Genome-Wide Association Studies (GWAS) have identified numerous genetic risk loci for Alzheimer's Disease (AD) and Parkinson's Disease (PD). This hub maps major GWAS hits to biological pathways and therapeutic targets, providing a comprehensive reference for understanding the genetic architecture of neurodegenerative diseases.
GWAS have revolutionized our understanding of neurodegenerative disease genetics by identifying common variants that contribute to disease risk. Unlike rare pathogenic mutations, GWAS variants typically have modest effect sizes but provide crucial insights into disease biology and therapeutic targets.
Genome-Wide Association Studies (GWAS) have identified numerous genetic risk loci for Alzheimer's Disease (AD) and Parkinson's Disease (PD). This hub maps major GWAS hits to biological pathways and therapeutic targets, providing a comprehensive reference for understanding the genetic architecture of neurodegenerative diseases.
GWAS have revolutionized our understanding of neurodegenerative disease genetics by identifying common variants that contribute to disease risk. Unlike rare pathogenic mutations, GWAS variants typically have modest effect sizes but provide crucial insights into disease biology and therapeutic targets.
| Gene | Chromosome | Odds Ratio | Pathway | Primary Mechanism |
|------|------------|------------|---------|-------------------|
| APOE | 19q13.32 | 3.5-4.0 (ε4) | Lipid metabolism, Aβ clearance | Amyloid clearance, neuroinflammation |
| TREM2 | 6p21.1 | 2.9-4.5 | Microglial activation | Phagocytosis, neuroinflammation |
| CLU | 8p21.1 | 1.1-1.2 | Complement system | Aβ clearance, synaptic protection |
| PICALM | 11q14.2 | 1.1-1.2 | Clathrin-mediated endocytosis | Synaptic vesicle trafficking, Aβ production |
| CR1 | 1q32.2 | 1.1-1.2 | Complement system | Aβ clearance, immune modulation |
| BIN1 | 2q14.3 | 1.1-1.2 | Membrane trafficking | Tau pathology, synaptic function |
| ABCA7 | 19p13.3 | 1.1-1.3 | Lipid transport | Aβ processing, phagocytosis |
| CD33 | 19q13.4 | 1.1-1.2 | Sialic acid signaling | Microglial activation, Aβ clearance |
| MS4A cluster | 11q12.2 | 1.1-1.2 | Membrane signaling | TREM2 ligand processing |
| EPHA1 | 7q34 | 1.1-1.2 | Ephrin signaling | Synaptic plasticity, neuroprotection |
| PTK2B | 8p21.1 | 1.1-1.2 | Tyrosine kinase signaling | Synaptic function, excitotoxicity |
| SORL1 | 11q24.1 | 1.2-1.4 | Retromer pathway | APP trafficking, Aβ production |
| PLCG2 | 16q23.1 | 1.1-1.2 | Phospholipase signaling | Microglial activation |
| ABI3 | 17q21.31 | 1.1-1.2 | Actin cytoskeleton | Phagocytosis, cell motility |
| SPI1 | 19q13.4 | 1.1-1.2 | Transcription factor | Microglial differentiation |
| Gene | Chromosome | Odds Ratio | Pathway | Primary Mechanism |
|------|------------|------------|---------|-------------------|
| SNCA | 4q21 | 1.3-1.5 | α-synuclein metabolism | Protein aggregation |
| LRRK2 | 12q12 | 1.4-3.0 | Kinase signaling | Protein trafficking, autophagy |
| GBA | 1q21 | 1.4-5.5 | Lysosomal function | Glucocerebrosidase, autophagy |
| PARK16 | 1q32 | 1.1-1.2 | Unknown | Putative ER function |
| GIGYF2 | 11q14 | 1.1-1.2 | Tyrosine kinase signaling | Insulin-like growth factor |
| MAPT | 17q21.31 | 1.2-1.4 | Tau pathology | Microtubule function, tau splicing |
| HLA-DRB1 | 6p21.3 | 1.1-1.3 | Immune response | Antigen presentation, autoimmunity |
| BST1 | 4p15 | 1.1-1.2 | ADP-ribosylation | Inflammatory response |
| RAB7L1 | 2q37 | 1.1-1.2 | Vesicle trafficking | Autophagy, lysosomal function |
| SLC41A1 | 1q32 | 1.1-1.2 | Ion transport | Magnesium homeostasis |
| NUCKS1 | 1q31 | 1.1-1.2 | DNA repair | Transcriptional regulation |
| LAMP3 | 3q27 | 1.1-1.2 | Lysosomal function | Autophagy, MHC II presentation |
| SCAF1 | 19q13 | 1.1-1.2 | SR-related | RNA processing |
| ITPR2 | 12p11 | 1.1-1.2 | Calcium signaling | ER calcium release |
| FAM47E | 4q21 | 1.1-1.2 | Unknown | Putative scaffold protein |
Several genetic loci influence risk for both AD and PD:
| Gene | AD Effect | PD Effect | Shared Pathway |
|------|-----------|-----------|----------------|
| MAPT | Moderate | Strong | Tau pathology, neurodegeneration |
| HLA region | Moderate | Moderate | Neuroinflammation, immune response |
| GAPD | Moderate | Moderate | Energy metabolism |
| MADD | Moderate | Moderate | Apoptosis, cell death |
The overlap between AD and PD genetics suggests:
| Target | Gene | Therapeutic Approach | Status |
|-------|------|----------------------|--------|
| TREM2 agonism | TREM2 | Antibody agonists | Preclinical/Phase 1 |
| APOE modulators | APOE | Gene therapy, small molecules | Research |
| BACE inhibitors | CLU, PICALM | Small molecule inhibitors | Discontinued (toxicity) |
| Microglial modulators | CD33, PLCG2 | Antibody antagonists | Research |
| Retromer stabilizers | SORL1 | Small molecule stabilizers | Phase 2 |
| Target | Gene | Therapeutic Approach | Status |
|-------|------|----------------------|--------|
| LRRK2 kinase inhibitors | LRRK2 | Small molecule inhibitors | Phase 1/2 |
| GBA modulators | GBA | Gene therapy, enzyme enhancement | Research |
| α-synuclein aggregation inhibitors | SNCA | Antibody, small molecules | Phase 2/3 |
| Autophagy enhancers | GBA, RAB7L1 | mTOR inhibitors, autophagy modulators | Research |