title: Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci.
abstract: Late onset Alzheimer's disease (LOAD) is a genetically complex and clinically heterogeneous disease. Recent large-scale genome wide association studies (GWAS) have identified more than twenty loci that modify risk for AD. Despite the identification of these loci, little progress has been made in identifying the functional variants that explain the association with AD risk. Thus, we sought to determine whether the novel LOAD GWAS single nucleotide polymorphisms (SNPs) alter expression of LOAD GWAS genes and whether expression of these genes is altered in AD brains. The majority of LOAD GWAS SNPs occur in gene dense regions under large linkage disequilibrium (LD) blocks, making it unclear which gene(s) are modified by the SNP. Thus, we tested for brain expression quantitative trait loci (eQTLs) between LOAD GWAS SNPs and SNPs in high LD with the LOAD GWAS SNPs in all of the genes within the GWAS loci. We found a significant eQTL between rs1476679 and PILRB and GATS, which occurs within the ZCWPW1 locus. PILRB and GATS expression levels, within the ZCWPW1 locus, were also associated with AD status. Rs7120548 was associated with MTCH2 expression, which occurs within the CELF1 locus. Additionally, expression of several genes within the CELF1 locus, including MTCH2, were highly correlated with one another and were associated with AD status. We further demonstrate that PILRB, as well as other genes within the GWAS loci, are most highly expressed in microglia. These findings together with the function of PILRB as a DAP12 receptor supports the critical role of microglia and neuroinflammation in AD risk.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Lubov A
authors.initials: LA
authors.lastname: Ezerskiy
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States of America.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D000067879:CELF1 Protein / Q000235:genetics*; D016022:Case-Control Studies; D030541:Databases, Genetic; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D011971:Receptors, Immunologic / Q000235:genetics*; D012307:Risk Factors; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; C502207:MTCH2 protein, human; D008562:Membrane Glycoproteins; D033681:Mitochondrial Membrane Transport Proteins; C404960:PILRB protein, human; D011971:Receptors, Immunologic