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P2‐028: Apolipoprotein e ε4 domain interaction in size of hippocampal subregions, density of newborn neurons, and cognitive behaviors
Author(s) -
Adeosun Samuel O.,
Hou Xu,
Zhao Xueying,
Stockmeier Craig,
Mosley Tom,
Zheng Baoying,
Raffai Robert,
Zhang Qinli,
Weisgraber Karl H.,
Wang Jun Ming
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.06.564
Subject(s) - hippocampal formation , calretinin , hippocampus , neurogenesis , stereology , apolipoprotein e , endocrinology , medicine , dentate gyrus , neuroscience , subgranular zone , western blot , chemistry , biology , microbiology and biotechnology , neural stem cell , immunohistochemistry , disease , biochemistry , stem cell , gene , subventricular zone
Background: Progressive supranuclear palsy (PSP) is a rare movement disorder; abnormally phosphorylated tau is the primary pathological lesion. A genome-wide association study (GWAS) identified 3 significant PSP risk loci in addition to the established H1 risk haplotype at the MAPT locus. We and others have shown that some of the SNPs implicated by PSP GWAS also associate with altered expression of proximal genes (in-cis) implicating transcriptional alterations as a possible disease mechanism. Gene expression can be influenced by both genetic and epigenetic factors; identifying and understanding the role of transcriptional control in the brains of PSP subjects may identify novel genes and indicate mechanism of action for future therapeutic targeting. We have previously collected gene expression profiles from 107 temporal cortex and 98 cerebellum PSP samples using the IlluminaWhole-Genome DASL assay (WG-DASL) and 85 overlapping temporal cortex samples using RNAseq. DNA methylation (RRBS) was also investigated in 46 of the same temporal cortex samples. We are pursuing findings from these previous studies in an additional cohort of 192 temporal cortex PSP samples. Methods: RNA was isolated from brain tissue using the Ambion RNAqueous kit. Gene expression was studied in 192 temporal cortex PSP samples using WGDASL; all gene expression measures underwent appropriate data QC. All samples have existing GWAS genotypes (Hoglinger et al, 2011). eQTL analysis was implemented in PLINK using linear regression, additive model, including appropriate covariates. Results: One sample failed quality control. In the remaining 191 PSP samples, 25,809 of the 29,377 probes (18,516 genes) showed signal above background levels (detection p<0.05) in greater than 50% of the subjects. eQTL analysis of SNPs previously implicated by PSP GWAS and our eQTL studies (Zou et al, 2012) replicated our previous findings in the same direction as we had previously reported: rs11568653-SLCO1A2: beta1⁄4 -0.89, p1⁄4 6.32E-13 and rs1768208 MOBP: beta1⁄4 0.37, p1⁄4 2.85E-03. Genome-wide eQTLanalysis is currently underway.Conclusions:Herewe confirmed association of the PSP protective alleles for two PSP GWAS SNPs with decreased SLCO1A2 and increased MOBP levels. Genomewide eQTL analysis may reveal additional PSP candidate genes.