Role of ATP10B in Parkinson disease in a cohort from southern Spain.

The ATP10B gene has been proposed to play an important role in the development of early-onset Parkinson's disease (PD). Nevertheless, various studies have presented controversial conclusions regarding the involvement of this gene in PD. Here, we screened 1162 patients with PD, employing a targeted resequencing approach to investigate the putative relevance of this gene in a large independent cohort of these patients from southern Spain. Variations were classified according to the American College of Medical Genetics and Genomics criteria. Association studies were performed using data of a representative healthy Spanish population from the Medical Genome Project. Frequent variants were excluded. A total of 68 variants (rare or very rare) were detected in our cohort. Among ATP10B variant carriers, 12.9 % were putative compound heterozygous carriers; of these, 25 % were patients with early-onset PD. No evidence of a relation between any rare variants of ATP10B and PD risk was observed. Therefore, our results do not support a role for ATP10B in the onset of PD, or in the risk of developing it.

Peripheral Inflammation Is Associated with Dopaminergic Degeneration in Parkinson's Disease.

BACKGROUND: Peripheral inflammatory immune responses are suggested to play a major role in dopaminergic degeneration in Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR) is a well-established biomarker of systemic inflammation in PD. Degeneration of the nigrostriatal dopaminergic system can be assessed in vivo using [123 I]FP-CIT single photon emission computed tomography imaging of striatal dopamine transporter (DAT) density. OBJECTIVES: To assess the relationship between the peripheral immune profile (NLR, lymphocytes, and neutrophils) and striatal DAT density in patients with PD. METHODS: We assessed clinical features, the peripheral immune profile, and striatal [123 I]FP-CIT DAT binding levels of 211 patients with PD (primary-cohort). Covariate-controlled associations between the immune response and striatal DAT levels were assessed using linear regression analyses. For replication purposes, we also studied a separate cohort of 344 de novo patients with PD enrolled in the Parkinson's Progression Markers Initiative (PPMI-cohort). RESULTS: A higher NLR was significantly associated with lower DAT levels in the caudate (primary-cohort: ß = -0.01, p < 0.001; PPMI-cohort: ß = -0.05, p = 0.05) and the putamen (primary-cohort: ß = -0.05, p = 0.02; PPMI-cohort: ß = -0.06, p = 0.02). Intriguingly, a lower lymphocyte count was significantly associated with lower DAT levels in both the caudate (primary-cohort: ß = +0.09, p < 0.05; PPMI-cohort: ß = +0.11, p = 0.02) and the putamen (primary-cohort: ß = +0.09, p < 0.05, PPMI-cohort: ß = +0.14, p = 0.01), but an association with the neutrophil count was not consistently observed (caudate; primary-cohort: ß = -0.05, p = 0.02; PPMI-cohort: ß = 0, p = 0.94; putamen; primary-cohort: ß = -0.04, p = 0.08; PPMI-cohort: ß = -0.01, p = 0.73). CONCLUSIONS: Our findings across two independent cohorts suggest a relationship between systemic inflammation and dopaminergic degeneration in patients with PD. This relationship was mainly driven by the lymphocyte count. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Staging Parkinson's Disease According to the MNCD (Motor/Non-motor/Cognition/Dependency) Classification Correlates with Disease Severity and Quality of Life.

BACKGROUND: Recently, a novel simple classification called MNCD, based on 4 axes (Motor; Non-motor; Cognition; Dependency) and 5 stages, has been proposed to classify Parkinson's disease (PD). OBJECTIVE: Our aim was to apply the MNCD classification in a cohort of PD patients for the first time and also to analyze the correlation with quality of life (QoL) and disease severity. METHODS: Data from the baseline visit of PD patients recruited from 35 centers in Spain from the COPPADIS cohort fromJanuary 2016 to November 2017 were used to apply the MNCD classification. Three instruments were used to assess QoL:1) the 39-item Parkinson's disease Questionnaire [PDQ-39]); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8). RESULTS: Four hundred and thirty-nine PD patients (62.05±7.84 years old; 59% males) were included. MNCD stage was:stage 1, 8.4% (N = 37); stage 2, 62% (N = 272); stage 3, 28.2% (N = 124); stage 4-5, 1.4% (N = 6). A more advancedMNCD stage was associated with a higher score on the PDQ39SI (p < 0.0001) and a lower score on the PQ-10 (p< 0.0001) and EUROHIS-QOL8 (p< 0.0001). In many other aspects of the disease, such as disease duration, levodopa equivalent daily dose, motor symptoms, non-motor symptoms, and autonomy for activities of daily living, an association between the stage and severity was observed, with data indicating a progressive worsening related to disease progression throughout the proposed stages. CONCLUSION: Staging PD according to the MNCD classification correlated with QoL and disease severity. The MNCD could be a proper tool to monitor the progression of PD.

Functional Movement Disorders and Deep Brain Stimulation: A Multi-Center Study.

Background: Functional movement disorders (FMD) are a commonly under-recognized diagnosis in patients with underlying neurodegenerative diseases. FMD have been observed in patients undergoing deep brain stimulation (DBS) for Parkinson's disease (PD) and other movement disorders. The prevalence of coexisting FMD among movement disorder-related DBS patients is unknown, and it may occur more often than previously recognized. Methods: We retrospectively assessed the relative prevalence and clinical characteristics of FMD occurring post-DBS, in PD and dystonia patients (FMD+, n = 29). We compared this cohort with age at surgery-, sex-, and diagnosis-matched subjects without FMD post-DBS (FMD-, n = 29). Results: Both the FMD prevalence (0.2%-2.1%) and the number of cases/DBS procedures/year varied across centers (0.15-3.65). A total of nine of 29 FMD+ cases reported worse outcomes following DBS. Although FMD+ and FMD- manifested similar features, FMD+ showed higher psychiatric comorbidity. Conclusions: DBS may be complicated by the development of FMD in a subset of patients, particularly those with pre-morbid psychiatric conditions.

Peripheral inflammatory immune response differs among sporadic and familial Parkinson's disease.

Peripheral inflammatory immune responses are thought to play a major role in the pathogenesis of Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation, has been reported to be higher in patients with PD than in healthy controls (HCs). The present study was aimed at determining if the peripheral inflammatory immune response could be influenced by the genetic background of patients with PD. We included a discovery cohort with 222 patients with PD (132 sporadic PD, 44 LRRK2-associated PD (with p.G2019S and p.R1441G variants), and 46 GBA-associated PD), as well as 299 HCs. Demographic and clinical data were recorded. Leukocytes and their subpopulations, and the NLR were measured in peripheral blood. Multivariate lineal regression and post-hoc tests were applied to determine the differences among the groups. Subsequently, a replication study using the Parkinson's Progression Markers Initiative cohort was performed which included 401 patients with PD (281 sPD patients, 66 LRRK2-PD patients, 54 GBA-PD patients) and a group of 174 HCs. Patients with sporadic PD and GBA-associated PD showed a significantly lower lymphocyte count, a non-significantly higher neutrophil count and a significantly higher NLR than HCs. The peripheral inflammatory immune response of patients with LRRK2-associated PD did not differ from HCs. Our study supports the involvement of a peripheral inflammatory immune response in the pathophysiology of sPD and GBA-associated PD. However, this inflammatory response was not found in LRRK2-associated PD, probably reflecting different pathogenic inflammatory mechanisms.

Perfil clínico ­ epidemiológico de sepsis temprana en recién nacidos. Estudio observacional de centro único / Clinical-epidemiological profile of early sepsis in newborns. A single-center observational study

Introducción: La sepsis neonatal temprana se describe como un síndrome clínico que se caracteriza por signos y síntomas asociados a infección sistémica, se presenta en las primeras 72 horas posterior al nacimiento. El objetivo del presente estudio fue determinar el perfil clínico ­ epidemiológico de la sepsis neonatal temprana en una unidad de cuidados intensivos neonatales de un centro de referencia regional en Guayaquil-Ecuador. Métodos: El presente estudio observacional, realizado en el Hospital "Teodoro Maldonado Carbo" de enero del 2017 al diciembre del 2020 incluyó neonatos con sepsis neonatal temprana con muestra no probabilística. Las variables: edad, edad gestacional, sexo, vía de infección, presencia de infecciones de del tracto urinario, peso, genopatías, Apgar al 1er minuto, escala de Silverman, etapas clínicas, llenado capilar, gasto urinario, variables clínicas, de laboratorio, hemocultivo, organismo casal. El análisis es univariado, descriptivo con frecuencias y porcentajes. Resultados: Se incluyeron 278 pacientes con edad gestacio-nal promedio de 33 semanas, fueron 59.4% hombres. Los factores de riesgo materno fueron a IVU en el embarazo e infección transplacentaria. Entre los factores asociados al neonato son el bajo peso (56%), prematuridad (67%). La clínica más frecuente fue eutermia y taquipnea (54%). En el perfil de laboratorio la neu-tropenia predominó (49%), mientras que los agentes causales identificados Staphylococcus hominis 7%, Escherichia coli 4.3% y Klebsiella pneumoniae 4%. Conclusión: Se determinó la relación directa entre las características epidemiológicas y las etapas clínicas de la sepsis neonatal.

Introduction: Early neonatal sepsis is a clinical syndrome characterized by signs and symptoms associated with systemic infection; it occurs in the first 72 hours after birth. This study aimed to determine the clinical-epidemiological profile of early neonatal sepsis in a neonatal intensive care unit of a regional reference center in Guayaquil, Ecuador. Methods: The present observational study, carried out at the "Teodoro Maldonado Carbo" Hospital from January 2017 to December 2020, included neonates with early neonatal sepsis with a nonprobabilistic sample. The variables were age, gestational age, sex, route of infection, presence of urinary tract infections, weight, genopathies, Apgar at 1 minute, Silverman scale, clinical stages, capillary refill, urinary output, clinical and laboratory variables, haem culture, and causative organism. The analysis is univariate and descriptive with frequencies and percentages. Results: A total of 278 patients with a mean gestational age of 33 weeks were included, and 59.4% were men. Maternal risk factors were UTI in pregnancy and transplacental infection. Among the factors associated with the newborn were low weight (56%) and prematurity (67%). The most frequent symptoms were euthermia and tachypnea (54%). In the laboratory profile, neutropenia predominated (49%), while the causative agents were Staphylococcus hominis (7%), Escherichia coli (4.3%), and Klebsiella pneumoniae (4%). Conclusion: The direct relationship between the epidemiological characteristics and the clinical stages of neonatal sepsis was determined.

Factores asociados al síndrome de dificultad respiratoria neonatal severa / Factors associated with severe neonatal respiratory distress syndrome

Introducción: El síndrome de dificultad respiratoria neonatal es una patología asociada a neonatos de sexo masculino prematuros. Á nivel regional no se dispone de datos asociados al síndrome de dificultad respiratoria neonatal (SDR) severo, por lo que se desarrolló in estudio observacional para medir los factores de riesgo. Metodología: El presente estudio transversal ­ retrospectivo, fue realizado en el servicio de neonatología del Hospital "Teodoro Maldonado Carbo", de Guayaquil, Ecuador, de enero 2017 a diciembre 2020. Ingresaron al estudio, neonatos, con SDR con una muestra probabilística. Las variables fueron maternas, neonatales, escala de Silverman, valoración de Downes. En base a la escala de Silverman se analizan 2 grupos: SDR leve y moderado, versus SDR Severo, se presenta Odds Ratio, e intervalo de confianza del 95% con valor P. Resultados: Se analizan 302 casos, con edad gestacional de 33 ± 4.2 semanas. Puntaje de Silverman 5.07 ±2.06. Los factores de riesgos identificados fueron la cesárea OR 3.92 (IC 95% 2.13-7.21) P<0.0001, pre-eclampsia OR 1.73 (1.05-2.87) P=0.033. Edad gestacional <28 Semanas 7.626 (2.657-21.89) P=0.0002. Edad Gestacional >36 semanas OR 0.4 (0.273-0.782) P=0.004. Sexo hombre OR 2.19 (1.32-3.63) P=0.002. Conclusión: Se constituyeron los factores de riesgo la cesárea, la pre-eclampsia, la edad gestacional menor a 28 semanas y el sexo hombre. Un factor de protección fue la edad gestacional mayor a 36 semanas.

Introduction: Neonatal respiratory distress syndrome is a pathology associated with premature male neo-nates. At the regional level, no data is associated with severe neonatal respiratory distress syndrome (RDS), so an observational study was developed to measure risk factors. Methodology: The present cross-sectional - retrospective study was carried out in the neonatology service of the "Teodoro Maldonado Carbo" Hospital, in Guayaquil, Ecuador, from January 2017 to December 2020. Neonates with RDS entered the study with a probabilistic sample. The variables were maternal, neonatal, Silverman scale, and Downes assessment. Based on the Silverman scale, two groups are analyzed: mild and moderate RDS versus Severe RDS; Odds Ratio is presented, and a 95% confidence interval with a P value. Results: 302 cases were analyzed, with a gestational age of 33 ± 4.2 weeks. Silverman scores 5.07 ±2.06. The identified risk factors were cesarean section OR 3.92 (95% CI 2.13-7.21) P<0.0001, pre-eclampsia OR 1.73 (1.05-2.87) P=0.033. Gestational age <28 Weeks 7.626 (2.657-21.89) P=0.0002. Gestational age >36 weeks OR 0.4 (0.273-0.782) P=0.004. Sex male OR 2.19 (1.32-3.63) P=0.002. Conclusión: The risk factors were cesarean section, pre-eclampsia, gestational age les tan 28 weeks, and male sex. A protective factor was gestational age greater than 36 weeks.

Clinical and structural brain correlates of hypomimia in early-stage Parkinson's disease.

BACKGROUND AND PURPOSE: Reduced facial expression of emotions is a very frequent symptom of Parkinson's disease (PD) and has been considered part of the motor features of the disease. However, the neural correlates of hypomimia and the relationship between hypomimia and other non-motor symptoms of PD are poorly understood. METHODS: The clinical and structural brain correlates of hypomimia were studied. For this purpose, cross-sectional data from the COPPADIS study database were used. Age, disease duration, levodopa equivalent daily dose, Unified Parkinson's Disease Rating Scale part III (UPDRS-III), severity of apathy and depression and global cognitive status were collected. At the imaging level, analyses based on gray matter volume and cortical thickness were used. RESULTS: After controlling for multiple confounding variables such as age or disease duration, the severity of hypomimia was shown to be indissociable from the UPDRS-III speech and bradykinesia items and was significantly related to the severity of apathy (ß = 0.595; p < 0.0001). At the level of neural correlates, hypomimia was related to motor regions brodmann area 8 (BA 8) and to multiple fronto-temporo-parietal regions involved in the decoding, recognition and production of facial expression of emotions. CONCLUSION: Reduced facial expressivity in PD is related to the severity of symptoms of apathy and is mediated by the dysfunction of brain systems involved in motor control and in the recognition, integration and expression of emotions. Therefore, hypomimia in PD may be conceptualized not exclusively as a motor symptom but as a consequence of a multidimensional deficit leading to a symptom where motor and non-motor aspects converge.

Increased homocysteine levels correlate with cortical structural damage in Parkinson's disease.

BACKGROUND: Blood homocysteine appears to be increased in Parkinson's disease (PD) and may play a role in the development and progression of this disorder. However, the specific contribution of abnormal homocysteine levels to cortical degeneration in PD remains elusive. OBJECTIVE: To characterize the cortical structural correlates of homocysteine levels in PD. METHODS: From the COPPADIS cohort, we identified a subset of PD patients and healthy controls (HC) with available homocysteine and imaging data. Surface-based vertex-wise multiple regression analyses were performed to investigate the cortical macrostructural (cortical thinning) and microstructural (increased intracortical diffusivity) correlates of homocysteine levels in this sample. RESULTS: A total of 137 PD patients and 43 HC were included. Homocysteine levels were increased in the PD group (t = -2.2, p = 0.03), correlating in turn with cognitive performance (r = -0.2, p = 0.03). Homocysteine in PD was also associated with frontal cortical thinning and, in a subset of patients with available DTI data, with microstructural damage in frontal and posterior-cortical regions (p < 0.05 Monte-Carlo corrected). CONCLUSIONS: Homocysteine in PD appears to be associated with cognitive performance and structural damage in the cerebral cortex. These findings not only reinforce the presence and importance of cortical degeneration in PD, but also suggest that homocysteine plays a role among the multiple pathological processes thought to be involved in its development.

Directional Deep Brain Stimulation for Parkinson's Disease: Results of an International Crossover Study With Randomized, Double-Blind Primary Endpoint.

OBJECTIVE: Published reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease. MATERIALS AND METHODS: Participants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life. RESULTS: The study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs 21.2% (41/193) who preferred the omnidirectional period. CONCLUSION: Directional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians.

In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study.

INTRODUCTION: We aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson's disease (PD) without dementia. METHODS: The study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models. RESULTS: Compared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r = 0.37, p < 0.001), and this association remained significant after controlling for several potential confounding variables (p = 0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p = 0.02). CONCLUSIONS: Early cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition-relevant changes in non-demented PD.

Peripheral Immune Profile and Neutrophil-to-Lymphocyte Ratio in Parkinson's Disease.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) in peripheral blood is a well-established inflammatory marker, but its role in Parkinson's disease (PD) remains unclear. OBJECTIVES: To determine whether a different peripheral immune profile and NLR were present in PD patients. METHODS: We conducted a case-control study that included 377 PD patients and 355 healthy controls (HCs). Leukocytes, subpopulations, and the NLR were measured. Multivariate linear regression analyses were applied to determine the differences between groups and the association between NLR and clinical characteristics in PD. A meta-analysis was performed to clarify the association between NLR and PD. RESULTS: In our case-control study, the NLR was significantly higher in PD patients compared with HCs (2.47 ± 1.1 vs. 1.98 ± 0.91, P < 0.001). No association between NLR and age at onset, disease severity, or disease duration was found. The meta-analysis showed that the NLR was likely to be higher in PD patients. CONCLUSIONS: PD patients had an altered peripheral immune profile and a higher NLR compared with HCs. © 2021 International Parkinson and Movement Disorder Society.

MNCD: A New Tool for Classifying Parkinson's Disease in Daily Clinical Practice.

Background and objective: Parkinson's disease (PD) is a clinically heterogeneous disorder in which the symptoms and prognosis can be very different among patients. We propose a new simple classification to identify key symptoms and staging in PD. Patients and Methods: Sixteen movement disorders specialists from Spain participated in this project. The classification was consensually approved after a discussion and review process from June to October 2021. The TNM classification and the National Institutes of Health Stroke Scale (NIHSS) were considered as models in the design. Results: The classification was named MNCD and included 4 major axes: (1) motor symptoms; (2) non-motor symptoms; (3) cognition; (4) dependency for activities of daily living (ADL). Motor axis included 4 sub-axes: (1) motor fluctuations; (2) dyskinesia; (3) axial symptoms; (4) tremor. Four other sub-axes were included in the non-motor axis: (1) neuropsychiatric symptoms; (2) autonomic dysfunction; (3) sleep disturbances and fatigue; (4) pain and sensory disorders. According to the MNCD, 5 stages were considered, from stage 1 (no disabling motor or non-motor symptoms with normal cognition and independency for ADL) to 5 (dementia and dependency for basic ADL). Conclusions: A new simple classification of PD is proposed. The MNCD classification includes 4 major axes and 5 stages to identify key symptoms and monitor the evolution of the disease in patients with PD. It is necessary to apply this proof of concept in a properly designed study.

Mutational spectrum of GNAL, THAP1 and TOR1A genes in isolated dystonia: study in a population from Spain and systematic literature review.

OBJECTIVE: We aimed to investigate the prevalence of TOR1A, GNAL and THAP1 variants as the cause of dystonia in a cohort of Spanish patients with isolated dystonia and in the literature. METHODS: A population of 2028 subjects (including 1053 patients with different subtypes of isolated dystonia and 975 healthy controls) from southern and central Spain was included. The genes TOR1A, THAP1 and GNAL were screened using a combination of high-resolution melting analysis and direct DNA resequencing. In addition, an extensive literature search to identify original articles (published before 10 August 2020) reporting mutations in TOR1A, THAP1 or GNAL associated to dystonia was performed. RESULTS: Pathogenic or likely pathogenic variants in TOR1A, THAP1 and GNAL were identified in 0.48%, 0.57% and 0.29% of our patients, respectively. Five patients carried the variation p.Glu303del in TOR1A. A very rare variant in GNAL (p.Ser238Asn) was found as a putative risk factor for dystonia. In the literature, variations in TOR1A, THAP1 and GNAL accounted for about 6%, 1.8% and 1.1% of published dystonia patients, respectively. CONCLUSIONS: There is a different genetic contribution to dystonia of these three genes in our patients (about 1.3% of patients) and in the literature (about 3.6% of patients), probably due the high proportion of adult-onset cases in our cohort. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT-TOR1A and DYT-GNAL, with DYT-THAP1 likely to be an intermediate phenotype.

The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight.

BACKGROUND: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. OBJECTIVES: To perform the largest PD genome-wide association study restricted to a single country. METHODS: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. RESULTS: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. CONCLUSIONS: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society.