Table 1. Candidate genes with known or possible immune function in loci implicated by GWAS in AD and PD.A.
| GeneB | Disease | Evidence and Strength of Evidence for immune function in the brainC |
|---|---|---|
| CR1 | AD | Strong, complement receptor, minimal expression in CNS, soluble form present in plasma and CSF, association region includes the CR1L gene, a homologue of CR1 |
| INPP5D | AD | Strong, highly expressed in microglial cells, Is activated by immunoreceptor tyrosine-based inhibition motif receptors, acts as an intrinsic brake on activation signaling |
| HLA-DRB1 | AD | Strong, one chain of the heterodimeric MHC class II molecule, highly expressed in microglial cells, region of association includes other MHC genes and non MHC genes, involved in antigen presentation, but may play a role in innate immune responses |
| TREM2 | AD | Strong, an immunoreceptor tyrosine-based activation motif receptor, highly expressed on microglial cells (see main text for more details) |
| MS4A6A | AD | Strong, strongly expressed in microglial in the brain and in peripheral immune cells, but sparse functional data, other MS4A family members are within the region of association |
| SP1 | AD | Strong, a transcription factor highly expressed in myeloid cells and microglial cells in the brain. C1qTNF4 a molecule with cytokine like functions is also within the region ofassociation. |
| BIN1 | AD | Strong (peripherally) Weak (CNS), evidence for relatively high levels of RNA expression in microglial cells, indirectly influences function of immune cells in the periphery by regulating of expression of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO mRNA is barely detectable in the brain. |
| CLU | AD | Strong, a secreted chaperone, regulates Aβ deposition, regulates complement activity among many other activities, intracellular form can regulate NFKB |
| CD33 | AD | Strong, an immunoreceptor tyrosine-based inhibition motif receptor that binds to sialic acid residues, highly expressed on microglial cells, activation of CD33 opposes activation of ITAM receptors such as TREM2. |
| ABI3 | AD | Moderate, expressed selectively on microglial cells, may function as part of the WAVE complex, implicated in regulation of cell migration, rare variants associated with increased risk for AD (see Table 2) |
| ADAM10 | AD | Moderate, cell surface proteins with a unique structure possessing both potential adhesion and protease domains, functionally studied for its effects as an α-secretase that cleaves APP and TNF-α, appears to be expressed highly in human microglial/macrophages, this and other α-secretases are known to regulate immune responses through their sheddase activity |
| APOE | AD | Moderate, highly expressed in microglial, APOE genotype, clear role in regulation of peripheral immune responses, interaction with Aβ aggregates can alter clearance of Aβ by microglial cells |
| CASS4 | AD | Moderate, Docking protein that plays a role in tyrosine kinase-based signaling related to cell adhesion and cell spreading, selectively expressed in the brain in microglial cells. |
| ABCA7 | AD | Moderate, widely expressed on many CNS cell types, can regulate microglial phagocytosis, deletions in ABCA7 have been associated with AD risk in African Americans |
| SORL1 | AD | Weak, a multifunctional endocytic receptor, functionally studied in neurons for its effects on Aβ production, but appears to be expressed highly in human microglial/macrophages. |
| ALPK2 | AD | Weak, a kinase, low expression in CNS cells but expressed in human microglial/macrophages |
| PICALM | AD | Weak, a clathrin assembly protein expressed in many CNS cell-types but expressed strongly in microglial cells. |
| CD2AP | AD | Weak, widely expressed in CNS cell types, has been shown to play a role in T-cell function |
| Il1R2 | PD | Strong, binds interleukin alpha (IL1A), interleukin beta (IL1B), and interleukin 1 receptor, type I(IL1R1/IL1RA), and acts as a decoy receptor that inhibits the activity of its ligands, |
| highly expressed on microglial cells | ||
| TLR9 | PD | Strong, a member of the Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity, highly expressed on mouse microglial cells |
| STAB1 | PD | Strong, a large, transmembrane receptor protein which may function in angiogenesis, lymphocyte homing, cell adhesion, or receptor scavenging, highly expressed on microglial cells |
| HLA-DRB6 | PD | Strong, one chain of the heterodimeric MHC class II molecule, highly expressed in microglial cells, region of association includes other MHC genes and non-MHC genes, involved in antigen presentation, but may play a role in innate immune responses. This gene has been called a pseudogene, though there is evidence that it can generate a protein. |
| HLA-DQA1 | PD | Strong, one chain of the heterodimeric MHC class II molecule, highly expressed in microglial cells, region of association includes other MHC genes and non MHC genes, involved in antigen presentation, but may play a role in innate immune responses |
| CTSB | PD | Strong, a lysosomal protease, highly expressed in microglial cells, plays a role in antigen processing and protein turnover. |
| GCH1 | PD | Moderate, a member of the GTP cyclohydrolase family, highly expressed on microglial cells, |
| CD38 | PD | Moderate, act as a receptor for cells in the immune system, primarily expressed by astrocyte in the brain. |
| CRHR1 | PD | Moderate, Corticotropin Releasing Hormone Receptor 1 G-protein coupled receptor that binds neuropeptides of the corticotropin releasing hormone family that are major regulators of the hypothalamic-pituitary-adrenal pathway. This receptor regulates corticosteroid levels via the HPA axis, but is also present on immune cells and CRH has been shown to directly modulate immune cell function. |
| GBA | PD | Weak, a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide expressed on many CNS cell types but highly expressed in mouse microglial cells |
| SIPA1L2 | PD | Weak, a member of the signal-induced proliferation-associated 1 like family, highly expressed on microglial cells. |
| ARHGAP27 | PD | Weak, member of a large family of proteins that activate Rho-type guanosine triphosphate (GTP) metabolizing enzymes, highly expressed on mouse microglia cells. |
A
Adapted from (Chang et al., 2017; Hamza et al., 2010; Hill-Burns et al., 2011; International Genomics of Alzheimer’s Disease, 2015; Lambert et al., 2010; Lambert et al., 2009; Nalls et al., 2014; Reitz et al., 2013; Wissemann et al., 2013; Witoelar et al., 2017).
B
These refer to the candidate immune genes within the region of association, in many cases there are other non-immune genes within the region of association.
C
Evidence for immune function based on data in genecards (https://www.genecards.org/) and pubmed https://www.ncbi.nlm.nih.gov/pubmed/ is highlighted, expression data is based on (Zhang et al., 2014; Zhang et al., 2016). The classification of evidence for function in the immune system in these disease (Strong, Moderate, Weak), is somewhat subjective but based on current evidence for functional role in the immune system and RNA expression data.