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 journalArticlepeer-review

22 Scopus citations


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
Issue number17
StatePublished - Sep 1 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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