Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

in Movement Disorders (2023), n/a(n/a),

Abstract Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties ... [more ▼]

Abstract Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). Conclusions We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. [less ▲]

Genome-wide Association and Meta-analysis of Age-at-Onset in Parkinson Disease: Evidence From COURAGE-PD Consortium 10.1212/WNL.0000000000200699

in Neurology (2022)

Background and Objectives: Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson\textquoterights disease (PD), which could be ... [more ▼]

Background and Objectives: Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson\textquoterights disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.Methods: A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson\textquoterights Disease (COURAGE-PD) consortium. This was followed up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC).Results: The COURAGE-PD included a cohort of 8,535 patients with PD (91.9\%: Europeans, 9.1\%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation of females (40.2\%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE=0.057). None of the loci reached genome-wide significance (P\<5x10-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as genetic determinant of AAO of PD with Bonferroni-corrected nominal levels of significance (P\<0.025): (rs34311866:β(SE)COURAGE=0.477(0.203), PCOURAGE=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal=25,950) led to the identification of two genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361:β(SE)COURAGE+IPDGC=0.720(0.122), PCOURAGE+IPDGC=3.13x10-9) and a novel BST1 locus (rs4698412:β(SE)COURAGE+IPDGC=-0.526(0.096), PCOURAGE+IPDGC=4.41x10-8).Discussion: Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD. [less ▲]

Mendelian randomization study of smoking, alcohol, and coffee drinking in relation to Parkinso's disease

in Journal of Parkinson's Disease (2021)

Background:Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility ... [more ▼]

Background:Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective:To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods:We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results:We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion:Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power. [less ▲]

Editorial: Celebrating the Diversity of Genetic Research to Dissect the Pathogenesis of Parkinson's Disease

in Frontiers in Neurology (2021), 12

Parkinson's disease (PD) is the fastest growing neurological disorder worldwide, taking into account age-standardized rates for prevalence, disability and deaths (1). PD is characterized by a clinical ... [more ▼]

Parkinson's disease (PD) is the fastest growing neurological disorder worldwide, taking into account age-standardized rates for prevalence, disability and deaths (1). PD is characterized by a clinical symptomatology involving both motor and non-motor symptoms. According to the Global Burden of Disease study (2018), the global burden of this disorder has more than doubled over the past two decades from 2.5 million patients in 1990 to 6.1 million patients in 2016 (2). In this editorial and eBook, we highlight the research done on PD by members of a global consortium known as the Genetic Epidemiology of Parkinson's disease (GEoPD) Consortium. We begin the editorial by providing a brief history of how GEoPD was started and how it has subsequently developed into an international endeavor. We then briefly summarize the completed and ongoing projects, and conclude with the future vision of this unique consortium. [less ▲]

Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study.

in Neurobiology of Aging (2017), 49

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed ... [more ▼]

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted. [less ▲]

Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease.

in Neurology (2014)

OBJECTIVES: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO ... [more ▼]

OBJECTIVES: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort. METHODS: C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia. RESULTS: A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low. CONCLUSIONS: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease. [less ▲]

Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.

in Movement Disorders (2013), 28(12), 1740-4

BACKGROUND: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease ... [more ▼]

BACKGROUND: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's 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 Parkinson's disease. METHODS: The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. RESULTS: Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. CONCLUSIONS: Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. [less ▲]

Large-scale replication and heterogeneity in Parkinson disease genetic loci.

in Neurology (2012), 79(7), 659-67

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 ... [more ▼]

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 Parkinson's 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 (I(2) 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. [less ▲]

Role of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease.

in Neurobiology of Aging (2011), 32(11), 21081-5

Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for ... [more ▼]

Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's 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. [less ▲]

Biological effects of the PINK1 c.1366C>T mutation: implications in Parkinson disease pathogenesis.

in Neurogenetics (2007), 8(2), 103-9

PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T ... [more ▼]

PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T transition. The interpretation of this finding remains controversial. Furthermore, the c.1366C>T mutation is associated with lower levels of PINK1 transcript, raising the question of whether mRNA levels correlate with the clinical status. We sequenced genomic DNA and copy DNA (cDNA) from 20 subjects carrying the c.1366C>T mutation in the homozygous (n = 5) or heterozygous (n = 15) state. In 17 mutation carriers, messenger RNA (mRNA) was quantified by real-time PCR using four different assays (PINK1 exon 5-6 or exon 7-8 relative to control genes SDHA or YWHAZ). Genomic sequencing confirmed the presence and zygosity of PINK1 mutations. cDNA sequencing in heterozygous mutation carriers revealed a strong wild-type and a much weaker or almost absent mutant signal, whereas in the homozygous patients, only the mutant signal was detected. Homozygous and heterozygous carriers showed PINK1 mRNA levels relative to a reference gene in the range of 0.1-0.2 and 0.5-0.6, respectively, compared with values of 0.9-1.0 in mutation-negative individuals. Treatment of lymphoblasts from a heterozygous mutation carrier with cycloheximide markedly increased the mutant transcript signal. We conclude that the recurrent PINK1 c.1366C>T mutation exerts a major effect at the mRNA level (80-90% reduction), most likely via nonsense-mediated mRNA decay. The absence of correlation between PINK1 mRNA levels and clinical status in heterozygous mutation carriers suggests that other genetic or environmental factors play a role in determining the phenotypic variability associated with the c.1366C>T mutation. [less ▲]