Parkinson Disease Susceptibility Loci Research Articles

Fine-mapping of Parkinson's disease susceptibility loci identifies putative causal variants.

Recent genome-wide association studies have identified 78 loci associated with Parkinson’s disease susceptibility but the underlying mechanisms remain largely unclear. To identify likely causal variants for disease risk, we fine-mapped these Parkinson’s-associated loci using four different fine-mapping methods. We then integrated multi-assay cell type–specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus single nucleotide polymorphism (SNPs) that disrupt LRRK2 and FCGR2A regulatory elements in microglia, an MBNL2 enhancer in oligodendrocytes, and a DYRK1A enhancer in neurons. This genome-wide functional fine-mapping investigation of Parkinson’s disease substantially advances our understanding of the causal mechanisms underlying this complex disease while avoiding focus on spurious, non-causal mechanisms. Together, these results provide a robust, comprehensive list of the likely causal variants, genes and cell-types underlying Parkinson’s disease risk as demonstrated by consistently greater enrichment of our fine-mapped SNPs relative to lead GWAS SNPs across independent functional impact annotations. In addition, our approach prioritized an average of 3/85 variants per locus as putatively causal, making downstream experimental studies both more tractable and more likely to yield disease-relevant, actionable results. Large-scale studies comparing individuals with Parkinson’s disease to age-matched controls have identified many regions of the genome associated with the disease. However, there is widespread correlation between different parts of the genome, making it difficult to tell which genetic variants cause Parkinson’s and which are simply co-inherited with causal variants. We therefore applied a suite of statistical models to identify the most likely causal genetic variants (i.e. fine-mapping). We then linked these genetic variants with epigenomic and gene expression signatures across a wide variety of tissues and cell types to identify how these variants cause disease. Therefore, this study provides a comprehensive and robust list of cellular and molecular mechanisms that may serve as targets in the development of more effective Parkinson’s therapeutics.

Identifying Genetic Markers Associated with the Progression of Cognitive Decline in Parkinson's Disease: A Call Out for Replication.

Among patients with Parkinson's disease (PD), PD dementia (PDD) is among the greatest detriments to quality of life, and it is a hallmark of the progression of PD, making patient follow-up essential over time. To date, there have been three large, longitudinal, genome-wide studies for genetic determinants of dementia: Iwaki et al.1 (n = 4093, 12 cohorts), Tan et al.2 (n = 3364, 3 cohorts), and most recently, Liu et al.3 These authors have described longitudinal genome-wide survival studies in the search for genetic variants that influence the progression of PD to dementia endpoints in 3821 patients of European ancestry from 15 different cohorts in a span of 31 years. The most relevant outcome of this work is the discovery of a potential novel genome-wide signal within the RIMS2 locus, putatively associated with PDD. The RIMS2 variant was highlighted as a stronger predictor of PDD than GBA and APOE, which, surprisingly, did not reach genome-wide significance. The role of RIMS2 on PDD warrants further study because of the fact that: (1) its rare allele frequency could limit imputation accuracy4 and statistical power, and (2) it is not reported to be in linkage disequilibrium with any coding variant or act as a quantitative trait locus of expression or splicing of any gene. Because heterogeneity values across the 15 cohorts under study were not specified and authors report some genomic inflation (used to correct the test statistics downward), analyzing the contribution of RIMS2 to cognitive progression for each cohort is essential to ascertain that inflation is due to polygenicity (multigenic inheritance) and not population substructure (differences in allele frequencies between cases and controls as a result of systematic differences in ancestry) or other confounders. Two other suggestive association signals were reported in the TMEM108 and WWOX loci. Previous genome-wide association studies aimed at exploring cognitive progression in PD did not nominate any of these three loci.1, 2 In this study,3 the reported effect estimate for RIMS2 is massive, with a relatively small sample size for low minor allele frequency of the rare variant of interest. Previous studies should have detected this association if the effect estimate generalized across datasets. Moreover, cognitive polygenic hazard scores revealed that 18% of investigated cases carried at least one of the three nominated prognosis locus variants. However, the best model to predict whether a patient will experience development of dementia within 10 years from disease onset also included GBA and APOE loci. The authors also performed a polygenic risk score including 90 PD susceptibility loci associated with dementia prognosis, but no significant association was detected, indicating that PD progression may be controlled by separate genetic mechanisms and influenced by specific not yet discovered loci.5 This study3 represents a potential yet debatable step forward in our understanding of genetic markers associated with PD progression to dementia. Further robust replication in additional cohorts of diverse ancestry populations is imperative to confidently link this locus to PDD. This work was carried out with the support and guidance of the ‘GP2 Trainee Network’ which is part of the Global Parkinson's Genetics Program and funded by the Aligning Science Across Parkinson's (ASAP) initiative. Both authors contributed equally to the initial manuscript preparation, manuscript editing, and commentary. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Meta-analysis of whole-exome sequencing data from two independent cohorts finds no evidence for rare variant enrichment in Parkinson disease associated loci.

Parkinson disease (PD) is a complex neurodegenerative disorder influenced by both environmental and genetic factors. While genome wide association studies have identified several susceptibility loci, many causal variants and genes underlying these associations remain undetermined. Identifying these is essential in order to gain mechanistic insight and identify biological pathways that may be targeted therapeutically. We hypothesized that gene-based enrichment of rare mutations is likely to be found within susceptibility loci for PD and may help identify causal genes. Whole-exome sequencing data from two independent cohorts were analyzed in tandem and by meta-analysis and a third cohort genotyped using the NeuroX-array was used for replication analysis. We employed collapsing methods (burden and the sequence kernel association test) to detect gene-based enrichment of rare, protein-altering variation within established PD susceptibility loci. Our analyses showed trends for three genes (GALC, PARP9 and SEC23IP), but none of these survived multiple testing correction. Our findings provide no evidence of rare mutation enrichment in genes within PD-associated loci, in our datasets. While not excluding that rare mutations in these genes may influence the risk of idiopathic PD, our results suggest that, if such effects exist, much larger sequencing datasets will be required for their detection.

Skewed X-chromosome inactivation and XIST locus methylation levels do not contribute to the lower prevalence of Parkinson's disease in females

Parkinson's disease (PD) is a degenerative disorder of the nervous system and the cause of the majority of sporadic cases is unknown. Females are relatively protected from PD as compared with males and linkage studies suggested a PD susceptibility locus on the X chromosome. To determine a putative association of skewed X-chromosome inactivation (XCI) and PD, we examined XCI patterns using a human androgen receptor gene–based assay (HUMARA) and did not identify any association of skewed or random X inactivation with clinical heterogeneity among female PD patients. In addition, we sought to determine methylation-specific changes at the X-inactive specific transcript (XIST) locus, which is known to be responsible for initiating X inactivation. We observed a trend towards hypomethylation in the gene body region of the XIST locus in PD females which did not reach significance. Furthermore, we extended our analysis of DNA methylation across the entire X-chromosome which revealed no methylation-specific differences between PD females and healthy controls. Thus, we propose that skewed XCI and methylation levels on the entire X chromosome did not reveal changes which could account for the decreased PD susceptibility in females or suitable to use as a biomarker.

High-Resolution Melting Analysis as a Developed Method for Genotyping the PD Susceptibility Loci in LRRK2 Gene.

Single-nucleotide polymorphisms (SNPs) have been reported as a highly relevant point for the mechanisms of Parkinson's disease (PD). The invention of saturating dye makes it possible to identify heteroduplex DNA without redistribution during melting, which allows using high-resolution melting (HRM) to detect SNPs. However, the HRM analysis for detection of those SNPs associated with PD was rarely applied. Two SNPs, G2385R and R1628P, located in leucine-rich repeat kinase 2 (LRRK2) gene were individually and multiplexedly genotyped using HRM analysis. The sequence variant observed in unexpected HRM curves was confirmed by DNA sequencing. HRM analysis identified successfully all genotypes both on R1628P and G2385R loci. The unexpected HRM curves appeared in R1628P amplicon generated from combinations of R1628P and rs11176013 loci. A multiplexed HRM assay that genotyped R1628P, rs11176013, and G2385R loci was efficiently established. The present HRM assay is a reliable and rapid method for genotyping R1628P and G2385R loci in LRRK2 gene, and multiplex HRM analysis results in high throughput and has the potential to facilitate a wide range of genotyping studies on PD susceptibility genes.

Association of Parkinson disease risk loci with mild parkinsonian signs in older persons.

Parkinsonian motor signs are common in the aging population and are associated with adverse health outcomes. Compared with Parkinson disease (PD), potential genetic risk factors for mild parkinsonian signs have been largely unexplored. To determine whether PD susceptibility loci are associated with parkinsonism or substantia nigra pathology in a large community-based cohort of older persons. Eighteen candidate single-nucleotide polymorphisms from PD genome-wide association studies were evaluated in a joint clinicopathologic cohort. Participants included 1698 individuals and a nested autopsy collection of 821 brains from the Religious Orders Study and the Rush Memory and Aging Project, 2 prospective community-based studies. The primary outcomes were a quantitative measure of global parkinsonism or component measures of bradykinesia, rigidity, tremor, and gait impairment that were based on the motor Unified Parkinson's Disease Rating Scale. In secondary analyses, we examined associations with additional quantitative motor traits and postmortem indices, including substantia nigra Lewy bodies and neuronal loss. Parkinson disease risk alleles in the MAPT (rs2942168; P = .0006) and CCDC62 (rs12817488; P = .004) loci were associated with global parkinsonism, and these associations remained after exclusion of patients with a PD diagnosis. Based on motor Unified Parkinson's Disease Rating Scale subscores, MAPT (P = .0002) and CCDC62 (P = .003) were predominantly associated with bradykinesia, and we further discovered associations between SREBF1 (rs11868035; P = .005) and gait impairment, SNCA (rs356220; P = .04) and rigidity, and GAK (rs1564282; P = .03) and tremor. In the autopsy cohort, only NMD3 (rs34016896; P = .03) was related to nigral neuronal loss, and no associations were detected with Lewy bodies. In addition to the established link to PD susceptibility, our results support a broader role for several loci in the development of parkinsonian motor signs and nigral pathology in older persons.

An Exploratory Analysis on Gene-Environment Interactions for Parkinson Disease (PD4.003)

Objective: To explore potential interactions between variations of Parkinson disease (PD) susceptibility genes with smoking and caffeine intake. Background Gene-environment interaction is critical to understanding the etiology of PD. Little, however, is known about whether PD susceptibility genes interact with known environmental risk factors for PD. Design/Methods: We examined potential interactions of prospectively collected data on smoking and caffeine intake with several PD susceptible SNPs selected from previous GWAS, among 584 non-Hispanic Caucasian cases and 1,571 controls. Genotyping data were primarily from the replication sample of a previous GWAS study, and we focused on ten tag SNPs at or flanking the SNCA, MAPT, LRRK2 and HLA-DRA loci. Results: The main effects of PD susceptibility loci and environmental exposures were consistent with previous reports. Family history was also associated with PD risk (OR=2.71, 95% CI: 1.97 3.37), which was little affected after further adjusting for these SNPs and environmental exposures. Overall, we did not find significant interactions of either smoking or caffeine intake with these SNPs. However, with a combined smoking and caffeine exposure, we found a significant interaction with rs2896905 near the LRRK2 gene (uncorrected p = 0.0008), which remained statistically significant even after Bonferroni correction. Each A allele was associated with a 35% higher PD risk (OR=1.35, 95% CI: 1.01 – 1.82, p = 0.04) among never smokers with low caffeine intake, but with a 32% lower PD risk (OR=0.68, 95% CI: 0.51 – 0.90, p = 0.007) among smokers with high caffeine intake. Conclusions: This study provides preliminary evidence that smoking and caffeine intake may modify the association of rs2896905 with PD, which should be confirmed and investigated in future studies. Supported by: The intramural research program of the NIH, the National Institute of Environmental Health Sciences (Z01-ES-101986), the National Cancer Institute (Z01 CP010196-02), and a NIH extramural grant (R01 NS060722) to Dr Huang. Disclosure: Dr. Gao has nothing to disclose. Dr. Nalls has nothing to disclose. Dr. Shi has nothing to disclose. Dr. Joubert has nothing to disclose. Dr. Hernandez has nothing to disclose. Dr. Huang has nothing to disclose. Dr. Hollenbeck has nothing to disclose. Dr. Singleton has nothing to disclose. Dr. Chen has nothing to disclose.

Meta‐analysis of Parkinson's Disease: Identification of a novel locus, RIT2

Genome-wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility. A 2-stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 single-nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls). Genome-wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio [OR]=1.37; p=9.3×10(-21)), MAPT (rs242559; C: OR=0.78; p=1.5×10(-10)), GAK/DGKQ (rs11248051; T: OR=1.35; p=8.2×10(-9)/rs11248060; T: OR=1.35; p=2.0×10(-9)), and the human leukocyte antigen (HLA) region (rs3129882; A: OR=0.83; p=1.2×10(-8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR=1.71; p=5×10(-8) Combined Sample) (N370; OR=3.08; p=7×10(-5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5×10(-5) Discovery Sample; p=1.52×10(-7) Replication sample; p=2×10(-10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes. We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA.

Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease

To identify susceptibility variants for Parkinson's disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 x 10(-12)) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 x 10(-9)). We also detected strong associations at SNCA on 4q22 (P = 7.35 x 10(-17)) and LRRK2 on 12q12 (P = 2.72 x 10(-8)), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.

α-Synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity

Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, collectively referred to as synucleinopathies, are associated with a diverse group of genetic and environmental susceptibilities. The best studied of these is PD. alpha-Synuclein (alpha-syn) has a key role in the pathogenesis of both familial and sporadic PD, but evidence linking it to other predisposition factors is limited. Here we report a strong genetic interaction between alpha-syn and the yeast ortholog of the PD-linked gene ATP13A2 (also known as PARK9). Dopaminergic neuron loss caused by alpha-syn overexpression in animal and neuronal PD models is rescued by coexpression of PARK9. Further, knockdown of the ATP13A2 ortholog in Caenorhabditis elegans enhances alpha-syn misfolding. These data provide a direct functional connection between alpha-syn and another PD susceptibility locus. Manganese exposure is an environmental risk factor linked to PD and PD-like syndromes. We discovered that yeast PARK9 helps to protect cells from manganese toxicity, revealing a connection between PD genetics (alpha-syn and PARK9) and an environmental risk factor (PARK9 and manganese). Finally, we show that additional genes from our yeast screen, with diverse functions, are potent modifiers of alpha-syn-induced neuron loss in animals, establishing a diverse, highly conserved interaction network for alpha-syn.

High-Resolution Whole-Genome Association Study of Parkinson Disease

We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P<.01 in tier 1) and 300 genomic control SNPs in 332 matched case-unrelated control pairs. We identified 11 SNPs that were associated with PD (P<.01) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined data from the case-unaffected sibling pair (tier 1) and case-unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P=7.62 x 10(-6)). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P=1.70 x 10(-5)). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P<.05) in tier 1 but that tested a priori biological and genetic hypotheses regarding susceptibility to PD (n=941 SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest P values (P=9.07 x 10(-6); P=2.96 x 10(-5)) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNPs in conferring PD susceptibility.