TY - JOUR
T1 - Identification of genetic modifiers of age-at-onset for familial Parkinson's disease
AU - Hill-Burns, Erin M.
AU - Ross, Owen A.
AU - Wissemann, William T.
AU - Soto-Ortolaza, Alexandra I.
AU - Zareparsi, Sepideh
AU - Siuda, Joanna
AU - Lynch, Timothy
AU - Wszolek, Zbigniew K.
AU - Silburn, Peter A.
AU - Mellick, George D.
AU - Ritz, Beate
AU - Scherzer, Clemens R.
AU - Zabetian, Cyrus P.
AU - Factor, Stewart A.
AU - Breheny, Patrick J.
AU - Payami, Haydeh
N1 - Funding Information:
We thank the persons with PD and volunteers who participated in this study. We thank Ryan J. Donahue for assistance with data management and double-checking. This work was supported by a grant from the National Institute of Neurological Disorders And Stroke [grant number R01NS036960]. Additional support was provided by National Institutes of Health [grant number P30AG08017]; a Merit Review Award from the Department of Veterans Affairs [grant number 1I01BX000531]; Office of Research & Development, Clinical Sciences Research & Development Service, Department of Veteran Affairs; and the Close to the Cure Foundation. Genomewide array genotyping was conducted by the Center for Inherited Disease Research, which is funded by the National Institutes of Health [grant number HHSN268200782096C]. Studies providing samples and data for replication were supported by National Institutes of Health [grant numbers U01NS082157, P50AG005134, R01ES010544, U54ES012078, R01NS078086 and P50NS72187]; a gift from Carl Edward Bolch, Jr. and Susan Bass Bolch; the American Parkinson's Disease Association; the Stowarzyszenie na Rzecz Rozwoju Neurologii Wieku Podeszlego grant; the Harvard NeuroDiscovery Center (HNDC); the Parkinson's Disease Biomarkers Program (PDBP); the U.S. Department of Defense; and the M.E.M.O. Hoffman Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding to pay the Open Access publication charges for this article was provided by the University of Alabama at Birmingham.
Funding Information:
This work was supported by a grant from the National Institute of Neurological Disorders And Stroke [grant number R01NS036960]. Additional support was provided by National Institutes of Health [grant number P30AG08017]; a Merit Review Award from the Department of Veterans Affairs [grant number 1I01BX000531]; Office of Research & Development, Clinical Sciences Research & Development Service, Department of Veteran Affairs; and the Close to the Cure Foundation. Genome-wide array genotyping was conducted by the Center for Inherited Disease Research, which is funded by the National Institutes of Health [grant number HHSN268200782096C]. Studies providing samples and data for replication were supported by National Institutes of Health [grant numbers U01NS082157, P50AG005134, R01ES010544, U54ES012078, R01NS078086 and P50NS72187]; a gift from Carl Edward Bolch, Jr. and Susan Bass Bolch; the American Parkinson’s Disease Association; the Stowarzyszenie na Rzecz Rozwoju Neurologii Wieku Podeszlego grant; the Harvard NeuroDiscovery Center (HNDC); the Parkinson’s Disease Biomarkers Program (PDBP); the U.S. Department of Defense; and the M.E.M.O. Hoffman Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding to pay the Open Access publication charges for this article was provided by the University of Alabama at Birmingham.
Publisher Copyright:
© The Author 2016. Published by Oxford University Press. All rights reserved.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Parkinson'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 nonfamilial 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.
AB - Parkinson'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 nonfamilial 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.
UR - http://www.scopus.com/inward/record.url?scp=85014315781&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014315781&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddw206
DO - 10.1093/hmg/ddw206
M3 - Article
C2 - 27402877
AN - SCOPUS:85014315781
SN - 0964-6906
VL - 25
SP - 3849
EP - 3862
JO - Human molecular genetics
JF - Human molecular genetics
IS - 17
ER -