Identification of genetic modifiers of age-at-onset for familial Parkinson's disease

Erin M. Hill-Burns, Owen A Ross, William T. Wissemann, Alexandra I. Soto-Ortolaza, Sepideh Zareparsi, Joanna Siuda, Timothy Lynch, Zbigniew K Wszolek, Peter A. Silburn, George D. Mellick, Beate Ritz, Clemens R. Scherzer, Cyrus P. Zabetian, Stewart A. Factor, Patrick J. Breheny, Haydeh Payami

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3849-3862
Number of pages14
JournalHuman Molecular Genetics
Volume25
Issue number17
DOIs
StatePublished - 2015

Fingerprint

Parkinson Disease
Age of Onset
Research
Parkinson Disease 10
Genome-Wide Association Study
Movement Disorders
Muscle Contraction
Tumor Suppressor Genes
Brain Neoplasms
Neurodegenerative Diseases
Dementia
Genome
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Hill-Burns, E. M., Ross, O. A., Wissemann, W. T., Soto-Ortolaza, A. I., Zareparsi, S., Siuda, J., ... Payami, H. (2015). Identification of genetic modifiers of age-at-onset for familial Parkinson's disease. Human Molecular Genetics, 25(17), 3849-3862. https://doi.org/10.1093/hmg/ddw206

Identification of genetic modifiers of age-at-onset for familial Parkinson's disease. / Hill-Burns, Erin M.; Ross, Owen A; Wissemann, William T.; Soto-Ortolaza, Alexandra I.; Zareparsi, Sepideh; Siuda, Joanna; Lynch, Timothy; Wszolek, Zbigniew K; Silburn, Peter A.; Mellick, George D.; Ritz, Beate; Scherzer, Clemens R.; Zabetian, Cyrus P.; Factor, Stewart A.; Breheny, Patrick J.; Payami, Haydeh.

In: Human Molecular Genetics, Vol. 25, No. 17, 2015, p. 3849-3862.

Research output: Contribution to journalArticle

Hill-Burns, EM, Ross, OA, Wissemann, WT, Soto-Ortolaza, AI, Zareparsi, S, Siuda, J, Lynch, T, Wszolek, ZK, Silburn, PA, Mellick, GD, Ritz, B, Scherzer, CR, Zabetian, CP, Factor, SA, Breheny, PJ & Payami, H 2015, 'Identification of genetic modifiers of age-at-onset for familial Parkinson's disease', Human Molecular Genetics, vol. 25, no. 17, pp. 3849-3862. https://doi.org/10.1093/hmg/ddw206
Hill-Burns EM, Ross OA, Wissemann WT, Soto-Ortolaza AI, Zareparsi S, Siuda J et al. Identification of genetic modifiers of age-at-onset for familial Parkinson's disease. Human Molecular Genetics. 2015;25(17):3849-3862. https://doi.org/10.1093/hmg/ddw206
Hill-Burns, Erin M. ; Ross, Owen A ; Wissemann, William T. ; Soto-Ortolaza, Alexandra I. ; Zareparsi, Sepideh ; Siuda, Joanna ; Lynch, Timothy ; Wszolek, Zbigniew K ; Silburn, Peter A. ; Mellick, George D. ; Ritz, Beate ; Scherzer, Clemens R. ; Zabetian, Cyrus P. ; Factor, Stewart A. ; Breheny, Patrick J. ; Payami, Haydeh. / Identification of genetic modifiers of age-at-onset for familial Parkinson's disease. In: Human Molecular Genetics. 2015 ; Vol. 25, No. 17. pp. 3849-3862.
@article{12284b4abf684ca4a7e8b3a1622ed7d1,
title = "Identification of genetic modifiers of age-at-onset for familial Parkinson's disease",
abstract = "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.",
author = "Hill-Burns, {Erin M.} and Ross, {Owen A} and Wissemann, {William T.} and Soto-Ortolaza, {Alexandra I.} and Sepideh Zareparsi and Joanna Siuda and Timothy Lynch and Wszolek, {Zbigniew K} and Silburn, {Peter A.} and Mellick, {George D.} and Beate Ritz and Scherzer, {Clemens R.} and Zabetian, {Cyrus P.} and Factor, {Stewart A.} and Breheny, {Patrick J.} and Haydeh Payami",
year = "2015",
doi = "10.1093/hmg/ddw206",
language = "English (US)",
volume = "25",
pages = "3849--3862",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "17",

}

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

PY - 2015

Y1 - 2015

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

VL - 25

SP - 3849

EP - 3862

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 17

ER -