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Acta Neuropathologica

, Volume 132, Issue 2, pp 197–211 | Cite as

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

  • Mariet Allen
  • Jeremy D. Burgess
  • Travis Ballard
  • Daniel Serie
  • Xue Wang
  • Curtis S. Younkin
  • Zhifu Sun
  • Naomi Kouri
  • Saurabh Baheti
  • Chen Wang
  • Minerva M. Carrasquillo
  • Thuy Nguyen
  • Sarah Lincoln
  • Kimberly Malphrus
  • Melissa Murray
  • Todd E. Golde
  • Nathan D. Price
  • Steven G. Younkin
  • Gerard D. Schellenberg
  • Yan Asmann
  • Tamas Ordog
  • Julia Crook
  • Dennis Dickson
  • Nilüfer Ertekin-TanerEmail author
Original Paper

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.

Keywords

Progressive supranuclear palsy Epigenetic Transcription Brain tissue Neuropathology traits Association Genetic risk 

Notes

Acknowledgments

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.).

Compliances with ethical standards

Conflict of interest

None.

Supplementary material

401_2016_1576_MOESM1_ESM.pdf (369 kb)
Supplementary material 1 (PDF 369 kb)
401_2016_1576_MOESM2_ESM.pdf (5 kb)
Supplementary material 2 (PDF 4 kb)
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Supplementary material 3 (PDF 41 kb)
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Supplementary material 4 (PDF 41 kb)
401_2016_1576_MOESM5_ESM.xlsx (202 kb)
Supplementary material 5 (XLSX 201 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Mariet Allen
    • 1
  • Jeremy D. Burgess
    • 1
  • Travis Ballard
    • 1
  • Daniel Serie
    • 2
  • Xue Wang
    • 2
  • Curtis S. Younkin
    • 1
  • Zhifu Sun
    • 3
  • Naomi Kouri
    • 1
  • Saurabh Baheti
    • 3
  • Chen Wang
    • 3
  • Minerva M. Carrasquillo
    • 1
  • Thuy Nguyen
    • 1
  • Sarah Lincoln
    • 1
  • Kimberly Malphrus
    • 1
  • Melissa Murray
    • 1
  • Todd E. Golde
    • 4
  • Nathan D. Price
    • 5
  • Steven G. Younkin
    • 1
  • Gerard D. Schellenberg
    • 6
  • Yan Asmann
    • 2
  • Tamas Ordog
    • 7
  • Julia Crook
    • 2
  • Dennis Dickson
    • 1
  • Nilüfer Ertekin-Taner
    • 1
    • 8
    Email author
  1. 1.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  2. 2.Department of Health Sciences ResearchMayo ClinicJacksonvilleUSA
  3. 3.Department of Health Sciences ResearchMayo ClinicRochesterUSA
  4. 4.Department of NeuroscienceCenter for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of FloridaGainesvilleUSA
  5. 5.Institute for Systems BiologySeattleUSA
  6. 6.Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUSA
  7. 7.Department of Physiology and Biomedical Engineering and Center for Individualized MedicineMayo ClinicRochesterUSA
  8. 8.Department of NeurologyMayo ClinicJacksonvilleUSA

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