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

doi:10.1093/hmg/ddw206

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

Journal article

Open access

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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, …

Human molecular genetics, Vol.25(17), pp.3849-3862

09/01/2016

DOI: 10.1093/hmg/ddw206

PMCID: PMC5216611

PMID: 27402877

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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 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 (P = 3E-8, P = 2E-5, P = 1E-11), the second mapped to TPM1 on 15q22.2 (P = 8E-9, P = 2E-4, P = 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.

Tropomyosin - genetics

Genetic Predisposition to Disease

Membrane Proteins - genetics

Humans

Middle Aged

Male

Parkinson Disease - genetics

Proteins - genetics

Age of Onset

Aged, 80 and over

Female

Aged

Polymorphism, Single Nucleotide

Genome-Wide Association Study - methods

Details

Title: Subtitle: Identification of genetic modifiers of age-at-onset for familial Parkinson's disease
Creators: Erin M Hill-Burns - Department of Neurology, University of Alabama at Birmingham, AL, USA
Owen A Ross - Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA
William T Wissemann - Department of Neurology, University of Alabama at Birmingham, AL, USA
Alexandra I Soto-Ortolaza - Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA
Sepideh Zareparsi - Department of Molecular and Medical Genetics, Oregon Health & Sciences University, Portland, OR, USA
Joanna Siuda - Department of Neurology, Medical University of Silesia, Katowice, Poland
Timothy Lynch - Dublin Neurological Institute at the Mater Misericordiae University Hospital, Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland
Zbigniew K Wszolek - Department of Neurology, Mayo Clinic Jacksonville, FL, USA
Peter A Silburn - Eskitis Institute for Drug Discovery, Griffith University, Queensland, Australia
George D Mellick - Eskitis Institute for Drug Discovery, Griffith University, Queensland, Australia
Beate Ritz - Department of Epidemiology, Fielding School of Public Health and Neurology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Clemens R Scherzer - The Neurogenomics Laboratory, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA, USA
Cyrus P Zabetian - VA Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA, USA
Stewart A Factor - Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
Patrick J Breheny - Department of Biostatistics, University of Iowa, Iowa City, IA, USA
Haydeh Payami - Center for Genomic Medicine, HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.25(17), pp.3849-3862
Publisher: England
DOI: 10.1093/hmg/ddw206
PMID: 27402877
PMCID: PMC5216611
ISSN: 0964-6906
eISSN: 1460-2083
Grant note: P50 AG005134 / NIA NIH HHS U01 NS082157 / NINDS NIH HHS P30 AG008017 / NIA NIH HHS P50 NS072187 / NINDS NIH HHS HHSN268200782096C / NHLBI NIH HHS I01 BX000531 / BLRD VA R01 ES010544 / NIEHS NIH HHS U54 ES012078 / NIEHS NIH HHS R01 NS036960 / NINDS NIH HHS R01 NS078086 / NINDS NIH HHS
Language: English
Date published: 09/01/2016
Academic Unit: Biostatistics
Record Identifier: 9983997313502771

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