Table 1. Overview of genomic risk loci and genes with common and rare variants identified through Alzheimer's disease (AD) linkage studies, genome-wide association studies (GWAS) and whole genome /whole exome sequencing (WGS/WES).
Identification of a functional variant in a specific causal gene has only been established for a few loci. In those cases the putative gene and variant are named in the table with additional information about the cell type-specific gene expression and related biological processes. The odds ratio from a case-control study tells about the association of disease outcome with the presence of certain genotype: increased (risk) or decreased (protection) chances of getting the disease for an individual with one risk allele versus having no risk alleles. Adjacent genes were selected with dbSNP database by searching for the tagging SNP. Definitive conclusion about SNP association requires replication in independent datasets. QTL: quantitative trait loci.
| Chr | SNPs | Closest gene name | Genes adjacent to the SNP | Putative gene with functional significance | Cell type-specific express ion of putative gene | Biological processes | Odds ratio meta-analysis for minor allele with 95% confidence interval (CI) (common/ rare variant) | References | |
|---|---|---|---|---|---|---|---|---|---|
| Loci | |||||||||
| Chr1 | rs6656401 | CR1 | CR2, CR1, CR1L | CR1 intragenic copy number variations leading to longer isoform overproduction | Microglia | Immune response and phagocytosis | 1.18 (1.14–1.22) | (32) | |
| Chr2 | rs6733839 | BIN1 | BIN1, CYP27C1 | BIN13 base pair insertion | Ubiquitous | Endocytosis | 1.22 (1.18– 1.25) | (32) | |
| Chr2 | rs35349669 | INPP5D | NEU2, INPP5D, ATG16L1 | / | / | / | 1.08 (1.05– 1.11) | (32) | |
| Chr5 | rs2074612 | HBEG F | CYSTM1 , PFDN1, HBEGF | / | / | / | 1.08 (1.05– 1.11) | (138, 139) | |
| Chr5 | rs190982 | MEF2 C | TMEM161B, MIR9-2, LINC00461, MEF2C, MEF2C-AS1 | / | / | / | 0.93 (0.90– 0.95) | (32) | |
| Chr6 | rs10948363 | CD2AP | TNFRSF21, CD2AP, ADGRF2, ADGRF4, OPN5 | / | / | / | 1.10 (1.07– 1.13) | (32) | |
| Chr6 | rs9271192 | HLA-DRB1 / HLA-DRB5 | C6orf10, BTNL2, HLA-DRA, HLA-DRB5, HLA-DRB6, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DQA2, HLA-DQB2, HLA-DOB | / | / | / | 1.11 (1.08– 1.15) | (32) | |
| Chr7 | rs11771145 | EPHA1 | ZYX, EPHA1, EPHA-AS1, TAS2R62P, TAS2R60 | / | / | / | 0.90 (0.88– 0.93) | (32) | |
| Chr7 | rs2718058 | NME8 | GPR141 , NME8, SFRP4, EPDR1 | / | / | / | 0.93 (0.90– 0.95) | (32) | |
| Chr7 | rs1476679 | ZCWP W1 | GPC2, STAG3, PVRIG, GATS, SPDYE3 , PILRB, PILRA, ZCWPW1, MEPCE, C7orf61 | PILRB expression QTL | Microglia | Inflammatory signal transduction | 0.91 (0.89– 0.94) | (32, 141) | |
| Chr8 | rs9331896 | CLU | EPHX2, CLU, SCARA3 | CLU rare coding variants and insertions / deletions | Astrocytes | Lipid metabolis m | 0.86 (0.84– 0.89) | (32) | |
| Chr8 | rs28834970 | PTK2 B | TRIM35, PTK2B, CHRNA2 | / | / | / | 1.10 (1.08– 1.13) | (32) | |
| Chr10 | rs7920721 | ECHDC3 | USP6NL , ECHDC3, PROSE R2 | / | / | / | 1.07 (1.04– 1.10) | (138, 139) | |
| Chr11 | rs10838725 | CELF1 | DDB2, ACP2, NR1H3, MADD, MYBPC3, SPI1, SLC39A13, PSMC3, RAPSN, CELF1, PTPMT1, KBTBD4, NDUFS3, FAM180B, C1QTN F4, MTCH2, AGBL2, FNBP4, NUP160 | SPI1 expression QTL | Myeloid cells | Myeloid lineage determination | 1.08 (1.05– 1.11) | (32, 136) | |
| Chr11 | rs983392 | MS4A6A | OOSP2, MS4A3, MS4A2, MS4A6A , MS4A4E , MS4A4A , MS4A6E , MS4A7, MS4A14 , MS4A5, MS4A1 | MS4A4A, MS4A6A expression QTL | Microglia | Chemosensory receptors | 0.90 (0.87– 0.92) | (32, 136) | |
| Chr11 | rs10792832 | PICAL M | CCDC83, PICALM , EED | / | / | / | 0.87 (0.85– 0.89) | (32) | |
| Chr11 | rs11218343 | SORL1 | SORL1 | SORL1 rare and common variants | Ubiquitous | Endocytosis and sorting | 0.77 (0.72– 0.82) / 5.03 (2.02– 14.99) | (32, 142) | |
| Chr14 | rs17125944 | FERM T2 | ERO1A, PSMC6, STYX, GNPNAT1, FERMT2 | / | / | / | 1.14 (1.09– 1.19) | (32) | |
| Chr14 | rs10498633 | SLC24 A4 / RIN3 | SLC24A4, RIN3, LGMN | / | / | / | 0.91 (0.88– 0.94) | (32) | |
| Chr15 | rs59685680 | SPPL2 A | USP8, USP50, TRPM7, SPPL2A | / | / | / | 0.92 (0.89– 0.95) | (138) | |
| Chr15 | rs74615166 | TRIP4 | CSNK1G1, KIAA0101, TRIP4, ZNF609 | / | / | / | 1.31 (1.19– 1.44) | (143) | |
| Chr17 | rs2632516 | BZRA P1-AS1 | TSPOAP1, BZRAP1 -AS1, SUPT4H1, RNF43 | / | / | / | 0.92 (0.91– 0.94) | (139) | |
| Chr17 | rs77493189 | SCIM P | ZFP3, ZNF232, USP6, ZNF594, SCIMP, RABEP1 , NUP88, RPAIN, C1QBP, DHX33 | / | / | / | 1.11 (1.07– 1.15) | (138) | |
| Chr18 | rs8093731 | DSG2 | DSG3, DSG2, DSG2-AS1 | / | / | / | 0.73 (0.62– 0.86) | (32) | |
| Chr19 | rs4147929 | ABCA7 | CNN2, ABCA7, HMHA1, POLR2E | ABCA7 rare and common loss-of-function mutations and deletions | Ubiquitous | Lipid metabolism and phagocytosis | 1.15 (1.11– 1.19) / 2.81 (1.89– 4.20) | (32, 86) | |
| Chr19 | rs429358 , rs7412 | APOE | APOE | ε4 genotype | Ubiquitous, major in astrocytes and microglia | Lipid metabolism and phagocytosis | ~3–12 | (72, 73) | |
| Chr19 | rs3865444 | CD33 | SIGLEC9, SIGLEC7, CD33, SIGLECL1 | CD33 alternative splicing of IgV domain | Microglia | Immune response and phagocytosis | 0.94 (0.91– 0.96) | (32) | |
| Chr20 | rs7274581 | CASS4 | AURKA, CSTF1, CASS4, RTFDC1, GCNT7 | / | / | / | 0.88 (0.84– 0.92) | (32) | |
| Genes | |||||||||
| Chr4 | rs137875858 | UNC5 C | UNC5C | UNC5C T835M |
Neuron s | Response to neurotoxic stimuli, cell death | / | (69) | |
| Chr6 | rs75932628 | TREM2 | TREM2 | TREM2 R47H |
Microglia | Immune response and phagocytosis | ~3–5 | (61, 62) | |
| Chr6 | rs3747742 | TREML2 | TREML2 | TREML2 S144G |
Microglia | Immune response | 0.91 (0.86– 0.97) | (144) | |
| Chr7 | rs144662445, rs149979685 | AKAP9 | AKAP9 | AKAP9 I2546M, S3767L |
Ubiquitous | Kinase signaling | 3.61 (1.51– 9.00) | (70) | |
| Chr15 | rs61751103, rs145518263 | ADAM10 | ADAM10 | ADAM10 Q170H, R181G |
Ubiquit ous | APP processing to Aβ | / | (24) | |
| Chr16 | rs72824905 | PLCG2 | PLCG2 | PLCG2 P522R |
Microglia | Phospholipase signaling | 0.68 (CI not reported) | (137) | |
| Chr17 | rs616338 | ABI3 | ABI3 | ABI3 S209F |
Microglia | Cell growth | 1.43 (CI not reported) | (137) | |
| Chr19 | rs145999145 | PLD3 | PLD3 | PLD3 V232M |
Ubiquit ous | Unknown | 2.75 (2.05– 3.68) | (68) | |
| Chr21 | rs63750847 | APP | APP | APP A673T |
Ubiquit ous | APP processing to Aβ | ~0.2 | (60) | |