Send to

Choose Destination
Hum Mol Genet. 2016 Sep 1;25(17):3849-3862. doi: 10.1093/hmg/ddw206. Epub 2016 Jul 11.

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

Author information

Department of Neurology, University of Alabama at Birmingham, AL, USA.
Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA.
Department of Molecular and Medical Genetics, Oregon Health & Sciences University, Portland, OR, USA.
Department of Neurology, Medical University of Silesia, Katowice, Poland.
Dublin Neurological Institute at the Mater Misericordiae University Hospital, Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland.
Department of Neurology, Mayo Clinic Jacksonville, FL, USA.
Eskitis Institute for Drug Discovery, Griffith University, Queensland, Australia.
Department of Epidemiology, Fielding School of Public Health and Neurology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
The Neurogenomics Laboratory, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA, USA.
VA Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA, USA.
Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
Department of Biostatistics, University of Iowa, Iowa City, IA, USA.
Department of Neurology, University of Alabama at Birmingham, AL, USA
Center for Genomic Medicine, HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center