Search for Genetic Factors in Parkinson's Disease - II

The recent discovery of genetic mutations causing Mendelian forms of
Parkinson's disease (PD), such as those in the a-synuclein, parkin, DJ-1,
PINK1, and the LRRK2 gene, have provided novel clues into the mechanisms of
this disease. However, none of these mutations is common in the Dutch
population, and the etiology of the disease remains here almost totally
unknown. Recent large­ scale genome-wide association studies (GWA) highlighted
the role of common variants in several loci as risk factors for the sporadic
forms of this disease in the population of European ancestry. However, these
variants possess very low penetrance, and while they only account for a portion
of the disease heritability at the population level, they do not explain the
familial aggregation of PD.
Taken together, these data suggest that most of the genetic determinants of PD
remain to be identified in several populations including the Dutch one, and
particularly, additional highly-penetrant mutations remain to be discovered in
one or several PD­ causing genes. The identification of further PD-causing
genes is urgently needed by the research community at large, as these genes
might provide further important clues for the dissection of the disease
pathogenesis, and for the identification of biomarkers and of innovative
therapeutic targets.
In the post-GWA era, the focus on families with PD, likely harboring
high-penetrance mutations is therefore gaining novel momentum. The Dutch
population appears very suitable for family-based genetic studies, because
large families are still frequently observed, family relationships are kept
strong, and excellent genealogical records are available to researchers.

The objectives of this study are:
1. to identify new genetic variants causing or predisposing to PD;
2. to characterize the clinical phenotype in PD associated to specific genetic
variants;
3. to investigate the molecular mechanisms of PD in patients with specific
genetic variants

The study involves the following steps:
1. recruitment of families segregating the disease of interest (PD), sporadic
PD cases of early-onset, and unrelated controls;
2. detailed characterization of the clinical phenotype;
3. analysis of known PD-causing genes;
4. genetic linkage analysis and next generation sequencing (whole exome, whole
genome sequencing) to identify new disease-causing genes;
5. screening of the entire series of cases (familial and sporadic PD) to
characterize the phenotype associated to newly identified genes;
6. investigating the molecular mechanisms of disease using in-vitro neuronal
and glial cell models obtained from the differentiation of induced pluripotent
stem cells (iPS) from patient derived cells with specific genetic mutations and
unrelated controls

Participating in this study only brings negligible risks and we expect no
serious adverse events. Peripheral venous blood sampling (max. 20 ml) is a
routine minimally-invasive procedure which will be performed only by highly
experienced and certified nurses or physicians. Further, our neurologic and
neuropsychological assessments are highly structured and have been extensively
tested, without any known serious adverse events.

Adverse events may include minor bruising or local tenderness at the site of
venous blood sampling. All patients will be monitored to ensure proper
hemostasis.
A selection of patients and family members will be asked to give consent for a
skin biopsy. This is a minimally invasive procedure that is not very painful
but might produces some discomfort. Prior to the biopsy, the skin is treated
with a creme as a local anesthetic. Some scar tissue could form and there is a
small chance to develop an infection.
During interviews and neuropsychological testing, the patient will be fully
aware of his/her right to terminate the testing at any time and for any reason.