Table 1.
Microglial genes and pathways contributing to AD risk implicated by AD genomics
| Gene | Protein description | Genetic link to AD | Type of variants | Microglial-related functions | References |
|---|---|---|---|---|---|
| APOE | Apolipoprotein; chaperone of Aβ | 3 Isomers | GWAS SNP | Chaperone Aβ and lipids; endocytosis; phagocytosis | Poirier (1993) |
| CLU | Clusterin; apolipoprotein; chaperone of Aβ | rs11787077; rs1532278; rs28834970; rs4236673; rs9331896 | GWAS SNP | Chaperone Aβ and lipids; inflammation; phagocytosis | Lambert (2013); Marioni (2018); Jansen (2019); Kunkle (2019) |
| I275T in exon5; R447W in exon8 | Rare variant | Zhang (2020) | |||
| TREM2 | Microglial PRR; binds apoptotic cells, debris, and Aβ | rs143332484; rs187370608; rs7748513 | GWAS SNP | ITAM signalling; actin cytoskeletal rearrangement; phagocytosis | Jansen (2019); Schwartzentruber (2021); Salih (2019) |
| R47H, R62H, H157Y, D87N, E151K, etc | GWAS SNP; rare variants | Jansen (2019); Kunkle (2019); Jonsson (2013); Guerrerio (2013); Sims (2017); Jiang (2016); Jin (2014); Jin (2015); Sirkis (2016); Zhang (2020) | |||
| SYK | Tyrosine kinases | – | Prioritised gene | TREM2 signalling; phagocytosis | Sierksma (2020) |
| LYN | Tyrosine kinases | – | Prioritised gene | TREM2 signalling; phagocytosis | Sierksma (2020) |
| INPP5D | Encode SHIP-1, a SH2-containing phosphatase | rs10933431; rs35349669; rs7421448 | GWAS SNP; prioritised gene | Bind to DAP12 to inhibit phagocytosis | Schwartzentruber (2021); Salih (2019) |
| PLCG2 | Encode PLC-γ2, a phospholipase | rs12444183; rs12446759 | GWAS SNP | TREM2 signalling; phagocytosis | Marioni (2018); Schwartzentruber (2021) |
| rs72824905 (P522R) | Rare variant | Sims (2017) | |||
| BLNK | SH2-containing protein | rs6584063 | GWAS SNP | Downstream TREM2 signalling | Sierksma (2020) |
| MS4A gene cluster | Transmembrane cell surface receptor | rs7933202; rs1582763; rs72924626; rs1582763; rs2081545; rs7935829; rs983392; rs636317 | GWAS SNP; prioritised gene | Intracellular protein trafficking; phagocytosis | Lambert (2013); Marioni (2018); Jansen (2019); Kunkle (2019); Schwartzentruber (2021); Novikova (2021); Salih (2019) |
| rs185080144 (A69V) | Rare variant | Zhang (2020) | |||
| ADAM10 | Metalloproteinase | rs442495; rs593742 | GWAS SNP | TREM2 shedding | Marioni (2018); Jansen (2019); Kunkle (2019); Schwartzentruber (2021) |
| CD33 | Siglec PRR that binds to sialic acids | rs3865444 | GWAS SNP | ITIM signalling; phagocytosis inhibition | Lambert (2013); Marioni (2018); Jansen (2019); Schwartzentruber (2021); Salih (2019) |
| E85V in exon2; I71M in exon2; T141A in exon 4 | Rare variants | Zhang (2020) | |||
| CLNK | SH2-containing adapter protein | rs4351014; rs6448451; rs6448453; rs6846529 | GWAS SNP | Phagocytosis | Jansen (2019); Schwartzentruber (2021) |
| SIGLEC11 | Siglec cell surface PRR | rs9304690 | GWAS SNP | ITIM signalling; | Schwartzentruber (2021) |
| LILRB4 | ITIM-containing transmembrane receptor | rs731170 | Prioritised gene | Putatively involved in ITIM signalling | Salih (2019) |
| CR1 | Complement receptor for C3b/C4b and C1q | rs2093760; rs4844610; rs6656401; rs679515 | GWAS SNP | Complement system cascade; mediate phagocytosis | Lambert (2013); Marioni (2018); Jansen (2019); Kunkle (2019); Schwartzentruber (2021) |
| chr1:207461994C>T | Somatic mutation | Helgadottir (2019) | |||
| TLR4 | Toll-like receptor | rs4986790 | Common variant | TLR signalling; mediate phagocytosis | Miron (2019) |
| SCIMP | Non-TIR-containing TLR adaptor protein | rs113260531; rs57402520; rs61182333; rs9916042 | GWAS SNP | TLR signalling to selectively produce IL-6 and IL12p; mediate phagocytosis | Jansen (2019); Schwartzentruber (2021) |
| BCL3 | Transcriptional coactivator | rs10401176; rs2927468; rs8103315 | GWAS SNP | NF-κB activation | Marioni (2018) |
| SHARPIN | Subunit of LUBAC regulating NF-κB and MAPK signalling | rs34173062 | GWAS SNP | NF-κB and MAPK activation | Schwartzentruber (2021) |
| ITGAM | Encode integrin CD11b; | rs79113991 | Prioritised gene | Integrin for focal adhesion | Salih (2019) |
| PTK2B | Protein kinase | rs1532278; rs28834970; rs34181358; rs4236673 | GWAS SNP | Focal adhesion; actin cytoskeletal rearrangement; phagocytosis | Lambert (2013); Marioni (2018); Jansen (2019) |
| chr8.27316070C>A | Somatic mutation | Helgadottir (2019) | |||
| CASS4 | Scaffolding protein | rs6014724; rs6024870; rs7274581 | GWAS SNP | Focal adhesion; cytoskeletal rearrangement | Lambert (2013); Jansen (2019); Kunkle (2019); Schwartzentruber (2021) |
| ABI3 | Actin binding protein | rs616338 (S209F) | Rare coding variant | Focal adhesion; actin polymerisation | Sims (2017) |
| CD2AP | Scaffolding protein co-localising with F-actin | rs10948363; rs1385742; rs7767350; rs9381563; rs9473117 | GWAS SNP; prioritised gene | Focal adhesion; pseudopod and phagosome formation; phagocytosis | Lambert (2013); Marioni (2018); Jansen (2019); Kunkle (2019); Schwartzentruber (2021); Novikova (2021) |
| ZYX/EPHA1 | Focal adhesion protein | rs10808026; rs11763230; rs11771145; rs12703526; rs7810606; rs35251323; rs9640386 | GWAS SNP; prioritised gene | Actin cytoskeletal rearrangement; focal adhesion | Lambert (2013); Marioni (2018); Jansen (2019); Kunkle (2019); Schwartzentruber (2021); Novikova (2021) |
| FERMT2 | Component of extracellular matrix structures | rs17125924 | GWAS SNP | Actin polymerisation; focal adhesion | Lambert (2013); Marioni (2018); Kunkle (2019); Schwartzentruber (2021) |
| H579D in exon14 | Rare variant | Zhang (2020) | |||
| BIN1 | Early endocytic protein | rs12989701; rs17014873; rs4663105; rs6733839 | GWAS SNP | Endo-lysosomal trafficking; phagocytosis | Lambert (2013); Marioni (2018); Jansen (2019); Kunkle (2019); Schwartzentruber (2021); Novikova (2021) |
| rs141119288 (P431L in exon15); rs117721706 (R263Q in exon10) | Rare variant | Zhang (2020) | |||
| rs61748157; chr2.128054946G>T | Somatic mutation | Parcerisas (2014); Helgadottir (2019) | |||
| RIN3/SLC24A4 | Early endocytic protein | rs12590654; rs10498633; rs12881735 | GWAS SNP | Recruit BIN1, CD2AP; endo-lysosomal trafficking; phagocytosis | Lambert (2013); Marioni 2018; Jansen (2019); Kunkle (2019); Schwartzentruber (2021) |
| RABEP1 | Rab-GTPase binding effector protein | rs7225151 | GWAS SNP | Endosome trafficking and fusion | Lambert (2013); Marioni 2018 |
| RAB10 | Rab superfamily member | rs142787485 | Rare variant | Endosomal trafficking and fusion | Ridge 2017 |
| PICALM | Endocytic adaptor | rs10792832; rs3844143; rs3851179; rs867611 | GWAS SNP | Endo-lysosomal trafficking; phagocytosis | Lambert (2013); Marioni 2018; Jansen (2019); Kunkle (2019); Schwartzentruber (2021) |
| SORL1 | Endosomal trafficking receptor | rs11218343; rs74685827 | GWAS SNP | Endo-lysosomal network; lipid metabolism; intracellular sorting via retromer pathway | Lambert (2013); Marioni 2018; Jansen (2019); Kunkle (2019); Schwartzentruber (2021) |
| Many rare variants | Zhang (2020); Campion (2019) | ||||
| Several somatic mutations | Nicolas 2018; Keogh 2018; Helgadottir (2019) | ||||
| APBB3 | Intracellular APP binding protein | – | Prioritised gene | Internalisation of APP; unclear in microglia | Novikova (2021) |
| SPPL2A | Aspartyl protease in late endosomes and lysosomes | rs10467994; rs12592778; rs59685680; rs8025980; rs8035452 | GWAS SNP | Intramembrane proteolysis of TNFα and CD74; unclear in microglia | Lambert (2013); Marioni 2018; Kunkle (2019); Schwartzentruber (2021) |
| HEXB | Lysosomal enzyme | – | Prioritised gene | Lysosomal function in microglia | Sierksma (2020) |
| LAPTM5 | Lysosomal protein | – | Prioritised gene | Activation of cysteine-type endopeptidase activity in lysosomes; unclear in microglia | Salih (2019) |
| GRN | Lysosomal protein | rs5848 | GWAS SNP | Lysosomal degradation | Schwartzentruber (2021) |
| KAT8 | Histone acetyltransferases | rs59735493; rs889555; rs2884738; | GWAS SNP | Reduce IRF3 transcriptions; suppress innate immunity | Marioni 2018; Jansen (2019); Schwartzentruber (2021) |
| RELB | Transcription factor | rs117612135; rs187270432 | GWAS SNP | Transcriptional activation of lymphokines | Marioni 2018 |
| SPI1 | Transcription factor PU.1 | rs1057233 | Common variant | Transcription factor regulating many microglial-specific gene expressions | Huang 2017; Sierksma (2020); Pimenova (2021); Novikova (2021) |
| HLA cluster | Human leukocyte antigen | rs36096565; rs6605556; rs6931277; rs9269853; rs9469112; rs9271058 | GWAS SNP | Antigen presentation to T cells; adaptive immune responses | Jansen (2019); Kunkle (2019); Schwartzentruber (2021); Sierksma (2020); Salih (2019) |