Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

Naomi Kouri; Owen A. Ross; Beth Dombroski; Curtis S. Younkin; Daniel J. Serie; Alexandra Soto-Ortolaza; Matthew Baker; Ni Cole A Finch; Hyejin Yoon; Jungsu Kim; Shinsuke Fujioka; Catriona A. Mclean; Bernardino Ghetti; Salvatore Spina; Laura B. Cantwell; Martin R. Farlow; Jordan Grafman; Edward D. Huey; Mi Ryung Han; Sherry Beecher; Evan T. Geller; Hans A. Kretzschmar; Sigrun Roeber; Marla Gearing; Jorge L. Juncos; Jean Paul G Vonsattel; Vivianna M. Van Deerlin; Murray Grossman; Howard I. Hurtig; Rachel G. Gross; Steven E. Arnold; John Q. Trojanowski; Virginia M. Lee; Gregor K. Wenning; Charles L. White; Günter U. Höglinger; Ulrich Müller; Bernie Devlin; Lawrence I. Golbe; Julia Crook; Joseph E. Parisi; Bradley F. Boeve; Keith A. Josephs; Zbigniew K. Wszolek; Ryan J. Uitti; Neill R. Graff-Radford; Irene Litvan; Steven G. Younkin; Li San Wang; Nilüfer Ertekin-Taner; Rosa Rademakers; Hakon Hakonarsen; Gerard D. Schellenberg; Dennis W. Dickson

doi:10.1038/ncomms8247

Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

Naomi Kouri, Owen A. Ross, Beth Dombroski, Curtis S. Younkin, Daniel J. Serie, Alexandra Soto-Ortolaza, Matthew Baker, Ni Cole A Finch, Hyejin Yoon, Jungsu Kim, Shinsuke Fujioka, Catriona A. Mclean, Bernardino Ghetti, Salvatore Spina, Laura B. Cantwell, Martin R. Farlow, Jordan Grafman, Edward D. Huey, Mi Ryung Han, Sherry BeecherEvan T. Geller, Hans A. Kretzschmar, Sigrun Roeber, Marla Gearing, Jorge L. Juncos, Jean Paul G Vonsattel, Vivianna M. Van Deerlin, Murray Grossman, Howard I. Hurtig, Rachel G. Gross, Steven E. Arnold, John Q. Trojanowski, Virginia M. Lee, Gregor K. Wenning, Charles L. White, Günter U. Höglinger, Ulrich Müller, Bernie Devlin, Lawrence I. Golbe, Julia Crook, Joseph E. Parisi, Bradley F. Boeve, Keith A. Josephs, Zbigniew K. Wszolek, Ryan J. Uitti, Neill R. Graff-Radford, Irene Litvan, Steven G. Younkin, Li San Wang, Nilüfer Ertekin-Taner, Rosa Rademakers, Hakon Hakonarsen, Gerard D. Schellenberg, Dennis W. Dickson

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Abstract

Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10-12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10-8), and 2p22 at SOS1 (rs963731; P=1.76 × 10-7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10-7) and MAPT H1c (17q21; rs242557; P=7.91 × 10-6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).

Original language	English (US)
Article number	7247
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8247
State	Published - Jun 16 2015

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Kouri, N., Ross, O. A., Dombroski, B., Younkin, C. S., Serie, D. J., Soto-Ortolaza, A., Baker, M., Finch, N. C. A., Yoon, H., Kim, J., Fujioka, S., Mclean, C. A., Ghetti, B., Spina, S., Cantwell, L. B., Farlow, M. R., Grafman, J., Huey, E. D., Ryung Han, M., ... Dickson, D. W. (2015). Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nature communications, 6, [7247]. https://doi.org/10.1038/ncomms8247

Kouri, N, Ross, OA, Dombroski, B, Younkin, CS, Serie, DJ, Soto-Ortolaza, A, Baker, M, Finch, NCA, Yoon, H, Kim, J, Fujioka, S, Mclean, CA, Ghetti, B, Spina, S, Cantwell, LB, Farlow, MR, Grafman, J, Huey, ED, Ryung Han, M, Beecher, S, Geller, ET, Kretzschmar, HA, Roeber, S, Gearing, M, Juncos, JL, Vonsattel, JPG, Van Deerlin, VM, Grossman, M, Hurtig, HI, Gross, RG, Arnold, SE, Trojanowski, JQ, Lee, VM, Wenning, GK, White, CL, Höglinger, GU, Müller, U, Devlin, B, Golbe, LI, Crook, J, Parisi, JE, Boeve, BF, Josephs, KA, Wszolek, ZK, Uitti, RJ, Graff-Radford, NR, Litvan, I, Younkin, SG, Wang, LS, Ertekin-Taner, N, Rademakers, R, Hakonarsen, H, Schellenberg, GD & Dickson, DW 2015, 'Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy', Nature communications, vol. 6, 7247. https://doi.org/10.1038/ncomms8247

@article{f028d991ff164da89e5186ac8796b1c5,

title = "Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy",

abstract = "Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10-12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10-8), and 2p22 at SOS1 (rs963731; P=1.76 × 10-7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10-7) and MAPT H1c (17q21; rs242557; P=7.91 × 10-6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).",

author = "Naomi Kouri and Ross, {Owen A.} and Beth Dombroski and Younkin, {Curtis S.} and Serie, {Daniel J.} and Alexandra Soto-Ortolaza and Matthew Baker and Finch, {Ni Cole A} and Hyejin Yoon and Jungsu Kim and Shinsuke Fujioka and Mclean, {Catriona A.} and Bernardino Ghetti and Salvatore Spina and Cantwell, {Laura B.} and Farlow, {Martin R.} and Jordan Grafman and Huey, {Edward D.} and {Ryung Han}, Mi and Sherry Beecher and Geller, {Evan T.} and Kretzschmar, {Hans A.} and Sigrun Roeber and Marla Gearing and Juncos, {Jorge L.} and Vonsattel, {Jean Paul G} and {Van Deerlin}, {Vivianna M.} and Murray Grossman and Hurtig, {Howard I.} and Gross, {Rachel G.} and Arnold, {Steven E.} and Trojanowski, {John Q.} and Lee, {Virginia M.} and Wenning, {Gregor K.} and White, {Charles L.} and H{\"o}glinger, {G{\"u}nter U.} and Ulrich M{\"u}ller and Bernie Devlin and Golbe, {Lawrence I.} and Julia Crook and Parisi, {Joseph E.} and Boeve, {Bradley F.} and Josephs, {Keith A.} and Wszolek, {Zbigniew K.} and Uitti, {Ryan J.} and Graff-Radford, {Neill R.} and Irene Litvan and Younkin, {Steven G.} and Wang, {Li San} and Nil{\"u}fer Ertekin-Taner and Rosa Rademakers and Hakon Hakonarsen and Schellenberg, {Gerard D.} and Dickson, {Dennis W.}",

note = "Funding Information: We gratefully acknowledge support of patients and their families for participating in this study, as well as the Foundation for PSP|CBD and Related Brain Diseases, and the PSP Genetics Study Group. N.K. is supported by a post-doctoral fellowship from the Karin & Sten Mortstedt CBD Solutions AB. O.A.R. is supported by NIH P50 NS072187 and R01 NS078086. D.W.D. is supported by NIH P50 NS072187, P50 AG016574, R01 AG037491, as well as State of Florida Alzheimer{\textquoteright}s Disease Initiative and the Foundation for PSP|CBD and Related Brain Diseases. GDS is supported by NIH P01 AG017586 and grants from Foundation for PSP|CBD and Related Brain Diseases and Peebler PSP Research Foundation. N.E.-T. is supported by R01 AG032990, R01 NS080820, and P50 AG0016574. J.K. is supported by GHR Foundation. J.Q.T. is supported by NIH P30 AG10124, P01 AG17586, and P50 NS53488. B.G. is supported by NIH P30 AG10133. C.L.W. is supported by NIH P30 AG012300. G.U.H. is funded by the Deutsche For-schungsgemeinschaft (DFG: HO2402/6–2) and Bundesministerium f{\"u}r Bildung und Forschung (BMBF: EpiPD). L.I.G. is supported by CBD Solutions, The Rainwater Charitable Foundation. and the American Parkinson{\textquoteright}s Disease Association. U.M. was supported by Foundation for PSP|CBD and Related Brain Diseases. I.L. is supported by MJFF, NIH, Foundation for PSP|CBD and Related Brain Diseases, and CBD Solutions. Z.K.W. is partially supported by the NIH P50 NS072187, the Mayo Clinic Center for Regenerative Medicine, Neuroscience Focused Research Team programme, and a gift from Carl Edward Bolch, Jr and Susan Bass Bolch. Funding Information: Supplementary Information accompanies this paper at http://www.nature.com/ naturecommunications Competing financial interests: Dr Trojanowski may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is the co-inventor and he received revenue from the sale of Avid to Eli Lily as co-inventor on imaging-related patents submitted by the University of Pennsylvania. He receives research support from the NIH, GSK, Janssen and several non-profits. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = jun,

day = "16",

doi = "10.1038/ncomms8247",

language = "English (US)",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

AU - Kouri, Naomi

AU - Ross, Owen A.

AU - Dombroski, Beth

AU - Younkin, Curtis S.

AU - Serie, Daniel J.

AU - Soto-Ortolaza, Alexandra

AU - Baker, Matthew

AU - Finch, Ni Cole A

AU - Yoon, Hyejin

AU - Kim, Jungsu

AU - Fujioka, Shinsuke

AU - Mclean, Catriona A.

AU - Ghetti, Bernardino

AU - Spina, Salvatore

AU - Cantwell, Laura B.

AU - Farlow, Martin R.

AU - Grafman, Jordan

AU - Huey, Edward D.

AU - Ryung Han, Mi

AU - Beecher, Sherry

AU - Geller, Evan T.

AU - Kretzschmar, Hans A.

AU - Roeber, Sigrun

AU - Gearing, Marla

AU - Juncos, Jorge L.

AU - Vonsattel, Jean Paul G

AU - Van Deerlin, Vivianna M.

AU - Grossman, Murray

AU - Hurtig, Howard I.

AU - Gross, Rachel G.

AU - Arnold, Steven E.

AU - Trojanowski, John Q.

AU - Lee, Virginia M.

AU - Wenning, Gregor K.

AU - White, Charles L.

AU - Höglinger, Günter U.

AU - Müller, Ulrich

AU - Devlin, Bernie

AU - Golbe, Lawrence I.

AU - Crook, Julia

AU - Parisi, Joseph E.

AU - Boeve, Bradley F.

AU - Josephs, Keith A.

AU - Wszolek, Zbigniew K.

AU - Uitti, Ryan J.

AU - Graff-Radford, Neill R.

AU - Litvan, Irene

AU - Younkin, Steven G.

AU - Wang, Li San

AU - Ertekin-Taner, Nilüfer

AU - Rademakers, Rosa

AU - Hakonarsen, Hakon

AU - Schellenberg, Gerard D.

AU - Dickson, Dennis W.

N1 - Funding Information: We gratefully acknowledge support of patients and their families for participating in this study, as well as the Foundation for PSP|CBD and Related Brain Diseases, and the PSP Genetics Study Group. N.K. is supported by a post-doctoral fellowship from the Karin & Sten Mortstedt CBD Solutions AB. O.A.R. is supported by NIH P50 NS072187 and R01 NS078086. D.W.D. is supported by NIH P50 NS072187, P50 AG016574, R01 AG037491, as well as State of Florida Alzheimer’s Disease Initiative and the Foundation for PSP|CBD and Related Brain Diseases. GDS is supported by NIH P01 AG017586 and grants from Foundation for PSP|CBD and Related Brain Diseases and Peebler PSP Research Foundation. N.E.-T. is supported by R01 AG032990, R01 NS080820, and P50 AG0016574. J.K. is supported by GHR Foundation. J.Q.T. is supported by NIH P30 AG10124, P01 AG17586, and P50 NS53488. B.G. is supported by NIH P30 AG10133. C.L.W. is supported by NIH P30 AG012300. G.U.H. is funded by the Deutsche For-schungsgemeinschaft (DFG: HO2402/6–2) and Bundesministerium für Bildung und Forschung (BMBF: EpiPD). L.I.G. is supported by CBD Solutions, The Rainwater Charitable Foundation. and the American Parkinson’s Disease Association. U.M. was supported by Foundation for PSP|CBD and Related Brain Diseases. I.L. is supported by MJFF, NIH, Foundation for PSP|CBD and Related Brain Diseases, and CBD Solutions. Z.K.W. is partially supported by the NIH P50 NS072187, the Mayo Clinic Center for Regenerative Medicine, Neuroscience Focused Research Team programme, and a gift from Carl Edward Bolch, Jr and Susan Bass Bolch. Funding Information: Supplementary Information accompanies this paper at http://www.nature.com/ naturecommunications Competing financial interests: Dr Trojanowski may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is the co-inventor and he received revenue from the sale of Avid to Eli Lily as co-inventor on imaging-related patents submitted by the University of Pennsylvania. He receives research support from the NIH, GSK, Janssen and several non-profits. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/6/16

Y1 - 2015/6/16

N2 - Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10-12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10-8), and 2p22 at SOS1 (rs963731; P=1.76 × 10-7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10-7) and MAPT H1c (17q21; rs242557; P=7.91 × 10-6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).

AB - Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10-12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10-8), and 2p22 at SOS1 (rs963731; P=1.76 × 10-7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10-7) and MAPT H1c (17q21; rs242557; P=7.91 × 10-6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).

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JO - Nature Communications

JF - Nature Communications

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Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

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