Monogenetic causes do not appear to play a primary role in the majority of PD patients. Although in several studies a positive family history has been associated with an increased risk of PD,105-107 in most cases a clear mode of inheritance could not
be established. PD has therefore long been thought to be a purely sporadic disease, given that familial clustering might simply reflect the effect of shared environmental factors and does not necessarily imply a causal genetic pattern. A significant effect of genetic factors however was found in a study among almost 20,000 male twins, but predominantly in PD with onset before the age of 50 years.108 Since 1997, several
families have been identified with parkinsonism that displays a clear Mendelian mode of inheritance, and familial PD is now estimated to make up about 10% of all cases. Although methodological issues at first sight may not be a major concern in monogenetic disease, the discovery of genetic variants of PD has brought up some definition problems. First, one might wonder whether diseases with such a well- described cause as a single gene mutation are still to be classified as ‘Parkinson disease’, as according to current criteria this requires the parkinsonian syndrome to be idiopathic. While they are usually referred to as ‘familial PD’, it might also be argued that these diseases make up a distinct category of parkinsonian syndromes, especially because many of the familial forms display some atypical features like early onset, dystonia or occurrence of dementia. Second, a considerable variability of clinical manifestations has been found within families with the same gene mutation,
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whereas persons with different genetic defects and different neuropathology may clinically be indistinguishable from each other.109 These findings have led to the
notion of a spectrum of neurodegenerative diseases that partially overlap, where current classification systems do not longer suffice.110
Sporadic cases of PD are generally thought to be the result of complex interactions between different genetic and environmental factors. Many epidemiological studies have tried to identify susceptibility genes that might contribute to PD risk, usually through a candidate gene approach in which polymorphisms of a gene potentially involved in PD are compared between patients and controls. A major issue is that of insufficient statistical power. Given the supposed multifactorial etiology underlying PD, the impact of each individual susceptibility gene is expected to be only modest and large numbers of case-control pairs are required to detect these small effects. Many of the epidemiological studies on susceptibility genes have found no effects, or weak associations that could not be reproduced in a different setting. Apart from the fact that many studies were underpowered, interpretation of results and comparison across studies is also complicated by methodological differences. Genetic association studies may differ with respect to methods and accuracy of PD diagnosis, the selection of control subjects, or choice of a specific polymorphism of the candidate gene under study. Besides, certain polymorphisms, especially those involved in toxin metabolism, might only increase PD risk in combination with particular environmental exposures or lifestyle factors, which are often not assessed.111
Causative genes
So far, six genes have been identified that cause monogenetically inherited PD, three with an autosomal dominant inheritance pattern (alpha-synuclein, UCHL-1 and LRRK-2) and three associated with autosomal recessive disease (parkin, DJ-1 and PINK1). In addition, one potential causative gene (NR4A2) and another four loci with as yet unknown genes are identified which are associated to familial forms of parkinsonism (PARK3, PARK4, PARK9, PARK10). As these genetic advances have been extensively reviewed previously110, 112 we only summarize current genetic knowledge
on monogenetic PD in an updated113-115 table (table 7).
Susceptibility genes
A great number of potential susceptibility genes and their polymorphisms have been investigated in population-based association studies. Most of these were hypothesized to contribute to the risk of sporadic PD based on a biologically argued role in PD pathogenesis. The most frequently studied candidate genes are summarized in table 8 (grouped by supposed underlying pathogenetic mechanism) and include
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Epidemiology of Parkinson disease
Table 8. Most frequently studied candidate genes for PD, grouped by supposed
underlying pathogenetic mechanism
Candidate gene Abbreviation Meta-analysis (ref.)
Dopaminergic metabolism
Monoamine oxidase A / B 111 (MAO-A) NS111
(MAO-B) Sign111
Catechol-O-Methyltransferase 111 (COMT) NS111
Tyrosine hydroxylase 111 (TH) NA
Dopamine transporter 111 (DAT) NS111
Dopamine receptor 2, 4 111 (DRD2) NS111
(DRD4) NS111
Xenobiotic metabolism
Debrisoquine-4-hydroxylase 116,117 (CYP2D6) NS116
N-acetyltransferase 2 111,117 (NAT2) Sign111
Glutathione transferases 111 (GSTT1) Sign111
(GSTM1) NS111 (GSTP1) NS111 (GSTZ1) NS111 Multidrug resistance 118 (MDR-1) NA Mitochondrial metabolism tRNA-glu 111 Sign111 ND2 111 NS111 Homocysteine metabolism Methylenetetrahydrofolate reductase 123,124 (MTHFR) NA Lipoprotein-related
Apolipoprotein E 117,119 (APOE) Sign119
Genes involved in other neurodegenerative diseases
Tau-gene, H1 haplotype 121 Sign121
Hormonal factors
Estrogen receptor gene 122 (ER) NA
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genes involved in dopamine metabolism, mitochondrial metabolism, activation or detoxification of xenobiotics and exogenous toxins, other neurodegenerative diseases, familial PD and other putative relations, such as those to lipoproteins, hormonal factors and homocysteine metabolism.111, 116-124 Unfortunately, many studies were
methodologically flawed in terms of number of included subjects and inappropriate selection of controls. Most have shown either no or only small effects of these candidate genes, and often results have been contradicted or could not be replicated. Meta-analyses have been performed to allow pooling or aggregation of study results in order to increase statistical power. A meta-analysis of 84 association studies of 14 genes showed that polymorphisms in four genes (NAT2, MAOB, GST-T1, and tRNAGlu) were significantly associated with PD.111 Another meta-analysis recently showed that
the ε2 allele of the APOE gene was associated with an increased risk of PD119 and
a meta-analysis of seven case-control studies showed a significantly increased risk of PD in persons homozygous for the tau H1 haplotype.121 The pathophysiologic
significance of these polymorphisms is however not yet clear.