Identification of candidate Parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets

Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies

The role of RHOT1 and RHOT2 genetic variation on Parkinson disease risk and onset

International Parkinson’s Disease Genomics Consortium (IPDGC).Genetic variation within the mitochondrial pathway contributes to the risk of Parkinson’s disease (PD). Recent genetic analyses have investigated the association between the RHOT1 and RHOT2 genes and PD etiology. Furthermore, 4 mutations in the RHOT1 gene (p.R272Q, p.R450C, p.T351A, p.T610A) have been reported to be potentially associated with disease risk. As part of the International Parkinson Disease Genomics Consortium efforts to evaluate reported PD risk factors, we assessed the role of common and low frequency variants in both RHOT1 and also RHOT2 according to the high degree of homology in their amino acid sequences. Utilizing large-scale genotyping and whole-genome sequencing data from the International Parkinson Disease Genomics Consortium and the Accelerating Medicines Partnership – Parkinson Disease initiative, our analyses did not identify evidence to support the hypothesis that RHOT1 and RHOT2 are disease causing or modifying genes for PD risk or age at onset.This work was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences both part of the National Institutes of Health, Department of Health and Human Services; project numbers 1ZIA-NS003154, Z01-AG000949-02, and Z01-ES101986. In addition, this work was supported by the Department of Defense (award W81XWH-09-2-0128), and The Michael J. Fox Foundation for Parkinson’s Research. Data used in the preparation of this article were obtained from the AMP PD Knowledge Platform. For up-to-date information on the study, visit https://www.amp-pd.org. AMP PD—a public-private partnership—is managed by the FNIH and funded by Celgene, GSK, the Michael J. Fox Foundation for Parkinson’s Research, the National Institute of Neurological Disorders and Stroke, Pfizer, and Verily

A replication study of GWAS-genetic risk variants associated with Parkinson’s disease in a Spanish population

Recently, 5 previously Parkinson’s disease (PD)-related loci: ACMSD/TMEM163, STK39, MIR4697, SREBF1/RAI1PD and MAPT, have been associated to PD in a Southern Spanish population. However, due to the small sample size of the cohort, this association did not reach genome wide significance. Our aim was to investigate the robustness of this association in a larger and independent cohort from the South of Spain. Variants were genotyped employing TaqMan SNP Genotyping Assay and high resolution melting analysis in 738 PD patients and 1138 healthy controls. Furthermore, a meta-analysis study was carried out with both cohorts. In the replication analysis, only two loci (ACMSD/TMEM163 and MAPT) were replicated with a Bonferroni significance level. In the meta-analysis study no loci reached a genome-wide significance level (P<5xE-8), but a suggestive association (P-value = 1.04E-6) between rs6430538 (ACMSD/TMEM163) and an increased risk of PD was found. In addition, rs9468 (MAPT) was associated with a decreased risk of PD (P-value = 5.70E-7). Our results add further support for the genetic involvement of these two loci in the susceptibility to PD in population from the South of Spain. We believe that our findings will be very useful for future genetic studies on PD.This study was supported by grants from the Spanish Ministry of Economy and Competitiveness [PI14/01823, PI16/01575, PI18/01898], co-founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0437-2012, PI-0471-2013], the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña. Pilar Gómez-Garre was supported by the "Miguel Servet" (from ISCIII-FEDER) and “Nicolás Monardes” (from Andalusian Ministry of Health) programmes. Silvia Jesús Maestre was supported by the "Juan Rodés" programme and Daniel Macías-García was supported by the “Río Hortega) programme (both from ISCIII-FEDER). Cristina Tejera-Parrado was supported by VPPI-US from the Universidad de Sevilla.Peer reviewe

Integrating genetic and clinical data to predict impulse control disorders in Parkinson's disease

[Background and purpose] Impulse control disorders (ICDs) are frequent in Parkinson’s disease (PD), with associated clinical and genetic risk factors. This study was aimed at analyzing the clinical features and the genetic background that underlie ICDs in PD.[Methods] We included 353 patients with PD in this study (58.9% men, mean age 62.4 ± 10.58 years, mean age at disease onset 52.71 ± 11.94 years). We used the validated Questionnaire for Impulsive–Compulsive Disorders in Parkinson’s Disease for ICDs screening. Motor, nonmotor, and treatment‐related features were evaluated according to the presence of ICDs. Twenty‐one variants related to dopaminergic, serotonergic, glutamatergic, and opioid neurotransmitter systems were assessed. Association studies between polymorphisms and ICDs were performed. The combination of clinical and genetic variables was analyzed with receiver operating characteristic curves to assess the predictability of experiencing ICDs.[Results] Impulse control disorders appeared in 25.1% of the cases. Patients with ICDs were younger and presented a higher rate of anxiety. Treatment with dopamine agonists increased the risk of ICDs and it was dose dependent (P < 0.05). Genetic association studies showed that the DOPA decarboxylase gene (DDC), rs1451375, might modulate the risk of ICDs. Plotting the clinical–genetic model, the predictability of ICDs increased 11% (area under curve = 0.80; z = 3.22, P = 0.001) when adding the genotype data for single nucleotide polymorphisms.[Conclusions] Polymorphisms in DDC might act as risk markers for ICDs in PD. The predictability of experiencing ICDs increased by adding genetic factors to clinical features. It is therefore important to assess the patient’s genetic background to identify individuals at risk for ICDs.This research was supported by grants from the Ministerio de Economía y Competitividad de España (SAF2007‐60700), the Instituto de Salud Carlos III (PI13/01461, PI‐0459‐2018, PI16/01575, PI18/01898, PI19/01576), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI‐02526, CTS‐7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI‐0471/2013, PI‐0459‐2018, PE‐0210‐2018, PE‐0186‐2019), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña, and the Jaques and Gloria Gossweiler Foundation. S.J. and D.M.‐G. hold the competitive contract “Juan Rodés” (JR16/00031) and “Rio Hortega” (CM18/00142), respectively, both supported by the Instituto de Salud Carlos III

Analysis of p.Tyr307Asn variant in the LRP10 gene in Parkinson’s disease in southern Spain

Lipoprotein receptor-related protein 10 (LRP10) has been proposed as a novel causative gene for autosomal dominant Parkinson’s disease (PD), and the c.919T>A (p.Tyr307Asn) variant has been identified as possibly involved in the development of familial PD and PD with dementia. We screened for the p.Tyr307Asn variant in a southern Spain population of 679 PD patients, of who 129 were familial cases, and 1217 unrelated healthy controls. A total of 3 carriers of the LRP10 p.Tyr307Asn variant were identified: 1 PD patient and 2 healthy controls. Together with the absence of a family history of PD, this finding might suggest a low penetrance variant as well as a limited role for p.Tyr307Asn in PD in our cohort. Nevertheless, a family history of Alzheimer’s disease in the LRP10 p.Tyr307Asn carriers provides evidence for a possible association with dementia.This work was supported by the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER) [PI14/01823, PI16/01575, PI18/01898, PI19/01576], the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the by the “Juan Rodés” program [B-0007-2019] and Daniel Macías-García by the “Río Ho Consejería de Salud y Bienestar Social de la Junta de Andalucía” [PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019], and the Fundación Alicia Koplowitz. Pilar Gómez-Garre was supported by the “Miguel Servet” program [MSII14/00018] (from ISCIII-FEDER) and “Nicolás Monardes” program [C-0048-2017] (from Andalusian Regional Ministry of Health). Silvia Jesús was supported by the “Juan Rodés” program [B-0007-2019] and Daniel Macías-García by the “Río Hortega” program [CM18/00142] (both from ISCIII-FEDER). Maria Teresa Periñán was supported by the Spanish Ministry of Education [FPU16/05061]

TMEM230 in Parkinson’s disease in a southern Spanish population

TMEM230 has been associated with autosomal dominant Parkinson’s disease (PD). Subsequent studies have remained negative, and none of previous described mutation has been reported anymore. We investigated the implication of this gene in the PD in a population of 703 PD patients and 695 unrelated healthy controls from southern Spain. Thirteen variants were found, twelve of them observed only in controls or in patients and controls, and one (c.190A>G) observed only in one patient. Subsequent analysis of this variant indicates that probably it is not pathogenic. In addition, we found a variation in the 3’-UTR (rs183551373) and related with the miRNA hsa-miR-4299 but it was observed only in healthy controls. Our results suggest that variants in TMEM230 gene are not associated with the development of PD.This study was supported by grants from the Spanish Ministry of Economy and Competitiveness [PI14/01823 to Pilar Gómez-Garre, PI16/01575 to Pablo Mir] co-founded by the Instituto de Salud Carlos-III (ISCIII) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [ PI-0437-2012, PI-0471-2013], the Sociedad Andaluza de Neurología to Pablo Mir, the Jacques and Gloria Gossweiler Foundation to Pablo Mir, the Fundación Alicia Koplowitz to Pablo Mir, and the Fundación Mutua Madrileña. Pilar Gómez-Garre was supported by the "Miguel Servet" (from ISCIII-FEDER) and “Nicolás Monardes” (from Andalusian Ministry of Health) programmes. Silvia Jesús was supported by the "Juan Rodés" programme (from ISCIII-FEDER). Cristina Tejera-Parrado was supported by VPPI-US from the Universidad de Sevilla.Peer reviewe

The Parkinson's Disease Genome‐Wide Association Study Locus Browser

International Parkinson's Disease Genomics Consortium (IPDGC).[Background] Parkinson's disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome‐wide association studies. The most recent large‐scale PD genome‐wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome‐wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus.[Methods] We included all significant genome‐wide signals from multiple recent PD genome‐wide association studies including themost recent PD risk genome‐wide association study, age‐at‐onset genome‐wide association study, progression genome‐wide association study, and Asian population PD risk genome‐wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self‐ranked criteria. Multiple databases were queried for each gene to collect additional causal data.[Results] We created a PD genome‐wide association study browser tool (https://pdgenetics.shinyapps.io/GWASBrowser/) to assist the PD research community with the prioritization of genes for follow‐up functional studies to identify potential therapeutic targets.[Conclusions] Our PD genome‐wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large‐scale PD genome‐wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered. © 2020 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 US Government employees and their work is in the public domain in the USA.This work was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences, both part of the National Institutes of Health, Department of Health and Human Services (project numbers 1ZIA‐NS003154, Z01‐AG000949‐02, and Z01‐ES101986). We thank the research participants and employees of 23andMe for making this work possible. C.W. is supported by the UK Dementia Research Institute funded by the Medical Research Council (MRC), Alzheimer's Society and Alzheimer's Research UK. C.S. is supported by the Ser Cymru II program, which is partly funded by Cardiff University and the European Regional Development Fund through the Welsh Government. Data were generated as part of the PsychENCODE Consortium supported by: U01MH103339, U01MH103365, U01MH103392, U01MH103340, U01MH103346, R01MH105472, R01MH094714, R01MH105898, R21MH102791, R21MH105881, R21MH103877, and P50MH106934 awarded to Schahram Akbarian (Icahn School of Medicine at Mount Sinai), Gregory Crawford (Duke), Stella Dracheva (Icahn School of Medicine at Mount Sinai), Peggy Farnham (USC), Mark Gerstein (Yale), Daniel Geschwind (UCLA), Thomas M. Hyde (LIBD), Andrew Jaffe (LIBD), James A. Knowles (USC), Chunyu Liu (UIC), Dalila Pinto (Icahn School of Medicine at Mount Sinai), Nenad Sestan (Yale), Pamela Sklar (Icahn School of Medicine at Mount Sinai), Matthew State (UCSF), Patrick Sullivan (UNC), Flora Vaccarino (Yale), Sherman Weissman (Yale), Kevin White (UChicago), and Peter Zandi (JHU). The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this article were obtained from the GTEx Portal on February 12, 2020. Molecular data for the Trans‐Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Genome sequencing for “NHLBI TOPMed: Atherosclerosis Risk in Communities (ARIC)” (phs001211.v2.p2) was performed at the Broad Institute of MIT and Harvard (3R01HL092577‐06S1)and at the Baylor Human Genome Sequencing Center (3U54HG003273‐12S2, HHSN268201500015C). Genome sequencing for the “NHLBI TOPMed: Cleveland Clinic Atrial Fibrillation (CCAF) Study” (phs001189.v1.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL092577‐06S1). Genome sequencing for “NHLBI TOPMed: Trans‐Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Project: Cardiovascular Health Study (phs001368.v1.p1) was performed at the Baylor Human Genome Sequencing Center (3U54HG003273‐12S2, HHSN268201500015C). Genome sequencing for “NHLBI TOPMed: Partners HealthCare Biobank” (phs001024.v3.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL092577‐06S1). Genome sequencing for “NHLBI TOPMed: Whole Genome Sequencing of Venous Thromboembolism (WGS of VTE)” (phs001402.v1.p1) was performed at the Baylor Human Genome Sequencing Center (3U54HG003273‐12S2, HHSN268201500015C). Genome sequencing for “NHLBI TOPMed: Novel Risk Factors for the Development of Atrial Fibrillation in Women” (phs001040.v3.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL092577‐06S1). Genome sequencing for “NHLBI TOPMed: The Genetics and Epidemiology of Asthma in Barbados” (phs001143.v2.p1) was performed by Illumina Genomic Services (3R01HL104608‐04S1). Genome sequencing for “NHLBI TOPMed: The Vanderbilt Genetic Basis of Atrial Fibrillation” (phs001032.v4.p2) was performed at the Broad Institute of MIT and Harvard (3R01HL092577‐06S1). Genome sequencing for “NHLBI TOPMed: Heart and Vascular Health Study (HVH)” (phs000993.v3.p2) was performed at the Broad Institute of MIT and Harvard (3R01HL092577‐06S1) and at the Baylor Human Genome Sequencing Center (3U54HG003273‐12S2, HHSN268201500015C). Genome sequencing for “NHLBI TOPMed: Genetic Epidemiology of COPD (COPDGene)” (phs000951.v3.p3) was performed at the University of Washington Northwest Genomics Center (3R01HL089856‐08S1) and at the Broad Institute of MIT and Harvard (HHSN268201500014C). Genome sequencing for “NHLBI TOPMed: The Vanderbilt Atrial Fibrillation Ablation Registry” (phs000997.v3.p2) was performed at the Broad Institute of MIT and Harvard (3U54HG003067‐12S2, 3U54HG003067‐13S1). Genome sequencing for “NHLBI TOPMed: The Jackson Heart Study” (phs000964.v3.p1) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). Genome sequencing for “NHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish” (phs000956.v3.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL121007‐01S1). Genome sequencing for “NHLBI TOPMed: Massachusetts General Hospital Atrial Fibrillation (MGH AF) Study” (phs001062.v3.p2) was performed at the Broad Institute of MIT and Harvard (3R01HL092577‐06S1, 3U54HG003067‐12S2, 3U54HG003067‐13S1, 3UM1HG008895‐01S2). Genome sequencing for “NHLBI TOPMed: The Framingham Heart Study” (phs000974.v3.p2) was performed at the Broad Institute of MIT and Harvard (3U54HG003067‐12S2). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL‐117626‐02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample‐identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL‐120393; U01HL‐120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The Atherosclerosis Risk in Communities study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institute of Health, Department of Health and Human Services, under contract numbers (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. The research reported in this article was supported by grants from the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute grants R01 HL090620 and R01 HL111314, the NIH National Center for Research Resources for Case Western Reserve University and Cleveland Clinic Clinical and Translational Science Award (CTSA) UL1‐RR024989, the Department of Cardiovascular Medicine philanthropic research fund, Heart and Vascular Institute, Cleveland Clinic, the Fondation Leducq grant 07‐CVD 03, and the Atrial Fibrillation Innovation Center, state of Ohio. This research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01‐HC85079, N01‐HC‐85080, N01‐HC‐85081, N01‐HC‐85082, N01‐HC‐85083, N01‐HC‐85084, N01‐HC‐85085, N01‐HC‐85086, N01‐HC‐35129, N01‐HC‐15103, N01‐HC‐55222, N01‐HC‐75150, N01‐HC‐45133, and N01‐ HC‐85239; grant numbers U01 HL080295 and U01 HL130014 from the National Heart, Lung, and Blood Institute, and R01 AG023629 from the National Institute on Aging, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at https://chs-nhlbi.org/pi. This article was not prepared in collaboration with CHS investigators and does not necessarily reflect the opinions or views of CHS or the NHLBI. We thank the Broad Institute for generating high‐quality sequence data supported by NHLBI grant 3R01HL092577‐06S1 to Dr. Patrick Ellinor. Funded in part by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute (HL66216 and HL83141), and the National Human Genome Research Institute (HG04735). The Women's Genome Health Study (WGHS) is supported by HL 043851 and HL099355 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute, the Donald W. Reynolds Foundation with collaborative scientific support and funding for genotyping provided by Amgen. AF end‐point confirmation was supported by HL‐093613 and a grant from the Harris Family Foundation and Watkin's Foundation. The Genetics and Epidemiology of Asthma in Barbados is supported by National Institutes of Health (NIH) National Heart, Lung, and Blood Institute TOPMed (R01 HL104608‐S1), and R01 AI20059, K23 HL076322, and RC2 HL101651. The research reported in this article was supported by grants from the American Heart Association to Dr. Darbar (EIA 0940116N), and grants from the National Institutes of Health (NIH) to Dr. Darbar (HL092217), and Dr. Roden (U19 HL65962, and UL1 RR024975). This project was also supported by a CTSA award (UL1TR000445) from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences of the NIH. The research reported in this article was supported by grants HL068986, HL085251, HL095080, and HL073410 from the National Heart, Lung, and Blood Institute. This article was not prepared in collaboration with Heart and Vascular Health (HVH) Study investigators and does not necessarily reflect the opinions or views of the HVH Study or the NHLBI. This research used data generated by the COPDGene study, which was supported by NIH grants U01 HL089856 and U01 HL089897. The COPDGene project is also supported by the COPD Foundation through contributions made by an Industry Advisory Board composed of Pfizer, AstraZeneca, Boehringer Ingelheim, Novartis, and Sunovion. Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL‐117626‐02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample‐identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL‐120393‐02S1; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. This study is part of the Centers for Common Disease Genomics (CCDG) program, a large‐scale genome sequencing effort to identify rare risk and protective alleles that contribute to a range of common disease phenotypes. The CCDG program is funded by the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI). Sequencing was completed at the Human Genome Sequencing Center at Baylor College of Medicine under NHGRI grant UM1 HG008898. The research reported in this article was supported by grants from the American Heart Association to Dr. Shoemaker (11CRP742009) and Dr. Darbar (EIA 0940116N), and grants from the National Institutes of Health (NIH) to Dr. Darbar (R01 HL092217) and Dr. Roden (U19 HL65962 and UL1 RR024975). The project was also supported by a CTSA award (UL1 TR00045) from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the NIH. The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I/HHSN26800001), and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). The authors also thank the staffs and participants of the JHS. The Amish studies on which these data are based were supported by NIH grants R01 AG18728, U01 HL072515, R01 HL088119, R01 HL121007, and P30 DK072488. See publication PMID: 18440328. The research reported in this article was supported by NIH grants K23HL071632, K23HL114724, R21DA027021, R01HL092577, R01HL092577S1, R01HL104156, K24HL105780, and U01HL65962. The research has also been supported by an Established Investigator Award from the American Heart Association (13EIA14220013) and by support from the Fondation Leducq (14CVD01). This article was not prepared in collaboration with MGH AF Study investigators and does not necessarily reflect the opinions or views of the MGH AF Study investigators or the NHLBI. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (contract nos. N01‐HC‐25195, HHSN268201500001I, and 75N92019D00031). This article was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI

A genetic analysis of a Spanish population with early onset Parkinson’s disease

[Introduction] Both recessive and dominant genetic forms of Parkinson’s disease have been described. The aim of this study was to assess the contribution of several genes to the pathophysiology of early onset Parkinson’s disease in a cohort from central Spain.[Methods/patients] We analyzed a cohort of 117 unrelated patients with early onset Parkinson’s disease using a pipeline, based on a combination of a next-generation sequencing panel of 17 genes previously related with Parkinson’s disease and other Parkinsonisms and CNV screening.[Results] Twenty-six patients (22.22%) carried likely pathogenic variants in PARK2, LRRK2, PINK1, or GBA. The gene most frequently mutated was PARK2, and p.Asn52Metfs*29 was the most common variation in this gene. Pathogenic variants were not observed in genes SNCA, FBXO7, PARK7, HTRA2, DNAJC6, PLA2G6, and UCHL1. Co-occurrence of pathogenic variants involving two genes was observed in ATP13A2 and PARK2 genes, as well as LRRK2 and GIGYF2 genes.[Conclusions] Our results contribute to the understanding of the genetic architecture associated with early onset Parkinson’s disease, showing both PARK2 and LRRK2 play an important role in Spanish Parkinson’s disease patients. Rare variants in ATP13A2 and GIGYF2 may contribute to PD risk. However, a large proportion of genetic components remains unknown. This study might contribute to genetic diagnosis and counseling for families with early onset Parkinson’s disease.This study was supported by grants from the Spanish Ministry of Economy and Competitiveness [PI14/01823, PI16/01575, PI18/01898] co-founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0437-2012, PI-0471-2013], the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña. Pilar Gómez-Garre was supported by the "Miguel Servet" (from ISCIII-FEDER) and “Nicolás Monardes” (from Andalusian Ministry of Health) programs. Silvia Jesús Maestre was supported by the "Juan Rodés" program (from ISCIII-FEDER). Cristina Tejera was supported by VPPI-US from the Universidad de Sevilla

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.This research was supported, in part, by the Intramural Research Program of the National Institutes of Health (National Institute on Aging, National Institute of Neurological Disorders and Stroke; project numbers: 1ZIA‐NS003154‐03, Z01‐AG000949‐02, and Z01‐ES101986). In addition, this work was supported by the Department of Defense (award W81XWH‐09‐2‐0128), The Michael J Fox Foundation for Parkinson's Research, and the ISCIII Grants PI 15/0878 (Fondos Feder) to V.A. and PI 15/01013 to J,H. This study was supported by grants from the Spanish Ministry of Economy and Competitiveness (PI14/01823, PI16/01575, PI18/01898, [SAF2006‐10126 (2006‐2009), SAF2010‐22329‐C02‐01 (2010‐2012), and SAF2013‐47939‐R (2013‐2018)]), co‐founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía (CVI‐02526, CTS‐7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI‐0437‐2012, PI‐0471‐2013), the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, and the Fundación Mutua Madrileña. Pilar Gómez‐Garre was supported by the “Miguel Servet” (from ISCIII16 FEDER) and “Nicolás Monardes” (from Andalusian Ministry of Health) programmes. Silvia Jesús Maestre was supported by the “Juan Rodés” programme, and Daniel Macías‐García was supported by the “Río Hortega” programme (both from ISCIII‐FEDER). Cristina Tejera Parrado was supported by VPPI‐US from the Universidad de Sevilla. This research has been conducted using samples from the HUVR‐IBiS Biobank (Andalusian Public Health System Biobank and ISCIII‐Red de Biobancos PT13/0010/0056). This work was also supported by the grant PSI2014‐57643 from the Junta de Andalucía to the CTS‐438 group and a research award from the Andalusian Society of Neurology