Studies of genetic and environmental influences on Parkinson’s disease
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Little is known about the etiology of PD. Although several PD genes are known, these are thought to be involved in only a small proportion of all PD cases. Some environmental exposures are associated with PD, but there are few consistent findings. The overall aim of this thesis was to examine genetic and environmental factors of importance for PD.
In 12 families with autosomal dominant PD, linkage analyses were performed for 11 candidate loci associated with inherited diseases with clinical symptoms similar to PD or coding for proteins whose function might suggest involvement in the disease mechanism. Parametric lod scores were negative and non-parametric lod scores were close to zero. Nine of the 11 loci were excluded under an autosomal dominant model with reduced penetrance. There was no evidence for linkage to the examined loci considering the non-parametric results, although linkage could not be excluded. A few families showed positive lod scores indicating possible genetic heterogeneity.
a-Synuclein was the first gene genetically linked to PD. In cerebral cortex from eight patients with Lewy body disease and nine controls, the expression of a-Synuclein was assessed using mRNA in situ hybridization. The a-Synuclein probe labeled pyramidal-like cells in lamina III and V in both patients and controls. There was no difference in a-Synuclein mRNA levels between patients and controls, and among patients there was no relationship between a-Synuclein mRNA and number of Lewy bodies. Thus, up regulation of the a-Synuclein gene alone does not seem to explain the accumulation of the protein in Lewy bodies.
Heritability of PD was evaluated using the Swedish Twin Registry. PD cases were identified through telephone interviews and the Inpatient Discharge Register. In total 247 twins with self-reported PD or a PD diagnosis in the Inpatient Discharge Register were identified. There were only two concordant pairs. Thus, environmental factors appear to be most important in the etiology of clinically diagnosed PD.
In a co-twin control study that controls for confounding by genetic and familial environmental factors, the association between smoking and PD was evaluated. Exposure information was obtained prospectively and PD cases (N=476) were identified through the Inpatient Discharge Register and the Cause of Death Register. When controlling for alcohol, coffee and education there was an inverse association between smoking and PD using unrelated controls as well as co-twin controls. Thus, the protective effect of smoking on PD was confirmed. The association does not appear to be explained solely by genetic and familial environmental factors.
This thesis highlights the fact that PD most likely is influenced by various genetic and environmental factors. The failure to demonstrate linkage to any of the candidate loci in the PD families indicates that other genes may be involved. As shown by the twin data, environmental factors are most important for sporadic PD. Exploring interactions between genetic and environmental factors represents a challenge in future studies of PD.
List of scientific papers
I. Zareparsi S, Wirdefeldt K, Burgess CE, Nutt J, Kramer P, Schalling M, Payami H (1999). Exclusion of dominant mutations within the FTDP-17 locus on chromosome 17 for Parkinsons disease. Neurosci Lett. 272(2): 140-2.
https://pubmed.ncbi.nlm.nih.gov/10507561
II. Wirdefeldt K, Burgess CE, Westerberg L, Payami H, Schalling M (2003). A linkage study of candidate loci in familial Parkinsons Disease. BMC Neurol. 3(1): 6.
https://pubmed.ncbi.nlm.nih.gov/12882651
III. Wirdefeldt K, Bogdanovic N, Westerberg L, Payami H, Schalling M, Murdoch G (2001). Expression of alpha-synuclein in the human brain: relation to Lewy body disease. Brain Res Mol Brain Res. 92(1-2): 58-65.
https://pubmed.ncbi.nlm.nih.gov/11483242
IV. Wirdefeldt K, Gatz M, Schalling M, Pedersen NL (2004). No evidence for heritability of Parkinsons disease in Swedish twins. [Submitted]
V. Wirdefeldt K, Gatz M, Pawitan Y, Pedersen NL (2004). Smoking and Parkinsons disease: A study in Swedish twins. [Submitted]
History
Defence date
2004-02-20Department
- Department of Medical Epidemiology and Biostatistics
Publication year
2004Thesis type
- Doctoral thesis
ISBN-10
91-7349-771-1Number of supporting papers
5Language
- eng