Table 3.
Risk loci identified in cross-ancestry genome-wide association study (GWAS), the associated function and disease mechanism in Alzheimer’s disease.
| S.No. | Gene (AD) | Function | Disease Mechanism |
|---|---|---|---|
| 1 | SORT1 | Directs trafficking of APP into recycling pathways | Low level of SORT1 in AD causes increased Aβ deposition [157] |
| 2 | CR1 | Immune complement cascade | Regulates Aβ metabolism [158] |
| 3 | ADAM17 | Alpha-secretase imparts a role in APP processing | Causes increased APP production [159] |
| 4 | PRKD3 | Cell proliferation | Causes neuroinflammation [160] |
| 5 | NCK2 | Axon growth and synapse formation and Epinephrin-mediated axon guidance | Disturbs motor axon trajectory selection [161] |
| 6 | WDR12 | Ribosome biogenesis and cell proliferation | Possibly causing neuroinflammation [162] |
| 7 | BIN1 | Endocytosis and intracellular trafficking | Endosome defect [163] |
| 8 | INPP5D | Immune signaling | Inflammasome activation in microglia [164] |
| 9 | MME | Cleaves and degrades beta-amyloid | Increased Aβ deposition and axonal neuropathy [165] |
| 10 | IDUA | Lysosomal protein acts in degradation of misfolded protein | Lysosomal dysfunction and increased proteinopathy [166] |
| 11 | RHOH | Regulation of actin cytoskeleton, and dendrites formation | Synaptic loss and spinal dysfunction [167] |
| 12 | CLNK | Immunomodulatory function | Disturbed immune signaling and neuroinflammation [168] |
| 13 | ANKH | Regulating inflammation | NF-κB-mediated neuroinflammation [162] |
| 14 | COX7C | Mitochondrial bioenergetics | Mitochondrial respiratory defects [169] |
| 15 | TNIP1 | Inhibition of the TNF-α signaling pathway and NF-κB activation/translocation | Microglial activation and inflammation [170] |
| 16 | RASGEF1C | Associated with immune function | Neuroinflammation [171] |
| 17 | HS3ST5 | Cellular uptake and distribution of molecules like growth factors and morphogens | Promotes tau fibrillation into NFTs [172] |
| 18 | HLA-DQA1 | Dendritic cells, macrophages and B cells and involved in adaptive immune responses | Stimulates adaptive immune signaling in AD and also activates PKC and TLR signaling [173] |
| 19 | UNC5CL | Involved in mediating axon growth, neuronal migration in neuronal development, regulation of cell apoptosis. | Contributes to AD pathogenesis by activating DAPK1 which in turn causes aberrant tau, Aβ and neuronal apoptosis/autophagy |
| 20 | TREM2 | Regulates microglia proliferation, survival, migration, and phagocytosis. | Downregulation induces neuroinflammation [174] |
| 21 | TREML2 | Regulates microglial proliferation | Immune-related neuroinflammatory and increased tau deposition [175] |
| 22 | CD2AP | Early endosome formation and protein trafficking | Regulates Aβ generation by a neuron-specific polarization of Aβ in dendritic early endosomes [176] |
| 23 | UMAD1 | Involved in endosome-ubiquitin homeostasis [177] | Possibly defects in protein degradation cascade and increased deposit of Aβ and tau |
| 24 | ICA1 | ICA1 regulates AMPA receptor trafficking [178] | Possibly disturb synaptic signaling |
| 25 | TMEM106B | Brain lipid metabolism, | Disturbed lipid homeostasis [179] |
| 26 | JAZF1 | Lipid/cholesterol metabolism and microglial efferocytosis [180] | Neuroinflammation by defective efferocytosis and defective lipid metabolism (not clear) |
| 27 | SEC61G | Protein trafficking, ER calcium leak channel [181] | - |
| 28 | EPDR1 | Neurogenesis and synaptic signaling [162] | Not clear |
| 29 | SPDYE3 | Cell cycle regulator [182] | - |
| 30 | EPHA1 | Immune response, cholesterol metabolism, and synaptic function | Spine morphology abnormalities and synaptic dysfunction [183] |
| 31 | CTSB | Regulates apoptosis, neuroinflammation, and autophagy | lysosomal leakage of cathepsin B to the cytosol leads to neurodegeneration and behavioral deficits [184] |
| 32 | SHARPIN | Inflammation and immune system activation Synaptic signaling |
Attenuated inflammatory/immune response [185] |
| 33 | PTK2B | Ca2+-activated non-receptor tyrosine kinase, involved in synaptic plasticity | Neuronal hyperexcitability by neuronal differentiation and electrical maturation [186] |
| 34 | CLU | Secreted by glia binds to Aβ and plays a protective role by preventing Aβ aggregation | Aβ clearance [187] |
| 35 | ABCA1 | Cholesterol mobilization | Defective lipid metabolism, and neuroinflammation [188] |
| 36 | ANK3 | Scaffolding proteins recruit diverse membrane proteins, (ion channels and cell adhesion molecules) into subcellular membrane domains | Altered neuronal excitability and altered neuronal connectivity [138] |
| 37 | TSPAN14 | Regulates maturation and trafficking of the transmembrane metalloprotease ADAM10 [189] | Not clear |
| 38 | BLNK | Participates in the regulation of PLC-γ activity and the activation of Ras pathway [190] | Not clear. Possibly involved in immune regulation |
| 39 | PLEKHA1 | Adaptive immunity | Inflammatory responses [191] |
| 40 | USP6NL | GTPase-activating protein involved in control of endocytosis | Dysfunction of the myeloid endolysosomal system [192] |
| 41 | SPI1 | Controls microglial development and function | Regulating neuroinflammation [193] |
| 42 | EED | Catalyzes the methylation of histone and mediates the repressive chromatin | Synaptic dysfunction due to upregulation of synapse related gene [194] |
| 43 | SORL1 | Regulates the recycling of the APP out of the endosome | Endosomal swelling and APP misprocessing [195] |
| 44 | TPCN1 | Encodes a voltage-dependent calcium channel and involved in long-term potentiation in hippocampal neurons, | Altered calcium signaling and cognitive dysfunction [196] |
| 45 | IGH gene cluster | Immune response [197] | Not clear |
| 46 | FERMT2 | APP metabolism and axonal growth | Impaired synaptic connectivity, and long-term potentiation in an APP-dependent manner [198] |
| 47 | SLC24A4 | Neural development and cholesterol metabolism | Increased deposition of Ab and tau [199] |
| 48 | SPPL2A | Engaged in the function of B-cells and dendritic cells. | Activates TNF-α signaling [156] |
| 49 | MINDY2 | Deubiquitination | Not clear |
| 50 | APH1B | γ-secretase | Brain atrophy and amyloid-β deposition [200] |
| 51 | SNX1 | Endosome trafficking | Prevents BACE1 trafficking to the lysosomal degradation system, resulting in increased production of Aβ [201] |
| 52 | CTSH | Immune regulation | Role in neuroinflammation and amyloid β production [202] |
| 53 | BCKDK | Regulation of neurotransmitter synthesis, and mTOR activity. | Causes hyperexcitability, neuroinflammation, and dysregulation of neurotrophic factors [203] |
| 54 | IL34 | Stimulates proliferation of monocytes and macrophages | Triggers neuroinflammation via colony-stimulating factor-1 receptor (CSF-1r) [204]. |
| 55 | PLCG2 | Present on microglia and function as immune regulator | Upregulated and activates inflammation related pathway [205] |
| 56 | DOC2A | A calcium sensor, facilitates neurotranbsmitter release in Ca2+-dependent manner | Abnormality in synaptic transmission [206] |
| 57 | MAF | Regulates T-cell susceptibility to apoptosis | Probably immune cell dysfunction and neuroinflammation [207] |
| 58 | FOXF1 | Cell proliferation, cell cycle, and regulatory protein | Activated by PI3K/AKT and stress response and may cause inflammation [208] |
| 59 | PRDM7 | Methyltransferases induce trimethylation | Possibly suppresses the synaptic gene [209] |
| 60 | WDR81 | Facilitates the recruitment of autophagic protein aggregates and promotes autophagic clearance | Impaired autophagy [210] |
| 61 | MYO15A | A myosin involved in actin organization | Retromer dysfunction [211] |
| 62 | GRN | Regulates lysosomal biogenesis, inflammation, repair, stress response, and aging. | Neuroinflammation [211] |
| 63 | SCIMP | Immune regulation via major histocompatibility complex class II signaling. | Neuroinflammation [212] |
| 64 | WNT3 | Synaptic function and immune regulation |
Causes synaptic dysfunction and inflammation via Wnt3/β-catenin/GSK3β signaling pathway [213] |
| 65 | ABI3 | Regulator of microglia | Neuroinflammation [214] |
| 66 | TSPOAP1 | TSPO-associated protein 1, interacts with translocator protein (TSPO) and act indirectly to activate microglia | Neuroinflammation [215] |
| 67 | ACE | An endopeptidase | ACE has been shown to cleave amyloid-β (Aβ) [216] |
| 68 | KLF16 | Regulates dopamine receptors | Modulates dopaminergic transmission in the brain [217] |
| 69 | SIGLEC11 | Immune regulation | Proinflammation and phagocytosis [218] |
| 70 | LILRB2 | Aβ receptor | Perturbance in synaptic signaling and cognitive impairment [219] |
| 71 | ABCA7 | Lipid homeostasis and phagocytosis. | Disturbed lipid metabolism, ER stress. Impaired microglial response to inflammation |
| 72 | RBCK1 | Involved in ubiquitination | TNF-α-mediated activation of NF-κB pathway. |
| 73 | SLC2A4RG | Encodes solute carrier protein. Involved in cell cycle via CDK1 pathway [220] | Not clear. Possibly induces proliferation |
| 74 | CASS4 | Role in inflammation, calcium signaling, and microtubule stabilization. | Disturbed synaptic signaling and neuroinflammation [221] |
| 75 | APP | Proliferation, differentiation, and maturation of neural stem cells. | Abnormal cleavage causes plaque deposition [222] |
| 76 | ADAMTS1 | APP hydrolysis | Increased Aβ generation through β-secretase-mediated cleavage [223] |