A linkage study of candidate loci in familial Parkinson's Disease.
BACKGROUND
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Most cases are sporadic, however familial cases do exist. We examined 12 families with familial Parkinson's disease ascertained at the Movement Disorder clinic at the Oregon Health Sciences University for genetic linkage to a number of candidate loci. These loci have been implicated in familial Parkinson's disease or in syndromes with a clinical presentation that overlaps with parkinsonism, as well as potentially in the pathogenesis of the disease.


METHODS
The examined loci were PARK3, Parkin, DRD (dopa-responsive dystonia), FET1 (familial essential tremor), BDNF (brain-derived neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), Ret, DAT1 (the dopamine transporter), Nurr1 and Synphilin-1. Linkage to the alpha-synuclein gene and the Frontotemporal dementia with parkinsonism locus on chromosome 17 had previously been excluded in the families included in this study. Using Fastlink, Genehunter and Simwalk both parametric and model-free non-parametric linkage analyses were performed.


RESULTS
In the multipoint parametric linkage analysis lod scores were below -2 for all loci except FET1 and Synphilin-1 under an autosomal dominant model with incomplete penetrance. Using non-parametric linkage analysis there was no evidence for linkage, although linkage could not be excluded. A few families showed positive parametric and non-parametric lod scores indicating possible genetic heterogeneity between families, although these scores did not reach any degree of statistical significance.


CONCLUSIONS
We conclude that in these families there was no evidence for linkage to any of the loci tested, although we were unable to exclude linkage with both parametric and non-parametric methods.
Wirdefeldt
Karin
K
Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. karin.wirdefeldt@mep.ki.se
Burgess
Catherine E
CE
Westerberg
Lisa
L
Payami
Haydeh
H
Schalling
Martin
M
D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins; D020329:Essential Tremor / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage / Q000235:genetics*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D008126:Lod Score; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000235:genetics; D009414:Nerve Growth Factors / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C493214:SLC6A3 protein, human; C118958:SNCAIP protein, human; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein