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

摘要

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 (NGRG); 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 5ql4.1 (Pngrc=3E-8, PRepiication = 2E-5, PNGRC+Replication=1E-11), the second mapped to TPM1 on 15q22.2 (PNGRC = 8E-9, PRepiiCation - 2E- * 4, Pngrc+Replication=9E-11). The variants that were associated with accelerated onset had low frequencies (<0.02). The LHFPL2