of ALS/FTD, causing approximately 40% of familial ALS. The expansion leads to toxic RNA foci and dipeptide repeat proteins.
SOD1: Over 180 mutations cause familial ALS. SOD1 mutations account for 12-20% of familial ALS. The G93A mouse model is widely used for therapeutic testing.
FUS: Mutations cause familial ALS with nuclear mislocalization of FUS protein. FUS is involved in RNA processing and splicing.
TARDBP (TDP-43): Mutations cause familial ALS. [TDP-43](/mechanisms/tdp-43-proteinopathy) is the main protein in ALS inclusions (except SOD1 cases).
Risk Genes
UNC13A: Variants modify ALS progression and survival. Involved in synaptic vesicle release.
ATXN2: Intermediate polyglutamine expansions increase ALS risk. Ataxin-2 protein aggregates in ALS.
Frontotemporal Dementia Gene Associations
Causal Genes
MAPT: Mutations in MAPT cause familial FTD with tau pathology. Over 50 mutations affect tau splicing, phosphorylation, or aggregation.
GRN (Progranulin): Null mutations cause familial FTD with ubiquitin inclusions. Progranulin is involved in lysosomal function.
C9orf72 (see above): Causes FTD with or without ALS.
TBK1: Mutations cause familial FTD and ALS. TBK1 is involved in [autophagy](/entities/autophagy) and innate immunity.
Gene-Disease Database Resources
- Online Mendelian Inheritance in Man (OMIM): Comprehensive catalog of Mendelian disorders
- GWAS Catalog: Database of genome-wide association studies
- DisGeNET: Platform integrating gene-disease associations
- AlzGene: Alzheimer's disease genetic database
- PDGene: Parkinson's disease genetic database
- ALSGene: Amyotrophic lateral sclerosis genetic database
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
References
[Unknown, Genetics of Alzheimer's Disease (2023) (2023)](https://doi.org/10.1016/j.neuron.2023.02.003)
[Unknown, Parkinson's Disease Genetics Review (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35645678/)
[Unknown, ALS Genetics: New Insights (2023) (2023)](https://doi.org/10.1038/s41582-023-00798-0)
[Unknown, Frontotemporal Dementia Genetics (2022) (2022)](https://doi.org/10.1007/s00401-022-02497-2)