Table 1.
Genes/loci harboring rare variants in AD that need independent replication
| Gene symbol | Gene | Location | Variant | Ref | Pathway |
|---|---|---|---|---|---|
| AARD | Alanine and arginine rich domain containing protein | 8q24.11 | Gene burden | [69] | N.A. |
| ABCA1 | ATP binding cassette subfamily A member 1 | 9q31.1 | rs137854495, NM_005502.4:c.2810C>T:p.Ala937Val | [70] |
Aβ pathway Lipoprotein metabolism |
| ADAM10 | ADAM metallopeptidase domain 10 | 15q21.3 |
rs61751103, NM_001110.4:c.510G>C:p.Gln170His rs145518263, NM_001110.4:c.541A>G: p.Arg181Gly |
[71] |
Aβ pathway Apoptosis, phagocytosis, autophagy |
| ADAM17 | ADAM metallopeptidase domain 17 | 2p25.1 | rs142946965, NM_003183.6:c.644G>T:p.Arg215Ile | [72] |
Aβ pathway Immune system Apoptosis, phagocytosis, autophagy |
| ANXA5 | Annexin A5 | 4q27 | Gene burden | [73] | Immune system |
| APC | APC regulator of WNT signaling pathway | 5q22.2 | Spatial clustering | [67] |
Aβ pathway Axonal pathfinding Synaptic plasticity |
| ASRGL1 | Asparaginase and isoaspartyl peptidase 1 | 11q12.3 | chr11:62,343,562:G>C* | [55] |
Axonal guidance and cytoskeleton function Apoptosis, phagocytosis, autophagy |
| BACE2 | Beta-secretase 2 | 21q22.2-q22.3 | 12Kb intronic deletion | [74] |
Aβ pathway Apoptosis, phagocytosis, autophagy |
| C1orf173/ERICH3 | Glutamate rich 3 | 1p31.1 | Gene burden | [73] | N.A. |
| C15ORF41/CDIN1 | CDAN1 interacting nuclease 1 | 15q14 |
rs141228575, NM_001130010.3:c.213-2446C>T rs147002962, NM_001130010.3:c.102-13586C>G |
[67] | Erythrocyte differentiation |
| C2CD3 | C2 domain containing 3 centriole elongation regulator | 11q13.4 | Spatial clustering | [67] |
Cilium assembly Ciliary basal body plasma membrane docking |
| CASP7 | Caspase 7 | 10q25.3 | rs116437863, NM_001267057.1:c.1045A>G:p.Arg297Gly | [73] |
Aβ pathway Immune system Apoptosis, phagocytosis, autophagy |
| CD2AP | CD2 associated protein | 6p12.3 |
rs116754410, NM_012120.3:c.1898A>G:p.Lys633Arg rs138727736, NM_012120.3: c.1120A>G:p.Thr374Ala |
[49] |
Immune system Cytoskeleton function BBB integrity Apoptosis, phagocytosis, autophagy |
| CD55 | CD55 molecule (Cromer blood group) | 1q32.2 | chr1:207461994C>T (upstream of CD55) | [75] | Immune system |
| CLDN17 | Claudin 17 | 21q21.3 | Homozygosity and gene burden | [76] | BBB integrity |
| CLSTN2 | Calsyntenin 2 | 3q23 | Spatial clustering | [67] |
Morphology of synaptic complexes Calcium-mediated postsynaptic signaling Episodic memory Signal transduction |
| CR1 | Complement C3b/C4b receptor 1 | 1q32.2 |
rs11587944, NM_000651.6:c.313C>T:p.Arg105Cys rs372477607, NM_000651.6:c.4021C>T:p.Pro1341Ser |
[55] |
Aβ pathway Immune system Apoptosis, phagocytosis, autophagy |
| CSF1R | Colony stimulating factor 1 receptor | 5q32 |
rs281860278, NM_001288705.3:c.2603T>G:p.Leu868Arg rs748641028, NM_001288705.3: c.2073G>C: p.Gln691His rs111943087, NM_001288705.3:c.2107C>T:p.His703Tyr |
[34] |
Immune system BBB integrity Cytoskeleton function |
| CTNNA2 | Catenin alpha 2 | 2p12 | Spatial clustering | [67] |
Neuronal migration and neuritic outgrowth Cell-cell adhesion |
| CTSF | Cathepsin F | 11q13.2 | rs200426008, NM_003793.4:c.1243G>A: p.Gly415Arg | [65] |
Immune system Apoptosis, phagocytosis, autophagy |
| DPP6 | Dipeptidyl peptidase like 6 | 7q36.2 | Chr7:149,704,610 - 153,786,893 paracentric inversion* | [77] | Synaptic plasticity |
| EPHA1 | EPH receptor A1 | 7q34-q35 | rs202178565, NM_005232.5:c.1379C>T:p.Pro460Leu | [49] |
Immune system Axonal guidance Synaptic plasticity BBB integrity Apoptosis, phagocytosis, autophagy |
| ERN1 | Endoplasmic reticulum to nucleus signaling 1 | 17q23.3 | rs56201815, NM_001433.5:c.1017C>T:p.Asp339= | [68] |
Autophagy Unfolded protein response (UPR) and neuronal apoptosis |
| EXOC3L4/C14orf73 | Exocyst complex component 3 like 4 | 14q32.32 |
rs117708804, NM_001077594.1:c.1126G>T:p.Ala376Ser rs10142287, NM_001077594.1:c.687C>A:p.Pro229= rs9324055, NM_001077594.1: c.889G>A: p.Val297Met rs148718670, NM_001077594.1: c.1937G>A: p.Arg646Gln |
[78] | N.A. |
| FERMT2 | FERM domain containing kindlin 2 | 14q22.1 | rs17125944, NM_001134999.1:c.158-14555A>G | [70] | Cell adhesion |
| FNBP1L | Formin binding protein 1 like | 1p22.1 | rs192471919, NM_001164473.2:c.1652-634T>C | [67] |
Endocytosis Autophagy Neurite elongation and axonal branching (neuroplasticity) |
| FSIP2 | Fibrous sheath interacting protein 2 | 2q32.1 |
rs531170562, NM_173651.4:c.742C>T:p.Arg248Cys rs552474258, NM_173651.4:c.743G>T:p.Arg248Leu |
[70] | Spermatogenesis |
| IGHG3 | Immunoglobulin heavy constant gamma 3 (G3m marker) | 14q32.33 |
rs77307099, ENST00000390551.2:c.938G>A, p.Ser313Asn rs78376194, ENST00000390551.2: c.939C>T, p.Ser313= rs12890621, ENST00000390551.2: c.674A>T, p.Tyr225Phe |
[69] | Neuroinflammation |
| KIF2A | Kinesin family member 2A | 5q12.1 | Spatial clustering | [67] |
Mitotic spindle activity and normal brain development Microtubule-based processes Ciliogenesis Cortical development Spinal cord injuries |
| LHX9 | LIM homeobox 9 | 1q31.3 | Spatial clustering | [67] | Development of the forebrain |
| LincRNA LINC00298 | Long intergenic noncoding RNA LINC00298 | 2p25.1 | rs147918541, chr2:8073233:G>A | [67] | May be involved in neuronal plasticity |
| LncRNA AC099552.4 | Long non-coding RNA AC099552.4 | 7q36.3 | chr7:154988675:G>A | [69] | Gene expression regulation |
| LncRNA RP11-433J8 | Long non-coding RNA RP11-433J8 | 14q32.2 | chr14:97228875:A>G | [70] | N.A. |
| MAPT | Microtubule associated protein tau | 17q21.31 |
NM_001123066.3:c.370C>A: p.Gln124Ly NM_001123066.3:c.2203T>G:p.Ser735Ala |
[79] |
Tau pathway Axonal guidance and cytoskeleton functioning Apoptosis, phagocytosis, autophagy |
| MARK4 | Microtubule affinity regulating kinase 4 | 19q13.32 | NM_001199867.1: c.946_951delGGTGAGinsGAT:p.Gly316_Glu317delinsAsp | [74] |
Tau pathway Cytoskeleton function Apoptosis, phagocytosis, autophagy |
| MYRF | Myelin regulatory factor | 11q12.2 | rs34038946, NM_001127392.3:c.2167G>A:p.Ala723Thr | [55] |
Lipid metabolism Synaptic plasticity |
| NALCN | Sodium leak channel, non-selective | 13q32.3-q33.1 | Spatial clustering | [67] | Neuronal excitability |
| ND2 | NADH dehydrogenase subunit 2 | chrM:4,470-5,511 | m.5460G>A and m.5460G>T | [80] | Mitochondrial cascade hypothesis |
| PIN1 | Peptidylprolyl cis/trans isomerase, NIMA-interacting 1 | 19p13.2 | c.477C>T, p.Thr152Met* | [81] |
Aβ pathway Tau pathway Apoptosis, phagocytosis, autophagy |
| PINX1 | PIN2 (TERF1) interacting telomerase inhibitor 1 | 8p23.1 | Gene burden | [82] | Telomere integrity |
| PRKCH | Protein kinase C eta | 14q23.1 | Spatial clustering | [67] | Signal transduction |
| PSD2 | Pleckstrin and Sec7 domain containing 2 | 5q31.2 | rs138380367, NM_032289.4:c.1549G>A: p.Gly517Ser | [83] | Endolysosomal transport |
| RTN3 | Reticulon 3 | 11q13.1 |
rs372883387, NM_001265589.2:c.-8G>T NM_001265589.2:c.42C>T: p.Ser14= NM_001265589.2: c.116C>T:p.Thr39Met rs11551944: NM_001265589.2:c.17C>A:p.Ala6Glu |
[84] |
Aβ pathway Lipid metabolism Apoptosis, phagocytosis, autophagy |
| RUFY1 | RUN and FYVE domain containing 1 | 5q35.3 | rs138313632,NM_025158.5:c.2113T>G: p.Ser705Ala | [83] | Endolysosomal transport |
| SEL1L | SEL1L adaptor subunit of ERAD E3 ubiquitin ligase | 14q31.1 | rs74065194, chr14:82182068: C>T | [67] |
Aβ pathway Endoplasmic reticulum-associated degradation (ERAD) ER stress and cell death |
| SEZ6 | Seizure related 6 homolog | 17q11.2 | rs371753097, NM_178860.5:c.1844G>A:p.Arg615His | [85] |
Aβ pathway Synaptic plasticity |
| SLC24A4-RIN3 | Solute carrier family 24 member 4-Ras and Rab interactor 3 | 14q32.12 |
SLC24A4:rs10498633, NM_153646.4:c.1255+4000G>T RIN3:rs147042536, NM_024832.5:c.2377T>C, :p.Tyr793His RIN3: rs150221413, NM_024832.5:c.189G>T, :p.Trp63Cys |
[55, 83] |
SLC24A4: Na+Ca2+, K+ exchange RIN3:Endolysosomal transport |
| SRCAP | Snf2 related CREBBP activator protein | 16p11.2 | 10 ultra-rare missense mutations | [86] | Gene expression regulation |
| SYTL3 | Synaptotagmin like 3 | 6q25.3 | Spatial clustering | [67] | Vesicle trafficking |
| TCIRG1 | T cell immune regulator 1, ATPase H+ transporting V0 subunit a3 | 11q13.2 | rs34227834, NM_006019.4:c.482C>T, : p.Pro161Leu | [83] |
Endolysosomal transport Immune system |
| tRNAGLN | Transfer ribonucleic acid glutamine | chrM | m.4336A>G | [61] | Mitochondrial cascade hypothesis |
| TTC3 | Tetratricopeptide repeat domain 3 | 21q22.13 | rs377155188, NM_001001894.2:c.3113C>G: p.Ser1038Cys | [87] | Aβ pathway |
| TYROBP | Transmembrane immune signaling adaptor TYROBP | 19q13.12 |
rs200649978, NM_003332.4:c.5G>A:p.Gly2Glu NM_003332.3:c.163G>T: p.Val55Leu |
[88] |
Aβ pathway Immune system Lipid metabolism Apoptosis, phagocytosis, autophagy |
| VPS35 | VPS35 retromer complex component | 16q11.2 | NM_018206.6:c.1874T>C: p.Leu625Pro | [74] |
Aβ pathway Apoptosis, phagocytosis, autophagy |
| VWA2 | Von Willebrand factor A domain containing 2 | 10q25.3 | rs79009215, NM_001272046.2:c.1096G>A:p.Val366Met | [89] | N.A. |
| ZNF655 | Zinc finger protein 655 | 7q22.1 | Gene burden | [69] | Gene expression regulation |
Genes and loci reported to harbor rare variants that have been associated with AD, their chromosomal locations and respective biological pathways and processes. Variants shown here represent the original associations established with AD in the respective studies. When the findings were focused on gene or regional burden analyses, that is noted, instead of specific variants. *As reported in the original publication. AD, Alzheimer’s disease; Aβ, Amyloid-beta; BBB, Blood-Brain Barrier; ERAD, Endoplasmic reticulum-associated degradation; ER stress, Endoplasmic reticulum stress; UPR, Unfolded protein response.