MAPT haplotype diversity in multiple system atrophy

Catherine Labbé, Michael G. Heckman, Oswaldo Lorenzo-Betancor, Melissa E Murray, Kotaro Ogaki, Alexandra I. Soto-Ortolaza, Ronald L. Walton, Shinsuke Fujioka, Shunsuke Koga, Ryan J. Uitti, Jay A Van Gerpen, Ronald Carl Petersen, Neill R Graff Radford, Steven G Younkin, Bradley F Boeve, William P. Cheshire, Phillip Anson Low, Paola Sandroni, Elizabeth Coon, Wolfgang SingerZbigniew K Wszolek, Dennis W Dickson, Owen A Ross

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Introduction: Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder. MSA was originally considered exclusively sporadic but reports of association with genes such as . SNCA, . COQ2 and . LRRK2 have demonstrated that there is a genetic contribution to the disease. . MAPT has been associated with several neurodegenerative diseases and we previously reported a protective association of the . MAPT H2 haplotype with MSA in 61 pathologically confirmed cases. Methods: In the present study, we assessed the full . MAPT haplotype diversity in MSA patients using six . MAPT tagging SNPs. We genotyped a total of 127 pathologically confirmed MSA cases, 86 patients with clinically diagnosed MSA and 1312 controls. Results: We identified four significant association signals in our pathologically confirmed cases, two from the protective haplotypes H2 (MSA:16.2%, Controls:22.7%, p = 0.024) and H1E (MSA:3.0%, Controls:9.0%, p = 0.014), and two from the rare risk haplotypes H1x (MSA:3.7%, Controls:1.3%, p = 0.030) and H1J (MSA:3.0%, Controls:0.9%, p = 0.021). We evaluated the association of MSA subtypes with the common protective H2 haplotype and found a significant difference with controls for MSA patients with some degree of MSA-C (MSA-C or MSA-mixed), for whom H2 occurred in only 8.6% of patients in our pathologically confirmed series (P < 0.0001). Conclusions: Our findings provide further evidence that . MAPT variation is associated with risk of MSA. Interestingly, our results suggest a greater effect size in the MSA-C compared to MSA-P for H2. Additional genetic studies in larger pathologically confirmed MSA series and meta-analytic studies will be needed to fully assess the role of . MAPT and other genes in MSA.

Original languageEnglish (US)
JournalParkinsonism and Related Disorders
DOIs
StateAccepted/In press - Apr 14 2016

Fingerprint

Multiple System Atrophy
Haplotypes
Neurodegenerative Diseases

Keywords

  • Association study
  • Genetics
  • MAPT
  • Multiple system atrophy

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Clinical Neurology
  • Neurology

Cite this

MAPT haplotype diversity in multiple system atrophy. / Labbé, Catherine; Heckman, Michael G.; Lorenzo-Betancor, Oswaldo; Murray, Melissa E; Ogaki, Kotaro; Soto-Ortolaza, Alexandra I.; Walton, Ronald L.; Fujioka, Shinsuke; Koga, Shunsuke; Uitti, Ryan J.; Van Gerpen, Jay A; Petersen, Ronald Carl; Graff Radford, Neill R; Younkin, Steven G; Boeve, Bradley F; Cheshire, William P.; Low, Phillip Anson; Sandroni, Paola; Coon, Elizabeth; Singer, Wolfgang; Wszolek, Zbigniew K; Dickson, Dennis W; Ross, Owen A.

In: Parkinsonism and Related Disorders, 14.04.2016.

Research output: Contribution to journalArticle

Labbé, Catherine ; Heckman, Michael G. ; Lorenzo-Betancor, Oswaldo ; Murray, Melissa E ; Ogaki, Kotaro ; Soto-Ortolaza, Alexandra I. ; Walton, Ronald L. ; Fujioka, Shinsuke ; Koga, Shunsuke ; Uitti, Ryan J. ; Van Gerpen, Jay A ; Petersen, Ronald Carl ; Graff Radford, Neill R ; Younkin, Steven G ; Boeve, Bradley F ; Cheshire, William P. ; Low, Phillip Anson ; Sandroni, Paola ; Coon, Elizabeth ; Singer, Wolfgang ; Wszolek, Zbigniew K ; Dickson, Dennis W ; Ross, Owen A. / MAPT haplotype diversity in multiple system atrophy. In: Parkinsonism and Related Disorders. 2016.
@article{a9d3ff149f6d4dacb1e7c7a8dc5c0794,
title = "MAPT haplotype diversity in multiple system atrophy",
abstract = "Introduction: Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder. MSA was originally considered exclusively sporadic but reports of association with genes such as . SNCA, . COQ2 and . LRRK2 have demonstrated that there is a genetic contribution to the disease. . MAPT has been associated with several neurodegenerative diseases and we previously reported a protective association of the . MAPT H2 haplotype with MSA in 61 pathologically confirmed cases. Methods: In the present study, we assessed the full . MAPT haplotype diversity in MSA patients using six . MAPT tagging SNPs. We genotyped a total of 127 pathologically confirmed MSA cases, 86 patients with clinically diagnosed MSA and 1312 controls. Results: We identified four significant association signals in our pathologically confirmed cases, two from the protective haplotypes H2 (MSA:16.2{\%}, Controls:22.7{\%}, p = 0.024) and H1E (MSA:3.0{\%}, Controls:9.0{\%}, p = 0.014), and two from the rare risk haplotypes H1x (MSA:3.7{\%}, Controls:1.3{\%}, p = 0.030) and H1J (MSA:3.0{\%}, Controls:0.9{\%}, p = 0.021). We evaluated the association of MSA subtypes with the common protective H2 haplotype and found a significant difference with controls for MSA patients with some degree of MSA-C (MSA-C or MSA-mixed), for whom H2 occurred in only 8.6{\%} of patients in our pathologically confirmed series (P < 0.0001). Conclusions: Our findings provide further evidence that . MAPT variation is associated with risk of MSA. Interestingly, our results suggest a greater effect size in the MSA-C compared to MSA-P for H2. Additional genetic studies in larger pathologically confirmed MSA series and meta-analytic studies will be needed to fully assess the role of . MAPT and other genes in MSA.",
keywords = "Association study, Genetics, MAPT, Multiple system atrophy",
author = "Catherine Labb{\'e} and Heckman, {Michael G.} and Oswaldo Lorenzo-Betancor and Murray, {Melissa E} and Kotaro Ogaki and Soto-Ortolaza, {Alexandra I.} and Walton, {Ronald L.} and Shinsuke Fujioka and Shunsuke Koga and Uitti, {Ryan J.} and {Van Gerpen}, {Jay A} and Petersen, {Ronald Carl} and {Graff Radford}, {Neill R} and Younkin, {Steven G} and Boeve, {Bradley F} and Cheshire, {William P.} and Low, {Phillip Anson} and Paola Sandroni and Elizabeth Coon and Wolfgang Singer and Wszolek, {Zbigniew K} and Dickson, {Dennis W} and Ross, {Owen A}",
year = "2016",
month = "4",
day = "14",
doi = "10.1016/j.parkreldis.2016.06.010",
language = "English (US)",
journal = "Parkinsonism and Related Disorders",
issn = "1353-8020",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - MAPT haplotype diversity in multiple system atrophy

AU - Labbé, Catherine

AU - Heckman, Michael G.

AU - Lorenzo-Betancor, Oswaldo

AU - Murray, Melissa E

AU - Ogaki, Kotaro

AU - Soto-Ortolaza, Alexandra I.

AU - Walton, Ronald L.

AU - Fujioka, Shinsuke

AU - Koga, Shunsuke

AU - Uitti, Ryan J.

AU - Van Gerpen, Jay A

AU - Petersen, Ronald Carl

AU - Graff Radford, Neill R

AU - Younkin, Steven G

AU - Boeve, Bradley F

AU - Cheshire, William P.

AU - Low, Phillip Anson

AU - Sandroni, Paola

AU - Coon, Elizabeth

AU - Singer, Wolfgang

AU - Wszolek, Zbigniew K

AU - Dickson, Dennis W

AU - Ross, Owen A

PY - 2016/4/14

Y1 - 2016/4/14

N2 - Introduction: Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder. MSA was originally considered exclusively sporadic but reports of association with genes such as . SNCA, . COQ2 and . LRRK2 have demonstrated that there is a genetic contribution to the disease. . MAPT has been associated with several neurodegenerative diseases and we previously reported a protective association of the . MAPT H2 haplotype with MSA in 61 pathologically confirmed cases. Methods: In the present study, we assessed the full . MAPT haplotype diversity in MSA patients using six . MAPT tagging SNPs. We genotyped a total of 127 pathologically confirmed MSA cases, 86 patients with clinically diagnosed MSA and 1312 controls. Results: We identified four significant association signals in our pathologically confirmed cases, two from the protective haplotypes H2 (MSA:16.2%, Controls:22.7%, p = 0.024) and H1E (MSA:3.0%, Controls:9.0%, p = 0.014), and two from the rare risk haplotypes H1x (MSA:3.7%, Controls:1.3%, p = 0.030) and H1J (MSA:3.0%, Controls:0.9%, p = 0.021). We evaluated the association of MSA subtypes with the common protective H2 haplotype and found a significant difference with controls for MSA patients with some degree of MSA-C (MSA-C or MSA-mixed), for whom H2 occurred in only 8.6% of patients in our pathologically confirmed series (P < 0.0001). Conclusions: Our findings provide further evidence that . MAPT variation is associated with risk of MSA. Interestingly, our results suggest a greater effect size in the MSA-C compared to MSA-P for H2. Additional genetic studies in larger pathologically confirmed MSA series and meta-analytic studies will be needed to fully assess the role of . MAPT and other genes in MSA.

AB - Introduction: Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder. MSA was originally considered exclusively sporadic but reports of association with genes such as . SNCA, . COQ2 and . LRRK2 have demonstrated that there is a genetic contribution to the disease. . MAPT has been associated with several neurodegenerative diseases and we previously reported a protective association of the . MAPT H2 haplotype with MSA in 61 pathologically confirmed cases. Methods: In the present study, we assessed the full . MAPT haplotype diversity in MSA patients using six . MAPT tagging SNPs. We genotyped a total of 127 pathologically confirmed MSA cases, 86 patients with clinically diagnosed MSA and 1312 controls. Results: We identified four significant association signals in our pathologically confirmed cases, two from the protective haplotypes H2 (MSA:16.2%, Controls:22.7%, p = 0.024) and H1E (MSA:3.0%, Controls:9.0%, p = 0.014), and two from the rare risk haplotypes H1x (MSA:3.7%, Controls:1.3%, p = 0.030) and H1J (MSA:3.0%, Controls:0.9%, p = 0.021). We evaluated the association of MSA subtypes with the common protective H2 haplotype and found a significant difference with controls for MSA patients with some degree of MSA-C (MSA-C or MSA-mixed), for whom H2 occurred in only 8.6% of patients in our pathologically confirmed series (P < 0.0001). Conclusions: Our findings provide further evidence that . MAPT variation is associated with risk of MSA. Interestingly, our results suggest a greater effect size in the MSA-C compared to MSA-P for H2. Additional genetic studies in larger pathologically confirmed MSA series and meta-analytic studies will be needed to fully assess the role of . MAPT and other genes in MSA.

KW - Association study

KW - Genetics

KW - MAPT

KW - Multiple system atrophy

UR - http://www.scopus.com/inward/record.url?scp=84979695272&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84979695272&partnerID=8YFLogxK

U2 - 10.1016/j.parkreldis.2016.06.010

DO - 10.1016/j.parkreldis.2016.06.010

M3 - Article

C2 - 27374978

AN - SCOPUS:84979695272

JO - Parkinsonism and Related Disorders

JF - Parkinsonism and Related Disorders

SN - 1353-8020

ER -