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 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.
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, AL, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Hill-Burns
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, AL, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Wissemann
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA.
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Soto-Ortolaza
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Sciences University, Portland, OR, USA.
authors.forename: Sepideh
authors.initials: S
authors.lastname: Zareparsi
authors.affiliation: Department of Neurology, Medical University of Silesia, Katowice, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Siuda
authors.affiliation: Dublin Neurological Institute at the Mater Misericordiae University Hospital, Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland.
authors.forename: Timothy
authors.initials: T
authors.lastname: Lynch
authors.affiliation: Department of Neurology, Mayo Clinic Jacksonville, FL, USA.
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Queensland, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Silburn
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Queensland, Australia.
authors.forename: George D
authors.initials: GD
authors.lastname: Mellick
authors.affiliation: Department of Epidemiology, Fielding School of Public Health and Neurology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Beate
authors.initials: B
authors.lastname: Ritz
authors.affiliation: The Neurogenomics Laboratory, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA, USA.
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Scherzer
authors.affiliation: VA Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA, USA.
authors.forename: Cyrus P
authors.initials: CP
authors.lastname: Zabetian
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Factor
authors.affiliation: Department of Biostatistics, University of Iowa, Iowa City, IA, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Breheny
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, AL, USA haydehpayami@uabmc.edu.|Center for Genomic Medicine, HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
authors.forename: Haydeh
authors.initials: H
authors.lastname: Payami
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D014335:Tropomyosin / Q000235:genetics*
chemical_list: C000622016:LHFPL2 protein, human; D008565:Membrane Proteins; D011506:Proteins; C490775:TPM1 protein, human; D014335:Tropomyosin