TY - JOUR
T1 - Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci
AU - Allen, Mariet
AU - Burgess, Jeremy D.
AU - Ballard, Travis
AU - Serie, Daniel
AU - Wang, Xue
AU - Younkin, Curtis S.
AU - Sun, Zhifu
AU - Kouri, Naomi
AU - Baheti, Saurabh
AU - Wang, Chen
AU - Carrasquillo, Minerva M.
AU - Nguyen, Thuy
AU - Lincoln, Sarah
AU - Malphrus, Kimberly
AU - Murray, Melissa
AU - Golde, Todd E.
AU - Price, Nathan D.
AU - Younkin, Steven G.
AU - Schellenberg, Gerard D.
AU - Asmann, Yan
AU - Ordog, Tamas
AU - Crook, Julia
AU - Dickson, Dennis
AU - Ertekin-Taner, Nilüfer
N1 - Funding Information:
For the brain donations, we thank all patients and their families, without whom this work would not have been possible. This work is supported in part by Grants from National Institutes of Health, National Institute on Aging (R01 AG032990 and U01 AG046139 to N.E.T); National Institute of Neurological Disorders and Stroke (R01 NS080820 to N.E.T); Cure PSP (to N.E.T and D.W.D); Mayo Clinic Center for Individualized Medicine, Epigenetics Program Grant (to N.E.T and M.A.).
Publisher Copyright:
© 2016, Springer-Verlag Berlin Heidelberg.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
KW - Association
KW - Brain tissue
KW - Epigenetic
KW - Genetic risk
KW - Neuropathology traits
KW - Progressive supranuclear palsy
KW - Transcription
UR - http://www.scopus.com/inward/record.url?scp=84964426521&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964426521&partnerID=8YFLogxK
U2 - 10.1007/s00401-016-1576-7
DO - 10.1007/s00401-016-1576-7
M3 - Article
C2 - 27115769
AN - SCOPUS:84964426521
SN - 0001-6322
VL - 132
SP - 197
EP - 211
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 2
ER -