Fine-mapping and candidate gene investigation within the PARK10 locus.
Herein, we investigate whether single-nucleotide polymorphisms (SNPs) across the PARK10 locus are associated with susceptibility to Parkinson's disease (PD) or age at onset (AAO) of disease. One hundred and eighty-eight SNPs were genotyped across the PARK10 locus in 180 PD patients and 180 controls from central Norway (stage 1). We then used the linkage disequilibrium (LD) structure from stage 1 to select 75 SNPs for genotyping in 186 patients and 186 controls from Ireland (stage 2). Nineteen SNPs were selected from this and previous studies for follow-up in an extended Norwegian series (530 patients and 1142 controls), the Irish series and a US series (221 patients and 221 controls) (stage 3). After correction for multiple testing, markers within ubiquitin specific peptidase 24 (USP24) are significantly associated with PD within Norwegian, Irish, and US series combined (rs13312: odds ratio (OR) 0.78, P<0.001; rs487230: OR 0.80, P=0.001). Independently, the association for rs13312 is strongest in the extended Norwegian series (OR 0.76, P=0.005), although not significant after correction for multiple testing (P< or =0.003 is considered significant). ORs in the Irish series are almost identical, and a similar but a weaker effect was observed for the US series. No marker showed consistent association with AAO. Our data indicate that genetic variability in USP24 is associated with PD. Although our work extends and confirms a previous report, the observed effect size does not explain the PARK10 linkage peak.
Department of Neuroscience and Neurology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. haugarvoll@gmail.com
Kristoffer
K
Haugarvoll
Mathias
M
Toft
Lisa
L
Skipper
Michael G
MG
Heckman
Julia E
JE
Crook
Alexandra
A
Soto
Owen A
OA
Ross
Mary M
MM
Hulihan
Jennifer M
JM
Kachergus
Sigrid B
SB
Sando
Linda R
LR
White
Timothy
T
Lynch
J Mark
JM
Gibson
Ryan J
RJ
Uitti
Zbigniew K
ZK
Wszolek
Jan O
JO
Aasly
Matthew J
MJ
Farrer
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007494:Ireland; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009664:Norway; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide