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dc.contributor.authorHill-Burns, Erin M
dc.contributor.authorRoss, Owen A
dc.contributor.authorWissemann, William T
dc.contributor.authorSoto-Ortolaza, Alexandra I
dc.contributor.authorZareparsi, Sepideh
dc.contributor.authorSiuda, Joanna
dc.contributor.authorLynch, Timothy
dc.contributor.authorWszolek, Zbigniew K
dc.contributor.authorSilburn, Peter A
dc.contributor.authorMellick, George D
dc.contributor.authorRitz, Beate
dc.contributor.authorScherzer, Clemens R
dc.contributor.authorZabetian, Cyrus P
dc.contributor.authorFactor, Stewart A
dc.contributor.authorBreheny, Patrick J
dc.contributor.authorPayami, Haydeh
dc.date.accessioned2018-03-19T01:30:56Z
dc.date.available2018-03-19T01:30:56Z
dc.date.issued2016
dc.identifier.issn0964-6906
dc.identifier.doi10.1093/hmg/ddw206
dc.identifier.urihttp://hdl.handle.net/10072/143162
dc.description.abstractParkinson’s disease (PD) is the most common cause of neurodegenerative movement disorder and the second most common cause of dementia. Genes are thought to have a stronger effect on age-at-onset of PD than on risk, yet there has been a phenomenal success in identifying risk loci but not age-at-onset modifiers. We conducted a genome-wide study for age-at-onset. We analysed familial and non-familial PD separately, per prior evidence for strong genetic effect on age-at-onset in familial PD. GWAS was conducted in 431 unrelated PD individuals with at least one affected relative (familial PD) and 1544 non-familial PD from the NeuroGenetics Research Consortium (NGRC); an additional 737 familial PD and 2363 non-familial PD were used for replication. In familial PD, two signals were detected and replicated robustly: one mapped to LHFPL2 on 5q14.1 (PNGRC = 3E-8, PReplication = 2E-5, PNGRC + Replication = 1E-11), the second mapped to TPM1 on 15q22.2 (PNGRC = 8E-9, PReplication = 2E-4, PNGRC + Replication = 9E-11). The variants that were associated with accelerated onset had low frequencies (<0.02). The LHFPL2 variant was associated with earlier onset by 12.33 [95% CI: 6.2; 18.45] years in NGRC, 8.03 [2.95; 13.11] years in replication, and 9.79 [5.88; 13.70] years in the combined data. The TPM1 variant was associated with earlier onset by 15.30 [8.10; 22.49] years in NGRC, 9.29 [1.79; 16.79] years in replication, and 12.42 [7.23; 17.61] years in the combined data. Neither LHFPL2 nor TPM1 was associated with age-at-onset in non-familial PD. LHFPL2 (function unknown) is overexpressed in brain tumours. TPM1 encodes a highly conserved protein that regulates muscle contraction, and is a tumour-suppressor gene.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherOxford University Press
dc.relation.ispartofpagefrom1
dc.relation.ispartofpageto33
dc.relation.ispartofjournalHuman Molecular Genetics
dc.subject.fieldofresearchBiological Sciences not elsewhere classified
dc.subject.fieldofresearchBiological Sciences
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchcode069999
dc.subject.fieldofresearchcode06
dc.subject.fieldofresearchcode11
dc.titleIdentification of genetic modifiers of age-at-onset for familial Parkinson's disease
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by-nc/4.0/
dc.description.versionVersion of Record (VoR)
gro.description.notepublicThis publication has been entered into Griffith Research Online as an Advanced Online Version.
gro.rights.copyright© The Author(s) 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
gro.hasfulltextFull Text
gro.griffith.authorSilburn, Peter A.
gro.griffith.authorMellick, George


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