Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci.

TitleGene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci.
Publication TypeJournal Article
Year of Publication2016
AuthorsAllen M, Burgess JD, Ballard T, Serie D, Wang X, Younkin CS, Sun Z, Kouri N, Baheti S, Wang C, Carrasquillo MM, Nguyen T, Lincoln S, Malphrus K, Murray M, Golde TE, Price ND, Younkin SG, Schellenberg GD, Asmann Y, Ordog T, Crook J, Dickson D, Ertekin-Taner N
JournalActa Neuropathol
Volume132
Issue2
Pagination197-211
Date Published2016 08
ISSN1432-0533
KeywordsAged, Aged, 80 and over, Alleles, DNA Methylation, Female, Gene Expression, Genetic Loci, Genome-Wide Association Study, Humans, Male, Neuropathology, Polymorphism, Single Nucleotide, Risk, Supranuclear Palsy, Progressive, tau Proteins
Abstract

To determine the effects of single nucleotide polymorphisms (SNPs) identified in a genome-wide association study of progressive supranuclear palsy (PSP), we tested their association with brain gene expression, CpG methylation and neuropathology. In 175 autopsied PSP subjects, we performed associations between seven PSP risk variants and temporal cortex levels of 20 genes in-cis, within ±100 kb. Methylation measures were collected using reduced representation bisulfite sequencing in 43 PSP brains. To determine whether SNP/expression associations are due to epigenetic modifications, CpG methylation levels of associated genes were tested against relevant variants. Quantitative neuropathology endophenotypes were tested for SNP associations in 422 PSP subjects. Brain levels of LRRC37A4 and ARL17B were associated with rs8070723; MOBP with rs1768208 and both ARL17A and ARL17B with rs242557. Expression associations for LRRC37A4 and MOBP were available in an additional 100 PSP subjects. Meta-analysis revealed highly significant associations for PSP risk alleles of rs8070723 and rs1768208 with higher LRRC37A4 and MOBP brain levels, respectively. Methylation levels of one CpG in the 3' region of ARL17B associated with rs242557 and rs8070723. Additionally, methylation levels of an intronic ARL17A CpG associated with rs242557 and that of an intronic MOBP CpG with rs1768208. MAPT and MOBP region risk alleles also associated with higher levels of neuropathology. Strongest associations were observed for rs242557/coiled bodies and tufted astrocytes; and for rs1768208/coiled bodies and tau threads. These findings suggest that PSP variants at MAPT and MOBP loci may confer PSP risk via influencing gene expression and tau neuropathology. MOBP, LRRC37A4, ARL17A and ARL17B warrant further assessment as candidate PSP risk genes. Our findings have implications for the mechanism of action of variants at some of the top PSP risk loci.

DOI10.1007/s00401-016-1576-7
Alternate JournalActa Neuropathol.
PubMed ID27115769
PubMed Central IDPMC4947429
Grant ListP01 AG017586 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
P50 AG047266 / AG / NIA NIH HHS / United States
R01 AG032990 / AG / NIA NIH HHS / United States
R01 NS080820 / NS / NINDS NIH HHS / United States
P50 NS072187 / NS / NINDS NIH HHS / United States
U01 AG046139 / AG / NIA NIH HHS / United States