Karin Wirdefeldt

Epidemiology and etiology of Parkinson's disease: a review of the evidence

The etiology of Parkinson’s disease (PD) is not well understood but likely to involve both genetic and environmental factors. Incidence and prevalence estimates vary to a large extent—at least partly due to methodological differences between studies—but are consistently higher in men than in women. Several genes that cause familial as well as sporadic PD have been identified and familial aggregation studies support a genetic component. Despite a vast literature on lifestyle and environmental possible risk or protection factors, consistent findings are few. There is compelling evidence for protective effects of smoking and coffee, but the biologic mechanisms for these possibly causal relations are poorly understood. Uric acid also seems to be associated with lower PD risk. Evidence that one or several pesticides increase PD risk is suggestive but further research is needed to identify specific compounds that may play a causal role. Evidence is limited on the role of metals, other chemicals and magnetic fields. Important methodological limitations include crude classification of exposure, low frequency and intensity of exposure, inadequate sample size, potential for confounding, retrospective study designs and lack of consistent diagnostic criteria for PD. Studies that assessed possible shared etiological components between PD and other diseases show that REM sleep behavior disorder and mental illness increase PD risk and that PD patients have lower cancer risk, but methodological concerns exist. Future epidemiologic studies of PD should be large, include detailed quantifications of exposure, and collect information on environmental exposures as well as genetic polymorphisms.

Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles.

The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups. These findings have an impact on our views of genotypic and phenotypic diversity in monozygotic twins and suggest that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci. Our results also imply that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics.

Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study

BACKGROUND Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinsons disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. METHODS LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinsons Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. FINDINGS 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012). INTERPRETATION The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. FUNDING Michael J Fox Foundation and National Institutes of Health.

No evidence for heritability of Parkinson disease in Swedish twins

Background: Although several genes are implicated in Parkinson disease (PD), they explain only a small fraction of cases. The etiology of most cases is yet unknown. Objective: To evaluate heritability of PD in same-sexed and opposite-sexed twin pairs in the Swedish Twin Registry (STR). Methods: All twins in the STR born in 1950 or earlier and alive in 1998 (n = 50,150) were included. The authors screened 33,780 twins in 14,082 pairs for PD by telephone interviews and linked the STR to the Swedish Inpatient Discharge Register. Two hundred forty-seven twins with self-reported PD or a PD diagnosis in the Inpatient Discharge Register (called “possible PD”) and 517 twins who reported parkinsonian symptoms or use of antiparkinsonian medication (“suspected parkinsonism or movement disorder”) were identified. Results: For possible PD, there were only two concordant pairs, both female dizygotic. Similarly, concordances were low in all zygosity groups when the definition of affected was expanded to include twins with suspected parkinsonism or movement disorder in addition to possible PD. Sex differences in the relative importance of genetic and environmental effects were indicated with a marginally larger familial component in women. The best-fitting structural equation model included only environmental components of variance. Conclusions: These results suggest that environmental factors are most important in the etiology of PD. Compared with other complex diseases, the importance of genetic effects in PD is notably low. The preponderance of discordant twin pairs provides an ideal material for studying environmental risk factors and potential genotype-by-environment interaction.

Risk and protective factors for Parkinson's disease: a study in Swedish twins.

Many studies have shown a protective effect of cigarette smoking on Parkinsons disease. However, criticism has been raised concerning confounding by genetic factors. We investigated the associations between Parkinsons disease and smoking, alcohol, coffee, area of living, and education in a co‐twin control study. Because twins are matched for genetic and familial environmental factors, this design controls for confounding by these factors. We also examined control subjects unrelated to cases. Exposure information was taken from questionnaires answered in the 1960s and 1970s. Parkinsons disease cases were identified through the Swedish Inpatient Discharge Register (IDR) and the Cause of Death Register. In the unrelated control subject comparison, 476 Parkinsons disease cases and 2,380 control subjects were included. In the co‐twin control comparison, 415 same‐sex twin pairs were included. There was an inverse association between smoking and Parkinsons disease using unrelated control subjects and co‐twin control cases. There was no association between Parkinsons disease and alcohol, coffee, or area of living. High educational level was associated with Parkinsons disease in the unrelated control subject comparison but not in the co‐twin control comparison. We confirm the protective effect of smoking on Parkinsons disease and establish that the association is only partially explained by genetic and familial environmental factors. Ann Neurol 2004

Large-scale replication and heterogeneity in Parkinson disease genetic loci

Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Methods: Investigators from the Genetic Epidemiology of Parkinsons Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78–0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14–1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity. Neurology® 2012;79:659–667

Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson’s disease: a large-scale international study

BACKGROUND A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinsons disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain. METHODS Investigators from three Michael J Fox Foundation for Parkinsons Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinsons disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies. FINDINGS In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966. INTERPRETATION Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinsons disease.

Independent and joint effects of the MAPT and SNCA genes in Parkinson disease.

We studied the independent and joint effects of the genes encoding alpha‐synuclein (SNCA) and microtubule‐associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta‐analysis of individual data from case–control studies participating in the Genetic Epidemiology of Parkinsons Disease (GEO‐PD) consortium.

Heritability of Parkinson disease in Swedish twins: a longitudinal study.

Previous twin studies report no heritability of Parkinsons disease (PD) based on cross sectional information. Here, we apply a longitudinal design and re-evaluate cross sectional data in the population-based Swedish Twin Registry (STR) using clinical as well as hospital discharge and cause of death diagnoses. In the longitudinal analyses (based on 46,436 individuals), we identified 542 twins with PD and 65 twins with Parkinsonism. Concordance rates for PD were 11% for monozygotic and 4% for same-sexed dizygotic twin pairs, with a heritability estimate of 34%. Concordance rates for PD or parkinsonism were 13% for monozygotic and 5% for same-sexed dizygotic twin pairs, with a heritability estimate of 40%. In the cross sectional analyses (based on 49,814 individuals), we identified 287 twins with PD and 79 twins with parkinsonism. Concordance rates for PD were 4% for monozygotic and same-sexed dizygotic twin pairs and 0 for opposite-sexed twin pairs. Concordance rates for PD or parkinsonism were somewhat higher but the heritability estimate was nonsignificant. Our longitudinal analyses demonstrate that PD and parkinsonism are modestly heritable.

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.