Evidence for novel loci for late-onset Parkinson's disease in a genetic isolate from the Netherlands.
We studied patients with idiopathic Parkinson's disease (PD) from an isolated population in the Netherlands aiming to map gene(s) involved in PD susceptibility. A total of 109 parkinsonism patients were independently ascertained, of whom 62 presented late-onset, idiopathic PD. Genealogical research showed that 45 index cases with idiopathic PD were linked to a common ancestor, indicating familiar clustering among the patients. This strong familial clustering was highly significant (P = 0.005) when compared to random controls from the same population. We performed a genome wide scan using 382 polymorphic markers in 44 distantly related PD patients plus 112 unaffected first-degree relatives and spouses. Our genome wide association analysis (DISLAMB) revealed evidence of association at a nominal P-value < 0.01 for markers D2S2333, D4S405, D9S158, D13S153. Other regions on chromosomes 3p, 4q, 14q, 17p and 17q were found at a significance level of P < 0.05. In a follow-up study, we investigated all the positive regions using a denser marker set and a larger sample (total of 630 individuals including all late-onset PD patients). The strongest evidence for association remained for the 9q and 14q region. A significant association was found for marker D9S1838 (OR = 2.0, 95% CI 1.1-3.5, P = 0.014) and D14S65 (OR = 3.2, 95% CI 1.7-6.1, P < 0.001). Moreover, a common haplotype with excess of sharing among late-onset PD cases was observed on both regions. Our results suggest the existence of two loci influencing PD susceptibility on chromosome 9q and 14q.
Bertoli-Avella
Aida M
AM
Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, PO Box 1738, 3000 DR, Rotterdam, The Netherlands. a.bertoliavella@erasmusmc.nl
Dekker
Marieke C J
MC
Aulchenko
Yurii S
YS
Houwing-Duistermaat
Jeanine J
JJ
Simons
Erik
E
Testers
Leon
L
Pardo
Luba M
LM
Rademaker
Tessa A M
TA
Snijders
Pieter J L M
PJ
van Swieten
John C
JC
Bonifati
Vincenzo
V
Heutink
Peter
P
van Duijn
Cornelia M
CM
Oostra
Ben A
BA
D017668:Age of Onset; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14; D002899:Chromosomes, Human, Pair 9; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005828:Genetics, Population; D015894:Genome, Human; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009426:Netherlands / Q000453:epidemiology; D016017:Odds Ratio; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D051844:alpha-Synuclein / Q000235:genetics
D051844:alpha-Synuclein