Common variants in MS4A4/MS4A6E, CD2uAP, CD33, and EPHA1 are associated with late-onset Alzheimer’s disease

By A. Naj, G. Jun, G. Beecham, Li-San Wang, B. Vardarajan, Jacqueline Buros, P. Gallins, Joseph D. Buxbaum, G. Jarvik, Paul K. Crane and 145 more. Nature Genetics, 2011

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The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (PM) = 1.7 × 10−9, joint analysis P (PJ) = 1.7 × 10−9; stages 1, 2 and 3, PM = 8.2 × 10−12), CD2AP (rs9349407; stages 1, 2 and 3, PM = 8.6 × 10−9), EPHA1 (rs11767557; stages 1, 2 and 3, PM = 6.0 × 10−10) and CD33 (rs3865444; stages 1, 2 and 3, PM = 1.6 × 10−9). We also replicated previous associations at CR1 (rs6701713; PM = 4.6 × 10−10, PJ = 5.2 × 10−11), CLU (rs1532278; PM = 8.3 × 10−8, PJ = 1.9 × 10−8), BIN1 (rs7561528; PM = 4.0 × 10−14, PJ = 5.2 × 10−14) and PICALM (rs561655; PM = 7.0 × 10−11, PJ = 1.0 × 10−10), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/ba3f3958986bb2daa2d2e820037216728d1c6afd

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Citations in the corpus

Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. (2016, background): “The importance of microglia in Alzheimer’s disease has been highlighted by genome-wide association studies, which have identified a number of single nucleotide poly- morphisms (SNPs) associated with risk for the development of Alzheimer’s disease that are associated with microglia function, includin”
Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes (2018, background): “Ms4a family members are associated with Alzheimer’s risk (Hollingworth et al., 2011; Ma et al., 2015; Naj et al., 2011), but their role in the disease is not understood.”
The genetics of Alzheimer disease. (2012, background): “…US, Europe APOE, CLU, CR1 Harold et al. 2009 Case–control US, Europe APOE, CLU, PICALM Seshadri et al. 2010 Case–control US, Europe APOE, BIN1 Naj et al. 2011 Case–control US, Europe MS4A6A/MS4A4E, EPHA1, CD33, CD2AP Hollingworth et al. 2011 Case–control US, Europe ABCA7, MS4A6A/MS4A4E,…”
Upregulated function of mitochondria-associated ER membranes in Alzheimer disease (2012, positive): “Finally, our ﬁndings have implications for understanding the genetics of AD (Hollingworth et al , 2011; Naj et al , 2011).”
Epidemiology of Alzheimer Disease (2012, positive): “The NIA-LOAD Family Study also replicated the variants in BIN1 and provided modest confirmation for CLU, but not for CR1 or PICALM after APOE adjustment (Hollingworth et al. 2011; Naj et al. 2011).”
Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta (2013, positive): “The rs3865444 SNP in the CD33 gene was previously reported to confer protection against AD (Hollingworth et al., 2011; Naj et al., 2011).”
Alzheimer's disease risk genes and mechanisms of disease pathogenesis (2014, neutral): “The SNPs in BIN1 that increase risk for LOAD were identified by GWAS (3,4).”
Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies (2016, background): “Genetic variants of all of these genes have a relatively minor influence on AD progression when altered [114] and their influence on the development and course of sAD remains largely unknown [115–117].”