Hill-Burns, Erin M.Ross, Owen A.Wissemann, William T.Soto-Ortolaza, Alexandra I.Zareparsi, SepidehSiuda, JoannaLynch, TimothyWszolek, Zbigniew K.Silburn, Peter A.Mellick, George D.Ritz, BeateScherzer, ClemensZabetian, Cyrus P.Factor, Stewart A.Breheny, Patrick J.Payami, Haydeh2017-02-182016Hill-Burns, E. M., O. A. Ross, W. T. Wissemann, A. I. Soto-Ortolaza, S. Zareparsi, J. Siuda, T. Lynch, et al. 2016. “Identification of genetic modifiers of age-at-onset for familial Parkinson’s disease.” Human Molecular Genetics 25 (17): 3849-3862. doi:10.1093/hmg/ddw206. http://dx.doi.org/10.1093/hmg/ddw206.0964-6906http://nrs.harvard.edu/urn-3:HUL.InstRepos:30371016Parkinson’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.en-USJournal Article2017-02-1810.1093/hmg/ddw206