{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMS4A6A, a member of the membrane‐spanning 4-domains subfamily, has emerged as an important genetic modulator in Alzheimer’s disease (AD). Genome-wide association studies have identified common variants—most notably rs610932—in the MS4A gene cluster that confer significant susceptibility to AD in various populations, including Caucasians and Chinese (e.g., increased risk [1] and allele‐specific effects [2]). In parallel, expression analyses have revealed that elevated levels of MS4A6A transcripts are associated with AD and mild cognitive impairment, with higher expression correlating with accelerated cortical and hippocampal atrophy, while protective alleles are linked to lower MS4A6A expression (e.g., altered transcript dosage [3] and neuroimaging correlations [4])."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its genetic and transcriptomic associations with AD, MS4A6A appears to exert a functional role by modulating microglial activity and neuroinflammatory pathways. Evidence suggests that MS4A6A influences the efficiency of amyloid‑β clearance by microglia, a process central to the pathogenesis of AD; dysregulation of this pathway may contribute to neurodegeneration. Moreover, studies indicate that MS4A6A polymorphisms are also involved in other neurodegenerative processes, as certain alleles are associated with a delayed age at onset in Parkinson’s disease and with region-specific brain atrophy in populations at risk (e.g., altered neuroimmune signaling [6], structural imaging studies [7], and potential epistatic effects [8,9])."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond classical neurodegeneration, emerging studies have expanded the scope of MS4A6A’s involvement to other central nervous system disorders. Meta-analyses highlight that some MS4A6A alleles may even be protective in late-onset AD, while rare damaging variants within the broader MS4A gene cluster appear more prevalent in control populations, suggesting a modulatory—or even protective—role (e.g., variant enrichment and protective association [5], meta-analytic evidence [10]). Furthermore, recent findings in glioblastoma multiforme have shown that MS4A6A is markedly upregulated in microglia within the tumor microenvironment, where its overexpression promotes glioma cell proliferation and migration, thereby implicating MS4A6A in tumor progression and presenting a potential novel therapeutic target (e.g., emerging roles in oncogenesis [11], microglial regulation in GBM [12])."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Paul Hollingworth, Denise Harold, Rebecca Sims, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.803"}], "href": "https://doi.org/10.1038/ng.803"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21460840"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21460840"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yu-Lei Deng, Li-Hua Liu, Ying Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The prevalence of CD33 and MS4A6A variant in Chinese Han population with Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-012-1154-6"}], "href": "https://doi.org/10.1007/s00439-012-1154-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22382309"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22382309"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Petroula Proitsi, Sang Hyuck Lee, Katie Lunnon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alzheimer's disease susceptibility variants in the MS4A6A gene are associated with altered levels of MS4A6A expression in blood."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Aging (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neurobiolaging.2013.08.002"}], "href": "https://doi.org/10.1016/j.neurobiolaging.2013.08.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24064185"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24064185"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Leslie M Ramirez, Naira Goukasian, Shai Porat, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common variants in ABCA7 and MS4A6A are associated with cortical and hippocampal atrophy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Aging (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neurobiolaging.2015.10.037"}], "href": "https://doi.org/10.1016/j.neurobiolaging.2015.10.037"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26923404"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26923404"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Kuan Fan, Bei-Sha Tang, Ya-Qin Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The GBA, DYRK1A and MS4A6A polymorphisms influence the age at onset of Chinese Parkinson patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurosci Lett (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neulet.2016.04.014"}], "href": "https://doi.org/10.1016/j.neulet.2016.04.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27085534"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27085534"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jing Ma, Wei Zhang, Lin Tan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MS4A6A genotypes are associated with the atrophy rates of Alzheimer's disease related brain structures."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.9563"}], "href": "https://doi.org/10.18632/oncotarget.9563"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27244883"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27244883"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Alejandro Cáceres, José E Vargas, Juan R González "}, {"type": "b", "children": [{"type": "t", "text": "APOE and MS4A6A interact with GnRH signaling in Alzheimer's disease: Enrichment of epistatic effects."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Alzheimers Dement (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jalz.2016.05.009"}], "href": "https://doi.org/10.1016/j.jalz.2016.05.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27337227"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27337227"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Lígia Ramos Dos Santos, Lúcia Helena Sagrillo Pimassoni, Geralda Gillian Silva Sena, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Validating GWAS Variants from Microglial Genes Implicated in Alzheimer's Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Neurosci (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12031-017-0928-7"}], "href": "https://doi.org/10.1007/s12031-017-0928-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28477215"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28477215"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Mahdi Ghani, Christine Sato, Erfan Ghani Kakhki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer's disease data set."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Aging (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neurobiolaging.2016.03.009"}], "href": "https://doi.org/10.1016/j.neurobiolaging.2016.03.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27084067"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27084067"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Jucimara Ferreira Figueiredo Almeida, Lígia Ramos Dos Santos, Maira Trancozo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Updated Meta-Analysis of BIN1, CR1, MS4A6A, CLU, and ABCA7 Variants in Alzheimer's Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Neurosci (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12031-018-1045-y"}], "href": "https://doi.org/10.1007/s12031-018-1045-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29504051"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29504051"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Katie Bitting, Barry Hedgespeth, Lauren C Ehrhardt-Humbert, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of redundancy between human FcεRIβ and MS4A6A proteins points toward additional complex mechanisms for FcεRI trafficking and signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Allergy (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/all.15595"}], "href": "https://doi.org/10.1111/all.15595"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36424895"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36424895"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Wenhao Lv, Shengyan Lin, Zhenxing Zuo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of microglia-expressed MS4A6A in the onset of glioblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Neurosci (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/ejn.16309"}], "href": "https://doi.org/10.1111/ejn.16309"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38488530"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38488530"}]}]}]}