We wanted to compare cancer incidence rates between Parkinsons disease (PD) patients and persons without PD, as well as between siblings of these groups. We conducted a family-based matched cohort study based on nationwide Swedish health registries and the Swedish Multi-Generation Register. We assessed risk of incident cancer in PD patients (n = 11,786) during 1964-2009 versus a matched cohort of PD-free individuals (n = 58,930) and in siblings of PD patients (n = 16,841) versus siblings of PD-free individuals (n = 84,205). Hazard ratios with 95% confidence intervals were estimated using Cox proportional hazards regression. Cancer occurrence was slightly higher in PD patients than in PD-free individuals (hazard ratio (HR) = 1.05, 95% confidence interval (CI): 1.00, 1.10), largely because of cancers arising within 1 year before or after the index date for PD, but risk of smoking-related cancers was lower (HR = 0.87, 95% CI: 0.79, 0.96). PD patients had a higher risk of melanoma both up to 1 year before the PD index date (HR = 1.53, 95% CI: 1.23, 1.91) and from 1 year after the index date onward (HR = 1.46, 95% CI: 1.01, 2.10). In the sibling comparison, cancer occurrence was largely similar. These results indicate that melanoma risk is higher among PD patients and that mechanisms other than familial ones explain the association.
The best validated susceptibility variants for Parkinsons disease are located in the ?-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ? 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinsons disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.
To investigate the contribution of shared familial risk to the co-occurrence of dementia and parkinsonism by studying familial co-aggregation of Alzheimers disease (AD) and Parkinsons disease (PD). Using Swedish population-based registers we constructed two cohorts; a first-degree relative cohort of persons born 1932-1960 (n = 2,775,332) and a spouse cohort of persons born 1890-1960 (n = 4,736,006). Study persons were followed up between 1969 and 2009 in the National Patient and Cause of Death Registers. We modeled the association between incidence of disease and having at least one affected relative using Cox proportional hazard regression that estimated hazard ratios (HRs) with 95 % confidence intervals (CIs) adjusted for age, sex and number of relatives. Within each disorder; dementia, AD, parkinsonian disorders and PD, there was a strong association between risk of disease and having at least one affected sibling or parent. There was also a modest shared familial risk between the diseases; risk of parkinsonian disorders was associated with having a sibling with AD (HR 1.35, 95 % CI 1.11-1.65) and risk of dementia was associated with having a sibling with PD (HR 1.20, 95 % CI 1.02-1.41). There were no meaningful familial risks among spouses. The risk of co-occurring dementia in PD was considerably increased (HR 2.83, 95 % CI 2.76-2.89). There is strong familial aggregation within dementia, AD, parkinsonian disorders and PD, and modest familial co-aggregation between dementia and parkinsonism. Thus, co-occurrence of dementia and parkinsonism is not primarily caused by shared familial risk between AD and PD.
Comorbidity of cancer with ALS has been studied previously. Detailed description of the temporal relationship between cancer and ALS is, however, lacking. We conducted a nested case-control study of ALS in Sweden during 1987-2009, including 5481 cases of ALS identified from the Swedish Patient Register and 27,405 controls randomly selected from the general Swedish population. Odds ratios (ORs) for association of ALS with previous cancer diagnosis and incidence rate ratios (IRRs) of cancer after diagnosis were calculated to compare ALS patients with ALS-free individuals. Overall, a previous cancer diagnosis was not associated with subsequent risk of ALS (OR 1.00; 95% CI 0.91-1.10). No overall association was observed for any specific cancer type. An increased risk of ALS was observed during the first year after cancer diagnosis (OR 1.50; 95% CI 1.17-1.92). In contrast, a lower risk of cancer was observed in ALS patients after diagnosis compared with ALS-free individuals (IRR 0.84; 95% CI 0.69-1.02). The risk reduction was seen primarily two or more years after ALS diagnosis (IRR 0.64; 95% CI 0.45-0.88). Our results provide no evidence for comorbidity of cancer and ALS overall. Surveillance biases seem the most likely explanation for the limited associations detected.
Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinsons disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinsons disease.
Severe infections may lead to chronic inflammation in the central nervous system (CNS) which may in turn play a role in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). The relentless progression and invasive supportive treatments of ALS may on the other hand induce severe infections among ALS patients.
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.
Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinsons disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium. A total of 5 single nucleotide polymorphisms (3 in the promoter region and 2 in the 3 untranslated region [UTR]) were genotyped. Fixed as well as random effect models were used to provide summary risk estimates of SPR variants. A total of 19 sites provided data for 6547 cases and 9321 controls. Overall odds ratio estimates varied from 0.92 to 1.01. No overall association with the SPR gene using either fixed effect or random effect model was observed in the studied population. I(2) Metric varied from 0% to 36.2%. There was some evidence for an association for participants of North European/Scandinavian descent with the strongest signal for rs1876487 (odds ratio = 0.82; p value = 0.003). Interestingly, families which were used to map the PARK3 locus, have Scandinavian ancestry suggesting a founder effect. In conclusion, this large association study for the SPR gene revealed no association for PD worldwide. However, taking the initial mapping of the PARK3 into account, the role of a population-specific effect warrants consideration in future studies.
The etiology of Parkinsons 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.
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.
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.
Several occupations and occupational exposures have been investigated for associations with Parkinsons disease. Common findings are increased risk associated with pesticide exposure and no association between Parkinsons disease and welding.
High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinsons disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinsons disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3 kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I(2) estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest. This largest association study performed to define the role of any gene in the pathogenesis of Parkinsons disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide.
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.
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.
Swedish population-based national health registers are widely used data sources in epidemiological research. Register-based diagnoses of Parkinsons disease have not been validated against clinical information.
Related JoVE Video
Journal of Visualized Experiments
What is Visualize?
JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.
How does it work?
We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.
Video X seems to be unrelated to Abstract Y...
In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.