Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci.
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.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Mariet
M
Allen
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Jeremy D
JD
Burgess
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Travis
T
Ballard
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA.
Daniel
D
Serie
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA.
Xue
X
Wang
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Curtis S
CS
Younkin
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.
Zhifu
Z
Sun
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Naomi
N
Kouri
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.
Saurabh
S
Baheti
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.
Chen
C
Wang
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Minerva M
MM
Carrasquillo
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Thuy
T
Nguyen
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Sarah
S
Lincoln
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Kimberly
K
Malphrus
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Melissa
M
Murray
Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA.
Todd E
TE
Golde
Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA, 98109, USA.
Nathan D
ND
Price
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Steven G
SG
Younkin
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Gerard D
GD
Schellenberg
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA.
Yan
Y
Asmann
Department of Physiology and Biomedical Engineering and Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
Tamas
T
Ordog
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA.
Julia
J
Crook
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Dennis
D
Dickson
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA. taner.nilufer@mayo.edu.|Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA. taner.nilufer@mayo.edu.
Nilüfer
N
Ertekin-Taner
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000502:physiology*; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D000069338:Neuropathology / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012306:Risk; D013494:Supranuclear Palsy, Progressive / Q000235:genetics* / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D016875:tau Proteins
Association; Brain tissue; Epigenetic; Genetic risk; Neuropathology traits; Progressive supranuclear palsy; Transcription