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1.  Does α-Synuclein Have A Dual and Opposing Effect in Preclinical versus Clinical Parkinson’s Disease? 
α-Synuclein gene (SNCA) multiplications cause familial parkinsonism and allele-length polymorphisms within the SNCA dinucleotide repeat REP1 increase the risk for developing Parkinson’s disease (PD). Since SNCA multiplications increase SNCA expression, and REP1-genotypes that increase the risk of developing PD show increased SNCA expression in cell-culture systems, animal models, and human blood and brain, PD therapies seek to reduce SNCA expression. We conducted an observational study of 1,098 PD cases to test the hypothesis that REP1 genotypes correlated with reduced SNCA expression are associated with better motor and cognitive outcomes. We evaluated the association of REP1 genotypes with survival free of Hoehn and Yahr stages 4 or 5 (motor outcome) and of Modified Telephone Interview for Cognitive Status score ≤27 or Alzheimer’s Disease-8 score ≥2 (cognitive outcome). Median disease duration at baseline was 3.3 years and median lag time from baseline to follow-up was 7.8 years. Paradoxically, REP1 genotypes associated with increased risk of developing PD and increased SNCA expression were associated with better motor (HR=0.87, p=0.046 covariate-adjusted age-scale analysis; HR=0.85, p=0.020, covariate-adjusted time-scale analysis) and cognitive outcomes (HR=0.90, p=0.12, covariate-adjusted age-scale analysis; HR=0.85, p=0.023, covariate-adjusted time-scale analysis). Our findings raise the possibility that SNCA has a dual, opposing, and time-dependent role. This may have implications for the development of therapies that target SNCA expression.
PMCID: PMC4723426  PMID: 24656894
Parkinson’s disease; α-synuclein gene; outcomes
2.  Variants in estrogen-related genes and risk of Parkinson’s disease 
Incidence rates of Parkinson’s disease (PD) are higher in men than women at all ages, and these differences may be due to the neuroprotective effects of estrogen on the nigrostriatal pathway. We investigated the association of common variants in four estrogen-related genes with PD. Tagging single nucleotide polymorphisms (SNPs) in the CYP19A1, ESR1, ESR2, and PRDM2 genes were selected from the International Haplotype Map and genotyped in 1,103 PD cases from the Upper Midwest, USA and in 1,103 individually matched controls (654 unaffected siblings, and 449 unrelated controls from the same region). Out of 137 informative SNPs, two PRDM2 SNPs were significantly associated with an increased risk of PD at the Bonferroni-corrected significance level of 0.0004 (rs2744690: OR = 1.54, 99.96% CI = 1.05 – 2.26, uncorrected P = 0.0001; rs2744687: OR = 1.53, 99.96% CI = 1.03 – 2.29, uncorrected P = 0.0002); the association was significant in the women only stratum but not in the men only stratum. An additional six SNPs in PRDM2, two in ESR1, one in ESR2, and one in CYP19A1 had significant P-values in the overall sample before Bonferroni correction. None of the SNPs were significantly associated with age at onset of PD after Bonferroni correction. Our results confirm the association of PRDM2 variants with PD susceptibility, especially in women.
PMCID: PMC4723424  PMID: 21469201
3.  Genomic determinants of motor and cognitive outcomes in Parkinson’s disease 
Parkinsonism & related disorders  2012;18(7):881-886.
Little is known regarding genetic factors associated with motor or cognitive outcomes in Parkinson’s disease (PD).
To identify common genetic variants associated with motor and cognitive outcomes in PD.
The sample consisted of 443 PD cases included in the first genome-wide association study (GWAS) of PD. Methods included telephone interview assessments of motor and cognitive outcomes, a median 9 years following the initial clinical assessments. Analyses included Cox proportional hazard models to study the association of 198,345 single nucleotide polymorphisms (SNPs) with survival free of Hoehn-Yahr Stage ≥4 (motor outcome), and either TICS-M ≤27 or AD-8 ≥2 (cognitive outcomes).
The SNP rs10958605 in the C8orf4 gene had the smallest p-value in analyses of the motor outcome (HR = 1.81; 95% CI = 1.42 – 2.31; p = 1.51 × 10−6). The SNP rs6482992 in the CLRN3 gene had the smallest p-value in analyses of the cognitive outcome (HR = 2.03, 95% CI 1.47–2.79, p = 4.08 × 10−6). However, no SNP associations were significant after Bonferroni correction. The C8orf4 gene had small p-values for both motor and cognitive outcomes, highlighting inflammation as a possible pathogenesis mechanism for progression in PD.
This study suggests that common variants in several genes may be associated with motor and cognitive outcomes in PD, with biological plausibility.
PMCID: PMC3606821  PMID: 22658654
Genome wide association studies; Parkinson’s disease; outcomes
4.  Do interactions between SNCA, MAPT, and LRRK2 genes contribute to Parkinson’s disease susceptibility? 
Parkinsonism & related disorders  2011;17(10):730-736.
Polymorphisms in SNCA, MAPT and LRRK2 genes have recently been confirmed as risk factors for Parkinson’s disease (PD), although with small individual attributable risk. Here we investigated the association of PD with interactions between variants of these genes.
As part of a previous study of PD susceptibility genes 119 SNCA, MAPT, and LRRK2 haplotype tagging single nucleotide polymorphisms (SNPs) and two variable number tandem repeats (VNTRs) were genotyped in 1,098 PD cases from the upper Midwest, USA and 1,098 matched controls. Twenty-six of these SNPs were selected for SNP-SNP (or SNP-VNTR or VNTR-VNTR) interaction analysis (256 interaction pairs). Case-control analyses were performed to study association of pairwise SNP interactions with PD susceptibility.
Out of the 256 interaction pairs investigated, 10 had uncorrected p-values <0.05. These represented six SNCA-LRRK2 pairs, three SNCA-MAPT pairs, and one MAPT-LRRK2 pair. However, none of these pairwise interactions were significant after correction for multiple testing. Secondary analyses in strata defined by type of control (sibling or unrelated), sex, or age at onset of the case also did not reveal any significant interactions after accounting for multiple testing.
This study provides no statistically significant evidence of gene-gene interaction effects for the three confirmed genetic susceptibility loci for PD. However, this does not exclude the possibility that other genomic loci or environmental risk factors interact with these genes.
PMCID: PMC4723425  PMID: 21816655
Parkinson’s disease; gene-gene interaction; alpha-synuclein; microtubule associated protein tau; leucine rich repeat kinase 2
5.  Genetic susceptibility loci, environmental exposures, and Parkinson’s disease: a case-control study of gene-environment interactions 
Parkinsonism & related disorders  2013;19(6):595-599.
Prior studies causally linked mutations in SNCA, MAPT, and LRRK2 genes with familial parkinsonism. Genome-wide association studies have demonstrated association of single nucleotide polymorphisms (SNPs) in those three genes with sporadic Parkinson’s disease (PD) susceptibility worldwide. Here we investigated the interactions between SNPs in those three susceptibility genes and environmental exposures (pesticides application, tobacco smoking, coffee drinking, and alcohol drinking) also associated with PD susceptibility.
Pairwise interactions between environmental exposures and 18 variants (16 SNPs and two variable number tandem repeats, or “VNTRs”) in SNCA, MAPT and LRRK2, were investigated using data from 1,098 PD cases from the upper Midwest, USA and 1,098 matched controls. Environmental exposures were assessed using a validated telephone interview script.
Five pairwise interactions had uncorrected P-values < 0.05. These included pairings of pesticides x SNCA rs3775423 or MAPT rs4792891, coffee drinking x MAPT H1/H2 haplotype or MAPT rs16940806, and alcohol drinking x MAPT rs2435211. None of these interactions remained significant after Bonferroni correction. Secondary analyses in strata defined by type of control (sibling or unrelated), sex, or age at onset of the case also did not identify significant interactions after Bonferroni correction.
This study documented limited pairwise interactions between established genetic and environmental risk factors for PD; however, the associations were not significant after correction for multiple testing.
PMCID: PMC4685949  PMID: 23507417
6.  Coffee, Caffeine-Related Genes, and Parkinson's Disease: A Case–Control Study 
An inverse association between coffee and Parkinson's disease (PD) has been reported. However, it remains uncertain why some but not all coffee drinkers are less susceptible to PD. We considered the possibility of a pharmaco-genetic effect. In our study, we included 1,208 subjects (446 case-unaffected sibling pairs and 158 case-unrelated control pairs) recruited from an ongoing study of the molecular epidemiology of PD in the Upper Midwest (USA). We collected information on lifetime coffee drinking and we studied two genes: ADORA2A, which encodes the major receptor activity of caffeine in the brain (variants rs5751876 and rs3032740), and CYP1A2, which encodes the major rate-limiting step of caffeine metabolism (variants rs35694136 and rs762551). We did not observe significant associations of coffee drinking or of the genetic variants with PD susceptibility, either independently or jointly, in the sample overall and in most strata. Our study neither supports the hypothesis that coffee protects against PD nor provides evidence for a pharmacogenetic effect.
PMCID: PMC4554698  PMID: 18759349
Parkinson's disease; coffee; genes
7.  Alpha-synuclein REP1 variants and survival in Parkinson’s disease 
To determine if alpha-synuclein REP1 genotypes are associated with survival in Parkinson’s disease.
Investigators from the Genetic Epidemiology of Parkinson’s Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival.
Twenty-one sites contributed data for 6,154 cases. There was no significant association between alpha-synuclein REP1 genotypes and survival in Parkinson’s disease. However, there was a significant association between REP1 genotypes and age at onset of PD (Hazard Ratio = 1.06, 95% Confidence Interval = 1.01–1.10, p value = 0.01).
In our large consortium study, alpha-synuclein REP1 genotypes were not associated with survival in Parkinson’s disease. Further studies of α–synuclein’s role in disease progression and long-term outcomes are needed.
PMCID: PMC4172351  PMID: 24578302
Parkinson’s disease; α-synuclein; gene; survival; association
8.  Role for the microtubule-associated protein tau variant p.A152T in risk of α-synucleinopathies 
Neurology  2015;85(19):1680-1686.
To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies.
In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls.
The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63–2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62–20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04–12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85–25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution.
Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies.
PMCID: PMC4653108  PMID: 26333800
9.  Rationale for Therapeutic Silencing of Alpha-Synuclein in Parkinson’s Disease 
The purpose of this paper is to provide the rationale for therapeutic silencing of the alpha-synuclein gene (SNCA) in Parkinson’s disease (PD). The paper reviews the public health significance of PD; the causal links between rare SNCA variants and familial PD; the association of common SNCA variants and PD susceptibility; the association of SNCA variants also with age at onset and motor and cognitive outcomes in PD; therapeutic strategies targeting SNCA in PD; and preliminary findings and considerations on small interfering RNA-based therapies and PD.
PMCID: PMC4027709  PMID: 24868385
Parkinson’s disease; Alpha-synuclein; RNA-based therapies
10.  α-synuclein, alcohol use disorders, and Parkinson disease: a case-control study 
Parkinsonism & related disorders  2009;15(6):430-434.
Collaborative pooled analyses demonstrated that allele length variability of the dinucleotide repeat sequence within the alpha-synuclein gene promoter (SNCA REP1) is associated with Parkinson disease (PD) worldwide. Other studies demonstrated that variability in the SNCA promoter is also associated with alcohol use disorders, but not consistently. Yet other studies demonstrated that alcohol use disorders are inversely associated with PD, but not consistently. The aim of this study was to clarify the patterns of association between REP1 genotype, alcohol use disorders, and PD. Cases were recruited from the Department of Neurology of the Mayo Clinic in Rochester, MN. The controls included unaffected siblings and unrelated controls. We assessed alcohol use via a structured telephone interview and screened for alcohol use disorders using the CAGE questionnaire. REP1 genotyping was performed using an ABI 3730XL platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined using conditional logistic regression models. We recruited 893 case-control pairs. There was an increasing risk of PD with increasing SNCA REP1 allele length (OR 1.18 for each REP1 genotype score unit, 95% CI 1.02 to 1.35; p = 0.02). There was a decreasing risk of PD with increasing CAGE score (p = 0.01). The association of REP1 score with PD remained significant after adjusting for CAGE score, and the association of CAGE score with PD remained significant after adjusting for REP1 score. There were no pairwise interactions. Our findings suggest that SNCA REP1 genotype and alcohol use disorders are independently associated with PD.
PMCID: PMC3057130  PMID: 19196539
alpha-synuclein; alcohol use disorders; Parkinson disease
11.  A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson’s disease 
Neurobiology of aging  2009;32(3):548.e9-548.18.
High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson’s disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson’s 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; I2 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 Parkinson’s disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide.
PMCID: PMC4724437  PMID: 20036034
Omi; HtrA2; Genetics; Parkinson’s disease; PARK13
12.  Non-Replication of Association for Six Polymorphisms From Meta-Analysis of Genome-Wide Association Studies of Parkinson’s Disease: Large-Scale Collaborative Study 
Early genome-wide association (GWA) studies on Parkinson’s disease (PD) have not been able to yield conclusive, replicable signals of association, perhaps due to limited sample size. We aimed to investigate whether association signals derived from the meta-analysis of the first two GWA investigations might be replicable in different populations. We examined six single-nucleotide polymorphisms (SNPs) (rs1000291, rs1865997, rs2241743, rs2282048, rs2313982, and rs3018626) that had reached nominal significance with at least two of three different strategies proposed in a previous analysis of the original GWA studies. Investigators from the “Genetic Epidemiology of Parkinson’s Disease” (GEOPD) consortium were invited to join in this study. Ten teams contributed replication data from 3,458 PD cases and 3,719 controls. The data from the two previously published GWAs (599 PD cases, 592 controls and 443 sibling pairs) were considered as well. All data were synthesized using both fixed and random effects models. The summary allelic odds ratios were ranging from 0.97 to 1.09 by random effects, when all data were included. The summary estimates of the replication data sets (excluding the original GWA data) were very close to 1.00 (range 0.98–1.09) and none of the effects were nominally statistically significant. The replication data sets had significantly different results than the GWA data. Our data do not support evidence that any of these six SNPs reflect susceptibility markers for PD. Much stronger signals of statistical significance in GWA platforms are needed to have substantial chances of replication. Specifically in PD genetics, this would require much larger GWA studies and perhaps novel analytical techniques.
PMCID: PMC4699803  PMID: 19475631
Parkinson’s disease; meta-analysis; genome-wide association
13.  Quality improvement and practice-based research in neurology using the electronic medical record 
Neurology: Clinical Practice  2015;5(5):419-429.
We describe quality improvement and practice-based research using the electronic medical record (EMR) in a community health system–based department of neurology. Our care transformation initiative targets 10 neurologic disorders (brain tumors, epilepsy, migraine, memory disorders, mild traumatic brain injury, multiple sclerosis, neuropathy, Parkinson disease, restless legs syndrome, and stroke) and brain health (risk assessments and interventions to prevent Alzheimer disease and related disorders in targeted populations). Our informatics methods include building and implementing structured clinical documentation support tools in the EMR; electronic data capture; enrollment, data quality, and descriptive reports; quality improvement projects; clinical decision support tools; subgroup-based adaptive assignments and pragmatic trials; and DNA biobanking. We are sharing EMR tools and deidentified data with other departments toward the creation of a Neurology Practice-Based Research Network. We discuss practical points to assist other clinical practices to make quality improvements and practice-based research in neurology using the EMR a reality.
PMCID: PMC4634157  PMID: 26576324
14.  Prospective Differentiation of Multiple System Atrophy from Parkinson’s Disease, with and without Autonomic Failure 
Archives of neurology  2009;66(6):742-750.
The severity, distribution, and pattern of autonomic failure appear to be different in multiple system atrophy (MSA) compared with Parkinson’s disease (PD), but reports have been retrospective reviews and have tended to exclude PD with autonomic failure (PD_AF). We report preliminary results of a prospective ongoing study of MSA and PD, with a large subset of PD_AF (25%) to evaluate autonomic indices that distinguish MSA from PD.
We used Consensus criteria, detailed autonomic studies (composite autonomic symptom score (COMPASS), composite autonomic severity score (CASS), thermoregulatory sweat test percent anhidrosis (TST%), plasma catecholamines, and functional scales (Unified MSA rating scale (UMSARS) I–IV, Hoehn-Yahr grading) on a prospective, repeated, and ongoing basis.
We report the results of a study based on 52 patients with MSA (61.1±7.8 years; BMI 27.2±4.6; Hoehn-Yahr grade, 3.2±0.9; UMSARS_1 21.5±7.4; UMSARS_2, 22.7±9.0) and 29 patients with PD, including PD_AF (66.0±8.1 years; BMI 26.6±.5.5; Hoehn-Yahr grade, 2.2±0.8; UMSARS_1 10.4±6.1; UMSARS_2, 13.0±5.9). Autonomic indices were highly significantly more abnormal in MSA than PD (P<0.001) for each of: CASS (5.9±1.9 vs. 3.3±2.3), COMPASS (54.4±21.8 vs. 24.7±20.5), TST% (57.4±35.2 vs. 9.9±17.7). These differences were sustained and greater at 1 year follow-up indicating a greater rate of progression of dysautonomia in MSA than PD.
The severity, distribution, and pattern of autonomic deficits at entry will distinguish MSA from PD and MSA from PD_AF. These differences continue and increase with follow-up. Our ongoing conclusion is that autonomic function tests can separate MSA from PD. Autonomic indices support the notion that the primary lesion in PD is ganglionic/postganglionic while MSA is preganglionic.
PMCID: PMC2838493  PMID: 19506134
15.  The protective effect of LRRK2 p.R1398H on risk of Parkinson’s disease is independent of MAPT and SNCA variants 
Neurobiology of aging  2013;35(1):10.1016/j.neurobiolaging.2013.07.013.
The best validated susceptibility variants for Parkinson’s disease (PD) are located in the alpha-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 four SNCA variants (rs181489, rs356219, rs11931074, rs2583988), the MAPT H1-haplotype defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (N=10,322) and Asian (N=2,289) 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 PD is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.
PMCID: PMC3829604  PMID: 23962496
Parkinson disease; LRRK2; SNCA; MAPT; interaction; genetics
17.  Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology Of Parkinson’s Disease (GEO-PD) consortium 
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 susceptibility to disease displays many features that reflect the nature of complex late-onset sporadic disorders, such as Parkinson’s disease. 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. Herein we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) reported in the original publication. Simple population allele frequencies can not only provide an insight into the clinical relevance of specific variants but also help genetically define patient groups. Establishing individual patient-based genomic susceptibility profiles incorporating both risk and protective factors will determine future diagnostic and treatment strategies.
PMCID: PMC4108155  PMID: 23913756
Parkinson disease; LRRK2; genetics; association study
18.  Genomic investigation of α-Synuclein multiplication and parkinsonism 
Annals of neurology  2008;63(6):10.1002/ana.21380.
Copy number variation is a common polymorphic phenomenon within the human genome. While the majority of these events are non-deleterious they can also be highly pathogenic. Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the α-synuclein gene (SNCA).
A methodological approach employing fluorescent in situ hybridization (FISH) and Affymetrix 250K SNP microarrays (CHIPs) was used to characterize the multiplication in each family and identify the genes encoded within the region. The telomeric and centromeric breakpoints of each family were further narrowed using semi-quantitative PCR with microsatellite markers and then screened for transposable repeat elements.
The severity of clinical presentation is correlated with SNCA dosage and does not appear to be overtly effected by the presence of other genes in the multiplicated region. With the exception of the Lister kindred, in each family the multiplication event appears de novo. The type and position of Alu/LINE repeats are also different at each breakpoint. Microsatellite analysis demonstrates two genomic mechanisms are responsible for chromosome 4q21 multiplications, including both SNCA duplication and triplication.
SNCA dosage is responsible for parkinsonism, autonomic dysfunction and dementia observed within each family. We hypothesize dysregulated expression of wild-type α-synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson’s disease. SNCA genomic duplication results from intra-allelic (segmental duplication) or inter-allelic recombination with unequal crossing-over, whereas both mechanisms appear to be required for genomic SNCA triplication.
PMCID: PMC3850281  PMID: 18571778
Parkinsonism; SNCA; Genomic multiplication; Alu repeat; Parkinson’s disease
19.  Mutations in CIZ1 cause adult-onset primary cervical dystonia 
Annals of Neurology  2012;71(4):458-469.
Primary dystonia is usually of adult onset, can be familial, and frequently involves the cervical musculature. Our goal was to identify the causal mutation in a family with adult-onset, primary cervical dystonia.
Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in a large Caucasian pedigree with adult-onset, primary cervical dystonia to identify a cosegregating mutation. High-throughput screening and Sanger sequencing were completed in 308 Caucasians with familial or sporadic adult-onset cervical dystonia and matching controls for sequence variants in this mutant gene.
Exome sequencing led to the identification of an exonic splicing enhancer mutation in Exon 7 of CIZ1 (c.790A>G, p.S264G) which encodes CIZ1, Cip1-interacting zinc finger protein 1. CIZ1 is a p21Cip1/Waf1-interacting zinc finger protein expressed in brain and involved in DNA synthesis and cell-cycle control. Using a minigene assay, we showed that c.790A>G altered CIZ1 splicing patterns. The p.S264G mutation also altered the nuclear localization of CIZ1. Screening in subjects with adult-onset cervical dystonia identified two additional CIZ1 missense mutations (p.P47S and p.R672M).
Mutations in CIZ1 may cause adult-onset, primary cervical dystonia, possibly by precipitating neurodevelopmental abnormalities that manifest in adults and/or G1/S cell-cycle dysregulation in the mature central nervous system.
PMCID: PMC3334472  PMID: 22447717
20.  Common Variants in PARK Loci and Related Genes and Parkinson’s Disease 
Rare mutations in PARK loci genes cause Parkinson’s disease (PD) in some families and isolated populations. We investigated the association of common variants in PARK loci and related genes with PD susceptibility and age at onset in an outbred population. 1,103 PD cases from the upper Midwest, USA were individually matched to unaffected siblings (n = 654) or unrelated controls (n = 449) from the same region. Using a sequencing approach in 25 cases and 25 controls, single nucleotide polymorphisms (SNPs) in species-conserved regions of PARK loci and related genes were detected. We selected additional tag SNPs from the HapMap. We genotyped a total of 235 SNPs and two variable number tandem repeats (VNTRs) in the ATP13A2, DJ1, LRRK1, LRRK2, MAPT, Omi/HtrA2, PARK2, PINK1, SNCA, SNCB, SNCG, SPR, and UCHL1 genes in all 2,206 subjects. Case-control analyses were performed to study association with PD susceptibility, while cases-only analyses were used to study association with age at onset. Only MAPT SNP rs2435200 was associated with PD susceptibility after correction for multiple testing (OR = 0.74, 95% CI = 0.64 – 0.86, uncorrected P < 0.0001, log additive model); however, 16 additional MAPT variants, seven SNCA variants, and one LRRK2, PARK2, and UCHL1 variants each had significant uncorrected P-values. There were no significant associations for age at onset after correction for multiple testing. Our results confirm the association of MAPT and SNCA genes with PD susceptibility, but show limited association of other PARK loci and related genes with PD.
PMCID: PMC3606822  PMID: 21412835
21.  LRRK2 exonic variants and susceptibility to Parkinson’s disease 
Lancet neurology  2011;10(10):898-908.
Leucine-rich repeat kinase 2 (LRRK2) is known to harbor highly penetrant mutations linked to familial parkinsonism. However, its full polymorphic variability in relationship to Parkinson’s disease (PD) risk has not been systematically assessed.
We examined the frequency pathogenicity of 121 exonic LRRK2 variants in three ethnic series (Caucasian [N=12,590], Asian [N=2,338] and Arab-Berber [N=612]) consisting of 8,611 patients and 6,929 control subjects from 23 separate sites of the Genetic Epidemiology of Parkinson’s Disease Consortium.
Excluding carriers of previously known pathogenic mutations, new independent risk associations were found for polymorphic variants in Caucasian (p.M1646T, OR: 1.43, 95% CI: 1.15 – 1.78, P=0.0012) and Asian (p.A419V, OR: 2.27, 95% CI: 1.35 – 3.83, P=0.0011) populations. In addition, a protective haplotype was observed at >5% frequency (p.N551K-p.R1398H-p.K1423K) in the Caucasian and Asian series’, with a similar finding in the small Arab-Berber series that requires further study (combined 3-series OR: 0.82, 95% CI: 0.72 – 0.94, P=0.0043). Of the two previously reported Asian risk variants p.G2385R was found to be associated with disease (OR: 1.73, 95% CI: 1.20 – 2.49, P=0.0026) but no association was observed for p.R1628P (OR: 0.62, 95% CI: 0.36 – 1.07, P=0.087). Also in the Arab-Berber series, p.Y2189C showed potential evidence of risk association with PD (OR: 4.48, 95% CI: 1.33 – 15.09, P=0.012). Of note, two variants (p.I1371V and p.T2356I) which have been previously proposed as pathogenic were observed in patient and control subjects at the same frequency.
LRRK2 offers an example where multiple rare and common genetic variants in the same gene have independent effects on disease risk. Lrrk2, and the pathway in which it functions, is important in the etiology and pathogenesis of a greater proportion of patients with PD than previously believed.
The present study and original funding for the GEO-PD Consortium was supported by grants from Michael J. Fox Foundation. Studies at individual sites were supported by a number of funding agencies world-wide.
PMCID: PMC3208320  PMID: 21885347
Parkinson disease; LRRK2; genetics
22.  Incidental Lewy Body Disease: Do some cases represent a preclinical stage of Dementia with Lewy Bodies? 
Neurobiology of Aging  2009;32(5):857-863.
Lewy pathology occurs in 8–17% of neurologically-normal people >age 60, termed incidental Lewy body disease, (iLBD). It is often assumed to represent preclinical Parkinson disease (PD). However, some iLBD cases have diffuse pathology inconsistent with preclinical PD. We analyzed iLBD cases (α-synuclein immunohistochemistry) using the Braak PD staging scheme and determined if some had a neuropathological pattern suggestive of preclinical Dementia with Lewy bodies (DLB). Of the 235 brains examined, 34 had iLBD (14.5%) and all but one could be assigned a Braak PD stage. The distribution of α-synuclein pathology in the 33 cases fell into three patterns: (1) Diffuse cortical and subcortical α-synuclein pathology; (2) No cortical a-synuclein pathology, but a caudal-to-rostral ascending pattern, primarily involving brainstem; (3) Intermediate between these two categories. Also, 6/33 cases failed to follow the pattern of contiguous spread proposed by Braak. These findings suggest dichotomy in the distribution of iLBD: some cases fit the Braak ascending scheme, conceptually consistent with preclinical PD, whereas others displayed prominent cortical involvement that might represent preclinical DLB.
PMCID: PMC3366193  PMID: 19560232
incidental Lewy body disease; parkinson disease; dementia with Lewy bodies
23.  Independent and joint effects of the MAPT and SNCA genes in Parkinson's disease 
Annals of neurology  2011;69(5):778-792.
We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule associated protein tau (MAPT) in Parkinson's disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium.
Participants of Caucasian ancestry were genotyped for a total of four SNCA (rs2583988, rs181489, rs356219, rs11931074) and two MAPT (rs1052553, rs242557) SNPs. Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied both on a multiplicative and an additive scale, and using a case-control and case-only approach.
Fifteen GEO-PD sites contributed a total of 5302 cases and 4161 controls. All four SNCA SNPs and the MAPT H1-haplotype defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3′ end of the gene. There was no evidence of statistical interaction between any of the four SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale.
This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these two loci is consistent with independent effects of the genes without additional interacting effects.
PMCID: PMC3082599  PMID: 21391235
Parkinson disease; SNCA; MAPT; genetics; interaction; case-control
24.  Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database 
PLoS Genetics  2012;8(3):e1002548.
More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of ∼27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P<5×10−8) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3×10−8). All meta-analysis results are freely available on a dedicated online database (, which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.
Author Summary
The genetic basis of Parkinson's disease is complex, i.e. it is determined by a number of different disease-causing and disease-predisposing genes. Especially the latter have proven difficult to find, evidenced by more than 800 published genetic association studies, typically showing discrepant results. To facilitate the interpretation of this large and continuously increasing body of data, we have created a freely available online database (“PDGene”: which provides an exhaustive account of all published genetic association studies in PD. One particularly useful feature is the calculation and display of up-to-date summary statistics of published data for overlapping DNA sequence variants (polymorphisms). These meta-analyses revealed eleven gene loci that showed a statistically very significant (P<5×10−8; a.k.a. genome-wide significance) association with risk for PD: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, SYT11/RAB25. In addition and purely by data-mining, we identified one novel PD susceptibility locus in a gene called ITGA8 (rs7077361, P = 1.3×10−8). We note that our continuously updated database represents the most comprehensive research synopsis of genetic association studies in PD to date. In addition to vastly facilitating the work of other PD geneticists, our approach may serve as a valuable example for other complex diseases.
PMCID: PMC3305333  PMID: 22438815
25.  Anxious Personality Predicts an Increased Risk of Parkinson’s Disease 
We studied the association of three personality traits related to neuroticism with the subsequent risk of Parkinson’s disease (PD) using a historical cohort study. We included 7,216 subjects who resided within the 120-mile radius centered in Rochester, MN, at the time they completed the Minnesota Multiphasic Personality Inventory (MMPI) for research at the Mayo Clinic from 1962–1965. We considered three MMPI personality scales (pessimistic, anxious, and depressive traits). A total of 6,822 subjects (94.5%) were followed over 4 decades either actively or passively. During follow-up, 227 subjects developed parkinsonism (156 developed PD). An anxious personality was associated with an increased risk of PD (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.16–2.27). A pessimistic personality trait was also associated with an increased risk of PD but only in men (HR = 1.92; 95% CI = 1.20–3.07). By contrast, a depressive trait was not associated with increased risk. Analyses combining scores from the three personality scales into a composite neuroticism score showed an association of neuroticism with PD (HR = 1.54; 95% CI = 1.10–2.16). The association with neuroticism remained significant even when the MMPI was administered early in life (ages 20–39 years). By contrast, none of the three personality traits was associated with the risk of non-PD types of parkinsonism grouped together. Our long-term historical cohort study suggests that an anxious personality trait may predict an increased risk of PD developing many years later.
PMCID: PMC3089895  PMID: 20669309
Parkinson’s disease; parkinsonism; anxious personality; pessimistic personality; neuroticism; Minnesota Multiphasic Personality Inventory

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