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PLoS One. 2016 Feb 26;11(2):e0148717. doi: 10.1371/journal.pone.0148717. eCollection 2016.

Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci.

Collaborators (161)

Albert MS, Albin RL, Apostolova LG, Arnold SE, Baldwin CT, Barber R, Barmada MM, Barnes LL, Beach TG, Beecham GW, Beekly D, Bennett DA, Bigio EH, Bird TD, Blacker D, Boeve BF, Bowen JD, Boxer A, Burke JR, Buxbaum JD, Cairns NJ, Cantwell LB, Cao C, Carlson CS, Carney RM, Carrasquillo MM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Crane PK, Cribbs DH, Crocco EA, Cruchaga C, De Jager PL, DeCarli C, DeKosky ST, Demirci F, Dick M, Dickson DW, Duara R, Ertekin-Taner N, Evans D, Faber KM, Fallon KB, Farlow MR, Ferris S, Foroud TM, Frosch MP, Galasko DR, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Gilman S, Glass JD, Goate AM, Graff-Radford NR, Green RC, Growdon JH, Hakonarson H, Hamilton-Nelson KL, Hamilton RL, Hardy J, Harrell LE, Head E, Honig LS, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Jicha GA, Jin LW, Kamboh M, Karydas A, Kauwe JS, Kaye JA, Kim R, Koo EH, Kowall NW, Kramer JH, Kramer P, Kukull WA, LaFerla FM, Lah JJ, Larson EB, Leverenz JB, Levey AI, Li G, Lin CF, Lieberman AP, Lopez OL, Lunetta KL, Lyketsos CG, Mack WJ, Marson DC, Martin ER, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Montine TJ, Morris JC, Murrell JR, Myers AJ, Naj AC, Olichney JM, Pankratz VS, Parisi JE, Peskind E, Petersen RC, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Rajbhandary RA, Raskind M, Reiman EM, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosen HJ, Rosenberg RN, Sano M, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Tanzi RE, Trojanowski JQ, Troncoso JC, Tsuang DW, Valladares O, Van Deerlin VM, Van Eldik LJ, Vardarajan BN, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Woltjer RL, Wright CB, Younkin SG, Yu CE, Yu L.

Author information

1
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America.
2
Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, Missouri, United States of America.
3
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States of America.

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.

PMID:
26919393
PMCID:
PMC4769299
DOI:
10.1371/journal.pone.0148717
[Indexed for MEDLINE]
Free PMC Article

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