Novel late-onset Alzheimer disease loci variants associate with brain gene expression

Allen, Mariet; Zou, Fanggeng; Chai, High Seng; Younkin, Curtis S.; Crook, Julia E.; Pankratz, V. Shane; Carrasquillo, Minerva M.; Rowley, Christopher; Nair, Asha; Middha, Sumit; Maharjan, Sooraj; Nguyen, Thuy; Ma, Li; Malphrus, Kimberly G.; Palusak, Ryan; Lincoln, Sarah; Bisceglio, Gina; Georgescu, Constantin; Schultz, Debra A.; Rakhshan, Fariborz; Kolbert, Christopher P.; Jen, Jin; Haines, Jonathan L.; Mayeux, Richard; Pericak‐Vance, Margaret A.; Farrer, Lindsay A.; Schellenberg, Gerard D.; Petersen, Ronald C.; Graff‐Radford, Neill R.; Dickson, Dennis W.; Younkin, Steven G.; Ertekin-Taner, Nilüfer

doi:10.1212/wnl.0b013e3182605801

Cited by 147 publications

(102 citation statements)

References 33 publications

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“…Previous evidence has suggested that the expression of MS4A4A and MS4A6A was increased in the brain tissue of autopsied AD patients [45], confirming the expression of these genes in the cerebellum and frontal cortex and the expression levels that may well be related with disease status also have been found. Another study found that MS4A6A expression levels were associated with Braak tangle and Braak plaque scores and higher level of MS4A6A expression in the parietal lobe was associated with more advanced brain pathology in AD patients [46].…”

Section: The Expression Of Ms4a Gene Cluster In Adsupporting

confidence: 77%

MS4A Cluster in Alzheimer’s Disease

Tan

2014

Mol Neurobiol

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Several variants within membrane-spanning 4-domains subfamily A (MS4A) gene cluster have recently been implicated the association of Alzheimer's disease (AD) by serial recent genome-wide association studies (GWAS). As cell membrane proteins, MS4A family members are found to participate in the regulation of calcium signaling which have been widely discussed in neurodegeneration and AD. Besides, although the MS4A family members are poorly characterized, an important role in immunity has already been identified for several members of this cluster (such as MS4A1, MS4A2, and MS4A4B), indicating the possible involvement of MS4A gene cluster in AD pathogenesis. In this article, we briefly summarize the structure, localization, and function of MS4A gene cluster, review recent genetic and expression findings concerning the association of MS4A gene cluster with AD pathogenesis, and also speculate the possible roles of MS4A gene cluster in this disease. Based on the contributing effects of MS4A gene cluster in AD pathogenesis, targeting MS4A gene cluster might provide new opportunities for AD treatment.

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Section: The Expression Of Ms4a Gene Cluster In Adsupporting

confidence: 77%

MS4A Cluster in Alzheimer’s Disease

Tan

2014

Mol Neurobiol

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“…If the coinheritance between the AD SNP and the functional SNP is modest or if there is more than one functional SNP, discerning an association between the AD SNP and functional changes is especially challenging. Second, genetic expression studies often use microarray data (Guerreiro et al, 2010;Allen et al, 2012) that are often unable to accurately quantify individual mRNA isoforms. Finally, human brain samples are heterogeneous with regard to cell types, and most expression studies do not control for variation in the proportion of cell type.…”

Section: Discussionmentioning

confidence: 99%

CD33 Alzheimer's Risk-Altering Polymorphism, CD33 Expression, and Exon 2 Splicing

et al. 2013

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Genome-wide association studies are identifying novel Alzheimer's disease (AD) risk factors. Elucidating the mechanism underlying these polymorphisms is critical to the validation process and, by identifying rate-limiting steps in AD risk, may yield novel therapeutic targets. Here, we elucidate the mechanism of action of the AD-associated polymorphism rs3865444 in the promoter of CD33, a member of the sialic acid-binding Ig-superfamily of lectins (SIGLECs). Immunostaining established that CD33 is expressed in microglia in human brain. Consistent with this finding, CD33 mRNA expression correlated well with expression of the microglial genes CD11b and AIF-1 and was modestly increased with AD status and the rs3865444C AD-risk allele. Analysis of CD33 isoforms identified a common isoform lacking exon 2 (D2-CD33). The proportion of CD33 expressed as D2-CD33 correlated robustly with rs3865444 genotype. Because rs3865444 is in the CD33 promoter region, we sought the functional polymorphism by sequencing CD33 from the promoter through exon 4. We identified a single polymorphism that is coinherited with rs3865444, i.e., rs12459419 in exon 2. Minigene RNA splicing studies in BV2 microglial cells established that rs12459419 is a functional single nucleotide polymorphism (SNP) that modulates exon 2 splicing efficiency. Thus, our primary findings are that CD33 is a microglial mRNA and that rs3865444 is a proxy SNP for rs12459419 that modulates CD33 exon 2 splicing. Exon 2 encodes the CD33 IgV domain that typically mediates sialic acid binding in SIGLEC family members. In summary, these results suggest a novel model wherein SNP-modulated RNA splicing modulates CD33 function and, thereby, AD risk.

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“…Clusterin mRNA expression is elevated in AD brains (53, 54) and is detected in amyloid plaques (55, 56). Purified clusterin interacts with Aβ and influences fibril formation in vitro (57-59).…”

Section: Cholesterol Metabolismmentioning

confidence: 99%

Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis

Karch¹,

Goate²

2015

Biological Psychiatry

1,098

845

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Here, we review the genetic risk factors for late onset Alzheimer's disease (AD) and their role in AD pathogenesis. Recent advances in our understanding of the human genome, namely technological advances in methods to analyze millions of polymorphisms in thousands of subjects, have revealed new genes associated with AD risk: ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4 RIN3, SORL1, ZCWPW1. Emerging technologies to analyze the entire genome in large datasets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathological features of AD. Together, understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date.

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Novel late-onset Alzheimer disease loci variants associate with brain gene expression

Abstract: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.

Cited by 147 publications

References 33 publications

MS4A Cluster in Alzheimer’s Disease

MS4A Cluster in Alzheimer’s Disease

CD33 Alzheimer's Risk-Altering Polymorphism, CD33 Expression, and Exon 2 Splicing

Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis

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