A haplotype at the PARK3 locus influences onset age for Parkinson's disease -: The GenePD study

Objective: To identify a haplotype influencing onset age for Parkinson's disease ( PD) in the PARK3 region on chromosome 2p13. Methods: Single nucleotide polymorphisms ( SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families. Results: TT homozygotes for rs1876487 ( G/ T) had a 7.4- year younger mean age at onset ( p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase ( 7,8- dihydrobiopterin: NADP + oxidoreductase) ( SPR) gene, rs1876487 ( p = 0.02) and rs1150500 ( p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394. The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP - rs2421095, rs1876487, rs1561244 - revealed an association with onset age ( p = 0.023) and a haplotype of A- T- G alleles was associated with younger onset for PD ( p = 0.005). Conclusions: A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.