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1. Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia.

Author

Manzoni, Claudia, Kia, Demis, Ferrari, Raffaele, Leonenko, Ganna, Costa, Beatrice, Saba, Valentina, Jabbari, Edwin, Tan, Manuela, Albani, Diego, Alvarez, Victoria, Alvarez, Ignacio, Andreassen, Ole, Angiolillo, Antonella, Arighi, Andrea, Baker, Matt, Benussi, Luisa, Bessi, Valentina, Binetti, Giuliano, Blackburn, Daniel, Boada, Merce, Boeve, Bradley, Borrego-Ecija, Sergi, Borroni, Barbara, Bråthen, Geir, Brooks, William, Bruni, Amalia, Caroppo, Paola, Bandres-Ciga, Sara, Clarimon, Jordi, Colao, Rosanna, Cruchaga, Carlos, Danek, Adrian, de Boer, Sterre, de Rojas, Itziar, di Costanzo, Alfonso, Dickson, Dennis, Diehl-Schmid, Janine, Dobson-Stone, Carol, Dols-Icardo, Oriol, Donizetti, Aldo, Dopper, Elise, Durante, Elisabetta, Ferrari, Camilla, Forloni, Gianluigi, Frangipane, Francesca, Fratiglioni, Laura, Kramberger, Milica, Galimberti, Daniela, Gallucci, Maurizio, García-González, Pablo, Ghidoni, Roberta, Giaccone, Giorgio, Graff, Caroline, Graff-Radford, Neill, Grafman, Jordan, Halliday, Glenda, Hernandez, Dena, Hjermind, Lena, Hodges, John, Holloway, Guy, Huey, Edward, Illán-Gala, Ignacio, Josephs, Keith, Knopman, David, Kristiansen, Mark, Kwok, John, Leber, Isabelle, Leonard, Hampton, Libri, Ilenia, Lleo, Alberto, Mackenzie, Ian, Madhan, Gaganjit, Maletta, Raffaele, Marquié, Marta, Maver, Ales, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Morris, Christopher, Morris, Huw, Nacmias, Benedetta, Newton, Judith, Nielsen, Jørgen, Nilsson, Christer, Novelli, Valeria, Padovani, Alessandro, Pal, Suvankar, Pasquier, Florence, Pastor, Pau, Perneczky, Robert, Peterlin, Borut, Petersen, Ronald, Piguet, Olivier, Pijnenburg, Yolande, Puca, Annibale, Rademakers, Rosa, Rainero, Innocenzo, Reus, Lianne, Richardson, Anna, and Riemenschneider, Matthias

Subjects
Humans, Frontotemporal Dementia, tau Proteins, Genome-Wide Association Study, Apolipoproteins E, Male, Female, Genetic Predisposition to Disease, Aged, Polymorphism, Single Nucleotide, Genetic Loci, Middle Aged, Case-Control Studies, Myelin Proteins
Abstract

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

Published
2024

2. Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

Author

Wang, Hui, Chang, Timothy S, Dombroski, Beth A, Cheng, Po-Liang, Patil, Vishakha, Valiente-Banuet, Leopoldo, Farrell, Kurt, Mclean, Catriona, Molina-Porcel, Laura, Rajput, Alex, De Deyn, Peter Paul, Le Bastard, Nathalie, Gearing, Marla, Kaat, Laura Donker, Van Swieten, John C, Dopper, Elise, Ghetti, Bernardino F, Newell, Kathy L, Troakes, Claire, de Yébenes, Justo G, Rábano-Gutierrez, Alberto, Meller, Tina, Oertel, Wolfgang H, Respondek, Gesine, Stamelou, Maria, Arzberger, Thomas, Roeber, Sigrun, Müller, Ulrich, Hopfner, Franziska, Pastor, Pau, Brice, Alexis, Durr, Alexandra, Le Ber, Isabelle, Beach, Thomas G, Serrano, Geidy E, Hazrati, Lili-Naz, Litvan, Irene, Rademakers, Rosa, Ross, Owen A, Galasko, Douglas, Boxer, Adam L, Miller, Bruce L, Seeley, Willian W, Van Deerlin, Vivanna M, Lee, Edward B, White, Charles L, Morris, Huw, de Silva, Rohan, Crary, John F, Goate, Alison M, Friedman, Jeffrey S, Leung, Yuk Yee, Coppola, Giovanni, Naj, Adam C, Wang, Li-San, Dalgard, Clifton, Dickson, Dennis W, Höglinger, Günter U, Schellenberg, Gerard D, Geschwind, Daniel H, and Lee, Wan-Ping

Subjects
Biological Sciences, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Rare Diseases, Neurosciences, Dementia, Human Genome, Brain Disorders, Biotechnology, Aging, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease, 2.1 Biological and endogenous factors, Neurological, Progressive Supranuclear Palsy, Whole-Genome Sequencing, Genome-Wide Association Study, Structural Variants, Apolipoprotein E, P. S. P. genetics study group, Humans, Supranuclear Palsy, Progressive, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Female, Male, Whole Genome Sequencing, Clinical Sciences, Neurology & Neurosurgery, Biochemistry and cell biology
Abstract

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Published
2024

3. Network connectivity and structural correlates of survival in progressive supranuclear palsy and corticobasal syndrome.

Author

Whiteside, David, Street, Duncan, Murley, Alexander, Jones, P, Malpetti, Maura, Ghosh, Boyd, Coyle-Gilchrist, Ian, Gerhard, Alexander, Hu, Michele, Klein, Johannes, Leigh, P, Church, Alistair, Burn, David, Morris, Huw, Rowe, James, and Rittman, Timothy

Subjects
connectivity, corticobasal syndrome, fMRI, prediction, progressive supranuclear palsy, survival, tauopathies, Humans, Supranuclear Palsy, Progressive, Corticobasal Degeneration, Prognosis, Neurodegenerative Diseases
Abstract

There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson-plus and the UK National PSP Research Network (PROSPECT-MR). Resting-state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large-scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between-network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients demographics, structural imaging, and clinical scores using five-fold cross-validation. In PSP and CBS, between-network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between-network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics.

Published
2023

4. Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups.

Author

Kaivola, Karri, Shah, Zalak, Chia, Ruth, Black, Sandra E, Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian G, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J, Troakes, Claire, Albert, Marilyn S, Barrett, Matthew J, Beach, Thomas G, Bekris, Lynn M, Bennett, David A, Boeve, Bradley F, Dalgard, Clifton L, Dawson, Ted M, Dickson, Dennis W, Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, Gibbs, J Raphael, Goate, Alison, Goldstein, David S, Graff-Radford, Neill R, Kaufmann, Horacio, Kukull, Walter A, Leverenz, James B, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L, Palma, Jose Alberto, Pletnikova, Olga, Renton, Alan E, Resnick, Susan M, Rosenthal, Liana S, Ross, Owen A, Scherzer, Clemens R, Serrano, Geidy E, Shakkottai, Vikram G, Sidransky, Ellen, Tanaka, Toshiko, Topol, Eric, Torkamani, Ali, Troncoso, Juan C, Woltjer, Randy, Wszolek, Zbigniew K, and Scholz, Sonja W

Subjects
Genetics, Lewy Body Dementia, Neurodegenerative, Aging, Brain Disorders, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Alzheimer's Disease, Acquired Cognitive Impairment, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Alzheimer Disease, Apolipoprotein E4, Genome-Wide Association Study, Humans, Lewy Body Disease, alpha-Synuclein, International LBD Genomics Consortium, APOE, Alzheimer’s disease, co-pathology, dementia with Lewy bodies, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ε4 (P = 6.58 × 10-9, OR = 3.41, 95% CI = 2.25-5.17), but not with dementia with Lewy bodies with APOE ε4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05-3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer's disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer's disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer's disease co-pathology (n = 341). In each group, we tested the association of the APOE ε4 against the 2928 neurologically healthy controls. Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer's disease (P = 1.29 × 10-32, OR = 4.25, 95% CI = 3.35-5.39) and dementia with Lewy bodies + intermediate Alzheimer's disease (P = 0.0011, OR = 2.31, 95% CI = 1.40-3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43-1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

Published
2022

5. Current directions in tau research: Highlights from Tau 2020

Author

Sexton, Claire, Snyder, Heather, Beher, Dirk, Boxer, Adam L, Brannelly, Pat, Brion, Jean‐Pierre, Buée, Luc, Cacace, Angela M, Chételat, Gaël, Citron, Martin, DeVos, Sarah L, Diaz, Kristophe, Feldman, Howard H, Frost, Bess, Goate, Alison M, Gold, Michael, Hyman, Bradley, Johnson, Keith, Karch, Celeste M, Kerwin, Diana R, Koroshetz, Walter J, Litvan, Irene, Morris, Huw R, Mummery, Catherine J, Mutamba, James, Patterson, Marc C, Quiroz, Yakeel T, Rabinovici, Gil D, Rommel, Amy, Shulman, Melanie B, Toledo‐Sherman, Leticia M, Weninger, Stacie, Wildsmith, Kristin R, Worley, Susan L, and Carrillo, Maria C

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Alzheimer's Disease, Dementia, Aging, Brain Disorders, Neurodegenerative, Alzheimer Disease, Biomarkers, Cognitive Dysfunction, Drug Discovery, Humans, tau Proteins, Alzheimer's, biomarkers, neurodegeneration, tau, therapeutics, Geriatrics, Clinical sciences, Biological psychology
Abstract

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research.

Published
2022

6. Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial.

Author

Dam, Tien, Boxer, Adam L, Golbe, Lawrence I, Höglinger, Günter U, Morris, Huw R, Litvan, Irene, Lang, Anthony E, Corvol, Jean-Christophe, Aiba, Ikuko, Grundman, Michael, Yang, Lili, Tidemann-Miller, Beth, Kupferman, Joseph, Harper, Kristine, Kamisoglu, Kubra, Wald, Michael J, Graham, Danielle L, Gedney, Liz, O'Gorman, John, Haeberlein, Samantha Budd, and PASSPORT Study Group

Subjects
PASSPORT Study Group, Humans, Pneumonia, Supranuclear Palsy, Progressive, tau Proteins, Treatment Outcome, Double-Blind Method, Aged, Female, Male, Antibodies, Monoclonal, Humanized, Brain Disorders, Clinical Research, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Immunology, Medical and Health Sciences
Abstract

A randomized, double-blind, placebo-controlled, 52-week study (no. NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, in the treatment of progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to either gosuranemab (n = 321) or placebo (n = 165). Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P = 0.85, primary endpoint), or at secondary endpoints, resulting in discontinuation of the open-label, long-term extension. Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo (P

Published
2021

7. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Author

Nalls, Mike A, Blauwendraat, Cornelis, Vallerga, Costanza L, Heilbron, Karl, Bandres-Ciga, Sara, Chang, Diana, Tan, Manuela, Kia, Demis A, Noyce, Alastair J, Xue, Angli, Bras, Jose, Young, Emily, von Coelln, Rainer, Simón-Sánchez, Javier, Schulte, Claudia, Sharma, Manu, Krohn, Lynne, Pihlstrøm, Lasse, Siitonen, Ari, Iwaki, Hirotaka, Leonard, Hampton, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Scholz, Sonja W, Botia, Juan A, Martinez, Maria, Corvol, Jean-Christophe, Lesage, Suzanne, Jankovic, Joseph, Shulman, Lisa M, Sutherland, Margaret, Tienari, Pentti, Majamaa, Kari, Toft, Mathias, Andreassen, Ole A, Bangale, Tushar, Brice, Alexis, Yang, Jian, Gan-Or, Ziv, Gasser, Thomas, Heutink, Peter, Shulman, Joshua M, Wood, Nicholas W, Hinds, David A, Hardy, John A, Morris, Huw R, Gratten, Jacob, Visscher, Peter M, Graham, Robert R, Singleton, Andrew B, Team, 23andMe Research, Consortium, System Genomics of Parkinson's Disease, Consortium, International Parkinson's Disease Genomics, Adarmes-Gómez, Astrid D, Aguilar, Miquel, Aitkulova, Akbota, Akhmetzhanov, Vadim, Alcalay, Roy N, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesús Alberto Bergareche, Bernal-Bernal, Inmaculada, Billingsley, Kimberley, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Brockmann, Kathrin, Bubb, Vivien, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Chelban, Viorica, Clarimón, Jordi, Clarke, Carl, Compta, Yaroslau, Cookson, Mark R, Craig, David W, Danjou, Fabrice, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Escott-Price, Valentina, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, and Finkbeiner, Steven

Subjects
Neurosciences, Parkinson's Disease, Brain Disorders, Aging, Biotechnology, Prevention, Genetics, Human Genome, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Databases, Genetic, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Parkinson Disease, Risk Factors, 23andMe Research Team, System Genomics of Parkinson's Disease Consortium, International Parkinson's Disease Genomics Consortium, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundGenome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease.MethodsWe did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation.FindingsBetween Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10-7).InterpretationThese data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data.FundingThe National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).

Published
2019

8. The genetic and clinico-pathological profile of early-onset progressive supranuclear palsy.

Author

Jabbari, Edwin, Woodside, John, Tan, Manuela, Pavese, Nicola, Bandmann, Oliver, Ghosh, Boyd, Massey, Luke, Capps, Erica, Warner, Tom, Lees, Andrew, Revesz, Tamas, Holton, Janice, Williams, Nigel, Grosset, Donald, and Morris, Huw

Subjects
Parkinsons disease/parkinsonism, clinical neurology, genetics, progressive supranuclear palsy, Adult, Age of Onset, Aged, Aged, 80 and over, Diagnosis, Differential, Disease Progression, Female, Gait Disorders, Neurologic, Genetic Testing, Genotype, Humans, Male, Middle Aged, Parkinson Disease, Predictive Value of Tests, Supranuclear Palsy, Progressive, Tissue Banks, Young Adult
Abstract

BACKGROUND: Studies on early-onset presentations of progressive supranuclear palsy (PSP) have been limited to those where a rare monogenic cause has been identified. Here, we have defined early-onset PSP (EOPSP) and investigated its genetic and clinico-pathological profile in comparison with late-onset PSP (LOPSP) and Parkinsons disease (PD). METHODS: We included subjects from the Queen Square Brain Bank, PROSPECT-UK study, and Tracking Parkinsons study. Group comparisons of data were made using Welchs t-test and Kruskal-Wallis analysis of variance. EOPSP was defined as the youngest decile of motor age at onset (≤55 years) in the Queen Square Brain Bank PSP case series. RESULTS: We identified 33 EOPSP, 328 LOPSP, and 2000 PD subjects. The early clinical features of EOPSP usually involve limb parkinsonism and gait freezing, with 50% of cases initially misdiagnosed as having PD. We found that an initial clinical diagnosis of EOPSP had lower diagnostic sensitivity (33%) and positive predictive value (38%) in comparison with LOPSP (80% and 76%) using a postmortem diagnosis of PSP as the gold standard. 3/33 (9%) of the EOPSP group had an underlying monogenic cause. Using a PSP genetic risk score (GRS), we showed that the genetic risk burden in the EOPSP (mean z-score, 0.59) and LOPSP (mean z-score, 0.48) groups was significantly higher (P

Published
2019

9. How to apply the movement disorder society criteria for diagnosis of progressive supranuclear palsy.

Author

Grimm, Max-Joseph, Respondek, Gesine, Stamelou, Maria, Arzberger, Thomas, Ferguson, Leslie, Gelpi, Ellen, Giese, Armin, Grossman, Murray, Irwin, David J, Pantelyat, Alexander, Rajput, Alex, Roeber, Sigrun, van Swieten, John C, Troakes, Claire, Antonini, Angelo, Bhatia, Kailash P, Colosimo, Carlo, van Eimeren, Thilo, Kassubek, Jan, Levin, Johannes, Meissner, Wassilios G, Nilsson, Christer, Oertel, Wolfgang H, Piot, Ines, Poewe, Werner, Wenning, Gregor K, Boxer, Adam, Golbe, Lawrence I, Josephs, Keith A, Litvan, Irene, Morris, Huw R, Whitwell, Jennifer L, Compta, Yaroslau, Corvol, Jean-Christophe, Lang, Anthony E, Rowe, James B, Höglinger, Günter U, and Movement Disorder Society-endorsed PSP Study Group

Subjects
Movement Disorder Society-endorsed PSP Study Group, Brain, Humans, Parkinsonian Disorders, Supranuclear Palsy, Progressive, Ocular Motility Disorders, Sensation Disorders, Autopsy, Retrospective Studies, Cohort Studies, Adult, Aged, Aged, 80 and over, Middle Aged, Societies, Medical, Female, Male, Postural Balance, Cognitive Dysfunction, autopsy, diversity, phenotype, progressive supranuclear palsy, Brain Disorders, Pediatric, Neurosciences, Rare Diseases, Clinical Research, Perinatal Period - Conditions Originating in Perinatal Period, 4.2 Evaluation of markers and technologies, Neurology & Neurosurgery, Clinical Sciences, Human Movement and Sports Sciences
Abstract

BackgroundThe Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them.MethodsWe retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy-confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations.ResultsComprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1.ConclusionsThe proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society.

Published
2019

10. The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease

Author

Bandres‐Ciga, Sara, Saez‐Atienzar, Sara, Bonet‐Ponce, Luis, Billingsley, Kimberley, Vitale, Dan, Blauwendraat, Cornelis, Gibbs, Jesse Raphael, Pihlstrøm, Lasse, Gan‐Or, Ziv, Noyce, Alastair J, Kaiyrzhanov, Rauan, Middlehurst, Ben, Kia, Demis A, Tan, Manuela, Houlden, Henry, Morris, Huw R, Plun‐Favreau, Helene, Holmans, Peter, Hardy, John, Trabzuni, Daniah, Bras, Jose, Quinn, John, Mok, Kin Y, Kinghorn, Kerri J, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, RņBibo, Lea, Manzoni, Claudia, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott‐Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean‐Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, SimɃn‐Sȥnchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Nicolas, Aude, Cookson, Mark R, Craig, David W, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Van Keuren‐Jensen, Kendall, Shulman, Joshua M, Iwaki, Hirotaka, Leonard, Hampton L, Nalls, Mike A, Robak, Laurie, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E, Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W, Reed, Xylena, Alcalay, Roy N, Rouleau, Guy A, Hilten, Jacobus J, Marinus, Johan, Adarmes‐GɃmez, Astrid D, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesɐs Alberto Bergareche, Bernal‐Bernal, Inmaculada, Blazquez, Marta, Bonilla‐Toribio, Marta, Botȷa, Juan A, Boungiorno, Marȷa Teresa, Buiza‐Rueda, Dolores, Cȥmara, Ana, Carrillo, Fȥtima, CarriɃn‐Claro, Mario, Cerdan, Debora, ClarimɃn, Jordi, Compta, Yaroslau, Casa, Beatrȷz, Diez‐Fairen, Monica, Dols‐Icardo, Oriol, and Duarte, Jacinto

Subjects
Parkinson's Disease, Human Genome, Genetics, Neurosciences, Brain Disorders, Prevention, Neurodegenerative, Genetic Testing, 2.3 Psychological, social and economic factors, 2.1 Biological and endogenous factors, Aetiology, Decent Work and Economic Growth, Endocytosis, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Parkinson Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, International Parkinson's Disease Genomics Consortium, Parkinson's disease, endocytosis, genetic risk, heritability, polygenic risk score, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery
Abstract

BackgroundPD is a complex polygenic disorder. In recent years, several genes from the endocytic membrane-trafficking pathway have been suggested to contribute to disease etiology. However, a systematic analysis of pathway-specific genetic risk factors is yet to be performed.ObjectivesTo comprehensively study the role of the endocytic membrane-trafficking pathway in the risk of PD.MethodsLinkage disequilibrium score regression was used to estimate PD heritability explained by 252 genes involved in the endocytic membrane-trafficking pathway including genome-wide association studies data from 18,869 cases and 22,452 controls. We used pathway-specific single-nucleotide polymorphisms to construct a polygenic risk score reflecting the cumulative risk of common variants. To prioritize genes for follow-up functional studies, summary-data based Mendelian randomization analyses were applied to explore possible functional genomic associations with expression or methylation quantitative trait loci.ResultsThe heritability estimate attributed to endocytic membrane-trafficking pathway was 3.58% (standard error = 1.17). Excluding previously nominated PD endocytic membrane-trafficking pathway genes, the missing heritability was 2.21% (standard error = 0.42). Random heritability simulations were estimated to be 1.44% (standard deviation = 0.54), indicating that the unbiased total heritability explained by the endocytic membrane-trafficking pathway was 2.14%. Polygenic risk score based on endocytic membrane-trafficking pathway showed a 1.25 times increase of PD risk per standard deviation of genetic risk. Finally, Mendelian randomization identified 11 endocytic membrane-trafficking pathway genes showing functional consequence associated to PD risk.ConclusionsWe provide compelling genetic evidence that the endocytic membrane-trafficking pathway plays a relevant role in disease etiology. Further research on this pathway is warranted given that critical effort should be made to identify potential avenues within this biological process suitable for therapeutic interventions. © 2019 International Parkinson and Movement Disorder Society.

Published
2019

11. Assessing cognitive dysfunction in Parkinson's disease: An online tool to detect visuo‐perceptual deficits

Author

Weil, Rimona S, Schwarzkopf, Dietrich S, Bahrami, Bahador, Fleming, Stephen M, Jackson, Ben M, Goch, Tristam JC, Saygin, Ayse P, Miller, Luke E, Pappa, Katerina, Pavisic, Ivanna, Schade, Rachel N, Noyce, Alastair J, Crutch, Sebastian J, O'Keeffe, Aidan G, Schrag, Anette E, and Morris, Huw R

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Clinical Research, Dementia, Aging, Acquired Cognitive Impairment, Parkinson's Disease, Neurodegenerative, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Mental health, Adult, Aged, Aged, 80 and over, Cognition Disorders, Female, Humans, Male, Middle Aged, Motion Perception, Neuropsychological Tests, Online Systems, Parkinson Disease, Perceptual Disorders, Psychomotor Performance, Recognition, Psychology, Signal Detection, Psychological, Visual Acuity, Visual Perception, Parkinson's disease, vision, perception, hallucinations, signal detection theory, Human Movement and Sports Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundPeople with Parkinson's disease (PD) who develop visuo-perceptual deficits are at higher risk of dementia, but we lack tests that detect subtle visuo-perceptual deficits and can be performed by untrained personnel. Hallucinations are associated with cognitive impairment and typically involve perception of complex objects. Changes in object perception may therefore be a sensitive marker of visuo-perceptual deficits in PD.ObjectiveWe developed an online platform to test visuo-perceptual function. We hypothesised that (1) visuo-perceptual deficits in PD could be detected using online tests, (2) object perception would be preferentially affected, and (3) these deficits would be caused by changes in perception rather than response bias.MethodsWe assessed 91 people with PD and 275 controls. Performance was compared using classical frequentist statistics. We then fitted a hierarchical Bayesian signal detection theory model to a subset of tasks.ResultsPeople with PD were worse than controls at object recognition, showing no deficits in other visuo-perceptual tests. Specifically, they were worse at identifying skewed images (P

Published
2018

12. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases.

Author

Witoelar, Aree, Jansen, Iris E, Wang, Yunpeng, Desikan, Rahul S, Gibbs, J Raphael, Blauwendraat, Cornelis, Thompson, Wesley K, Hernandez, Dena G, Djurovic, Srdjan, Schork, Andrew J, Bettella, Francesco, Ellinghaus, David, Franke, Andre, Lie, Benedicte A, McEvoy, Linda K, Karlsen, Tom H, Lesage, Suzanne, Morris, Huw R, Brice, Alexis, Wood, Nicholas W, Heutink, Peter, Hardy, John, Singleton, Andrew B, Dale, Anders M, Gasser, Thomas, Andreassen, Ole A, Sharma, Manu, and International Parkinson’s Disease Genomics Consortium (IPDGC), North American Brain Expression Consortium (NABEC), and United Kingdom Brain Expression Consortium (UKBEC) Investigators

Subjects
International Parkinson’s Disease Genomics Consortium (IPDGC), North American Brain Expression Consortium (NABEC), and United Kingdom Brain Expression Consortium (UKBEC) Investigators, Humans, Arthritis, Rheumatoid, Colitis, Ulcerative, Crohn Disease, Celiac Disease, Multiple Sclerosis, Parkinson Disease, Psoriasis, Diabetes Mellitus, Type 1, Autoimmune Diseases, Genetic Predisposition to Disease, Risk Factors, Genome-Wide Association Study, Genetic Loci, Genetic Pleiotropy, Prevention, Neurosciences, Brain Disorders, Digestive Diseases, Autoimmune Disease, Aging, Arthritis, Biotechnology, Neurodegenerative, Parkinson's Disease, Genetics, Human Genome, Inflammatory Bowel Disease, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Neurological, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ImportanceRecent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes.ObjectivesTo test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach.Design, setting, and participantsUsing the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017.Main outcomes and measuresThe primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases.ResultsGenome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes.Conclusions and relevanceThe study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.

Published
2017

13. Which ante mortem clinical features predict progressive supranuclear palsy pathology?

Author

Respondek, Gesine, Kurz, Carolin, Arzberger, Thomas, Compta, Yaroslau, Englund, Elisabet, Ferguson, Leslie W, Gelpi, Ellen, Giese, Armin, Irwin, David J, Meissner, Wassilios G, Nilsson, Christer, Pantelyat, Alexander, Rajput, Alex, van Swieten, John C, Troakes, Claire, Josephs, Keith A, Lang, Anthony E, Mollenhauer, Brit, Müller, Ulrich, Whitwell, Jennifer L, Antonini, Angelo, Bhatia, Kailash P, Bordelon, Yvette, Corvol, Jean‐Christophe, Colosimo, Carlo, Dodel, Richard, Grossman, Murray, Kassubek, Jan, Krismer, Florian, Levin, Johannes, Lorenzl, Stefan, Morris, Huw, Nestor, Peter, Oertel, Wolfgang H, Rabinovici, Gil D, Rowe, James B, van Eimeren, Thilo, Wenning, Gregor K, Boxer, Adam, Golbe, Lawrence I, Litvan, Irene, Stamelou, Maria, Höglinger, Günter U, and Group, for the Movement Disorder Society‐Endorsed PSP Study

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Brain Disorders, Dementia, Alzheimer's Disease Related Dementias (ADRD), Pick's Disease, Rare Diseases, Acquired Cognitive Impairment, Neurodegenerative, Neurosciences, Aging, Parkinson's Disease, Frontotemporal Dementia (FTD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Neurological, Humans, Supranuclear Palsy, Progressive, Progressive supranuclear palsy, clinical features, diagnosis, clinico-pathological series, systematic review, Movement Disorder Society-Endorsed PSP Study Group, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundProgressive supranuclear palsy (PSP) is a neuropathologically defined disease presenting with a broad spectrum of clinical phenotypes.ObjectiveTo identify clinical features and investigations that predict or exclude PSP pathology during life, aiming at an optimization of the clinical diagnostic criteria for PSP.MethodsWe performed a systematic review of the literature published since 1996 to identify clinical features and investigations that may predict or exclude PSP pathology. We then extracted standardized data from clinical charts of patients with pathologically diagnosed PSP and relevant disease controls and calculated the sensitivity, specificity, and positive predictive value of key clinical features for PSP in this cohort.ResultsOf 4166 articles identified by the database inquiry, 269 met predefined standards. The literature review identified clinical features predictive of PSP, including features of the following 4 functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. No biomarker or genetic feature was found reliably validated to predict definite PSP. High-quality original natural history data were available from 206 patients with pathologically diagnosed PSP and from 231 pathologically diagnosed disease controls (54 corticobasal degeneration, 51 multiple system atrophy with predominant parkinsonism, 53 Parkinson's disease, 73 behavioral variant frontotemporal dementia). We identified clinical features that predicted PSP pathology, including phenotypes other than Richardson's syndrome, with varying sensitivity and specificity.ConclusionsOur results highlight the clinical variability of PSP and the high prevalence of phenotypes other than Richardson's syndrome. The features of variant phenotypes with high specificity and sensitivity should serve to optimize clinical diagnosis of PSP. © 2017 International Parkinson and Movement Disorder Society.

Published
2017

14. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria.

Author

Höglinger, Günter U, Respondek, Gesine, Stamelou, Maria, Kurz, Carolin, Josephs, Keith A, Lang, Anthony E, Mollenhauer, Brit, Müller, Ulrich, Nilsson, Christer, Whitwell, Jennifer L, Arzberger, Thomas, Englund, Elisabet, Gelpi, Ellen, Giese, Armin, Irwin, David J, Meissner, Wassilios G, Pantelyat, Alexander, Rajput, Alex, van Swieten, John C, Troakes, Claire, Antonini, Angelo, Bhatia, Kailash P, Bordelon, Yvette, Compta, Yaroslau, Corvol, Jean-Christophe, Colosimo, Carlo, Dickson, Dennis W, Dodel, Richard, Ferguson, Leslie, Grossman, Murray, Kassubek, Jan, Krismer, Florian, Levin, Johannes, Lorenzl, Stefan, Morris, Huw R, Nestor, Peter, Oertel, Wolfgang H, Poewe, Werner, Rabinovici, Gil, Rowe, James B, Schellenberg, Gerard D, Seppi, Klaus, van Eimeren, Thilo, Wenning, Gregor K, Boxer, Adam L, Golbe, Lawrence I, Litvan, Irene, and Movement Disorder Society-endorsed PSP Study Group

Subjects
Movement Disorder Society-endorsed PSP Study Group, Humans, Supranuclear Palsy, Progressive, Societies, Medical, Practice Guidelines as Topic, clinical diagnostic criteria, consensus-based, evidence-based, progressive supranuclear palsy, Brain Disorders, Neurosciences, Neurological, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery
Abstract

BackgroundPSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome.ObjectiveWe aimed to provide an evidence- and consensus-based revision of the clinical diagnostic criteria for PSP.MethodsWe searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles published in English since 1996, using postmortem diagnosis or highly specific clinical criteria as the diagnostic standard. Second, we generated retrospective standardized clinical data from patients with autopsy-confirmed PSP and control diseases. On this basis, diagnostic criteria were drafted, optimized in two modified Delphi evaluations, submitted to structured discussions with consensus procedures during a 2-day meeting, and refined in three further Delphi rounds.ResultsDefined clinical, imaging, laboratory, and genetic findings serve as mandatory basic features, mandatory exclusion criteria, or context-dependent exclusion criteria. We identified four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Within each of these domains, we propose three clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by three degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP). Clinical clues and imaging findings represent supportive features.ConclusionsHere, we present new criteria aimed to optimize early, sensitive, and specific clinical diagnosis of PSP on the basis of currently available evidence. © 2017 International Parkinson and Movement Disorder Society.

Published
2017

15. A genome-wide association study in multiple system atrophy

Author

Sailer, Anna, Scholz, Sonja W, Nalls, Michael A, Schulte, Claudia, Federoff, Monica, Price, T Ryan, Lees, Andrew, Ross, Owen A, Dickson, Dennis W, Mok, Kin, Mencacci, Niccolo E, Schottlaender, Lucia, Chelban, Viorica, Ling, Helen, O'Sullivan, Sean S, Wood, Nicholas W, Traynor, Bryan J, Ferrucci, Luigi, Federoff, Howard J, Mhyre, Timothy R, Morris, Huw R, Deuschl, Günther, Quinn, Niall, Widner, Hakan, Albanese, Alberto, Infante, Jon, Bhatia, Kailash P, Poewe, Werner, Oertel, Wolfgang, Höglinger, Günter U, Wüllner, Ullrich, Goldwurm, Stefano, Pellecchia, Maria Teresa, Ferreira, Joaquim, Tolosa, Eduardo, Bloem, Bastiaan R, Rascol, Olivier, Meissner, Wassilios G, Hardy, John A, Revesz, Tamas, Holton, Janice L, Gasser, Thomas, Wenning, Gregor K, Singleton, Andrew B, Houlden, Henry, Calandra-Buonaura, Giovanna, Capellari, Sabina, and Cortelli, Pietro

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Alkyl and Aryl Transferases, Brain, Cohort Studies, Europe, Genetic Loci, Genome-Wide Association Study, Genotyping Techniques, Humans, Multiple System Atrophy, Polymorphism, Single Nucleotide, RNA, Messenger, United States, Whites, alpha-Synuclein, European Multiple System Atrophy Study Group and the UK Multiple System Atrophy Study Group, White People, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS).MethodsWe performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed.ResultsWe found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10-6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA.ConclusionsWe present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.

Published
2016

16. Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study

Author

Nalls, Mike A, McLean, Cory Y, Rick, Jacqueline, Eberly, Shirley, Hutten, Samantha J, Gwinn, Katrina, Sutherland, Margaret, Martinez, Maria, Heutink, Peter, Williams, Nigel M, Hardy, John, Gasser, Thomas, Brice, Alexis, Price, T Ryan, Nicolas, Aude, Keller, Margaux F, Molony, Cliona, Gibbs, J Raphael, Chen-Plotkin, Alice, Suh, Eunran, Letson, Christopher, Fiandaca, Massimo S, Mapstone, Mark, Federoff, Howard J, Noyce, Alastair J, Morris, Huw, Van Deerlin, Vivianna M, Weintraub, Daniel, Zabetian, Cyrus, Hernandez, Dena G, Lesage, Suzanne, Mullins, Meghan, Conley, Emily Drabant, Northover, Carrie AM, Frasier, Mark, Marek, Ken, Day-Williams, Aaron G, Stone, David J, Ioannidis, John PA, Singleton, Andrew B, and investigators*, Parkinson's Disease Biomarkers Program and Parkinson's Progression Marker Initiative

Subjects
Aging, Prevention, Neurodegenerative, Brain Disorders, Neurosciences, Parkinson's Disease, Clinical Research, 2.1 Biological and endogenous factors, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Aetiology, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Good Health and Well Being, Aged, Cohort Studies, Disease Progression, Female, Humans, Male, Middle Aged, Models, Statistical, Parkinson Disease, Prodromal Symptoms, Parkinson's Disease Biomarkers Program and Parkinson's Progression Marker Initiative investigators, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundAccurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts.MethodsWe developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD).FindingsIn the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0·923 (95% CI 0·900-0·946) with high sensitivity (0·834, 95% CI 0·711-0·883) and specificity (0·903, 95% CI 0·824-0·946) at its optimum AUC threshold (0·655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0·894 (95% CI 0·867-0·921) in the PDBP cohort, 0·998 (0·992-1·000) in PARS, 0·955 (no 95% CI available) in 23andMe, 0·929 (0·896-0·962) in LABS-PD, and 0·939 (0·891-0·986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0·003).InterpretationOur model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions.FundingNational Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation.

Published
2015

17. Network connectivity and structural correlates of survival in progressive supranuclear palsy and corticobasal syndrome

Author

Whiteside, David J, Street, Duncan, Murley, Alexander G, Jones, P Simon, Malpetti, Maura, Ghosh, Boyd CP, Coyle-Gilchrist, Ian, Gerhard, Alexander, Hu, Michele T, Klein, Johannes C, Leigh, P Nigel, Church, Alistair, Burn, David J, Morris, Huw R, Rowe, James B, Rittman, Timothy, Whiteside, David J [0000-0002-5890-9220], Klein, Johannes C [0000-0002-8553-2801], Apollo - University of Cambridge Repository, Whiteside, David J. [0000-0002-5890-9220], and Klein, Johannes C. [0000-0002-8553-2801]

Subjects
Corticobasal Degeneration, connectivity, tauopathies, fMRI, Medizin, Humans, Neurodegenerative Diseases, corticobasal syndrome, prediction, progressive supranuclear palsy, Supranuclear Palsy, Progressive, Prognosis, survival
Abstract

in press; CA extern There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson-plus and the UK National PSP Research Network (PROSPECT-MR). Resting-state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large-scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between-network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five-fold cross-validation. In PSP and CBS, between-network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between-network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics.

Published
2023

18. Creation of an open-access, mutation-defined fibroblast resource for neurological disease research.

Author

Wray, Selina, Self, Matthew, NINDS Parkinson's Disease iPSC Consortium, NINDS Huntington's Disease iPSC Consortium, NINDS ALS iPSC Consortium, Lewis, Patrick A, Taanman, Jan-Willem, Ryan, Natalie S, Mahoney, Colin J, Liang, Yuying, Devine, Michael J, Sheerin, Una-Marie, Houlden, Henry, Morris, Huw R, Healy, Daniel, Marti-Masso, Jose-Felix, Preza, Elisavet, Barker, Suzanne, Sutherland, Margaret, Corriveau, Roderick A, D'Andrea, Michael, Schapira, Anthony HV, Uitti, Ryan J, Guttman, Mark, Opala, Grzegorz, Jasinska-Myga, Barbara, Puschmann, Andreas, Nilsson, Christer, Espay, Alberto J, Slawek, Jaroslaw, Gutmann, Ludwig, Boeve, Bradley F, Boylan, Kevin, Stoessl, A Jon, Ross, Owen A, Maragakis, Nicholas J, Van Gerpen, Jay, Gerstenhaber, Melissa, Gwinn, Katrina, Dawson, Ted M, Isacson, Ole, Marder, Karen S, Clark, Lorraine N, Przedborski, Serge E, Finkbeiner, Steven, Rothstein, Jeffrey D, Wszolek, Zbigniew K, Rossor, Martin N, and Hardy, John

Subjects
NINDS Parkinson's Disease iPSC Consortium, NINDS Huntington's Disease iPSC Consortium, NINDS ALS iPSC Consortium, Cell Line, Fibroblasts, Humans, Nervous System Diseases, Biopsy, Immunohistochemistry, Cell Differentiation, Cell Proliferation, Mutation, Models, Genetic, Access to Information, Databases, Factual, Tissue Banks, Induced Pluripotent Stem Cells, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research - Induced Pluripotent Stem Cell, Genetics, Stem Cell Research, Neurosciences, Brain Disorders, Aetiology, 2.6 Resources and infrastructure (aetiology), 2.1 Biological and endogenous factors, Generic health relevance, Neurological, General Science & Technology
Abstract

Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.

Published
2012

19. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Author

Swarup, Vivek, Hinz, Flora I., Rexach, Jessica E., Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T., Cheng, Chialin, Haggarty, Stephen J., Ferrari, Raffaele, Rohrer, Jonathan D., Ramasamy, Adaikalavan, Hardy, John, Hernandez, Dena G., Nalls, Michael A., Singleton, Andrew B., Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cairns, Nigel J., Cruchaga, Carlos, Binetti, Giuliano, Ghidoni, Roberta, Benussi, Luisa, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Jaros, Evelyn, Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Tierney, Michael C., Baborie, Atik, Pastor, Pau, Ortega-Cubero, Sara, Razquin, Cristina, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter St., Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., Pickering-Brown, Stuart, Momeni, Parastoo, van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Leber, Isabelle, Brice, Alexis, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Gasparoni, Gilles, Pichler, Sabrina, Ibach, Bernd, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Gerhard, Alexander, Richardson, Anna, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, Seeley, William W., van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Ferrucci, Luigi, Kapogiannis, Dimitrios, Lah, James J., Levey, Allan I., Kondou, Shinichi, Geschwind, Daniel H., Int Frontotemporal Dementia Gen, Swarup, Vivek, Hinz, Flora I., Rexach, Jessica E., Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T., Cheng, Chialin, Haggarty, Stephen J., Ferrari, Raffaele, Rohrer, Jonathan D., Ramasamy, Adaikalavan, Hardy, John, Hernandez, Dena G., Nalls, Michael A., Singleton, Andrew B., Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cairns, Nigel J., Cruchaga, Carlo, Binetti, Giuliano, Ghidoni, Roberta, Benussi, Luisa, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johanne, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Jaros, Evelyn, Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Tierney, Michael C., Baborie, Atik, Pastor, Pau, Ortega-Cubero, Sara, Razquin, Cristina, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagioti, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter St., Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, Jame, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., Pickering-Brown, Stuart, Momeni, Parastoo, van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Leber, Isabelle, Brice, Alexi, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthia, Mayhaus, Manuel, Gasparoni, Gille, Pichler, Sabrina, Ibach, Bernd, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Gerhard, Alexander, Richardson, Anna, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, Seeley, William W., van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Ferrucci, Luigi, Kapogiannis, Dimitrio, Lah, James J., Levey, Allan I., Kondou, Shinichi, and Geschwind, Daniel H.

Subjects
Proteomics, Genetics and Molecular Biology (all), 0301 basic medicine, Messenger, Gene regulatory network, Inbred C57BL, Biochemistry, Transgenic, Mice, 0302 clinical medicine, Gene Regulatory Networks, Regulation of gene expression, Cell Death, Drug discovery, Neurodegeneration, Neurodegenerative Diseases, General Medicine, Chemistry, Frontotemporal Dementia, 030220 oncology & carcinogenesis, Frontotemporal dementia, Evolution, Systems biology, Genetic Vectors, Animals, Dementia, Disease Models, Animal, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, RNA, Messenger, Reproducibility of Results, Transcriptome, tau Proteins, Evolution, Molecular, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, microRNA, medicine, Biochemistry, Genetics and Molecular Biology (all), Animal, Molecular, medicine.disease, 030104 developmental biology, Disease Models, RNA, Human medicine
Abstract

Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

Published
2018

20. Validation of the movement disorder society criteria for the diagnosis of 4-repeat tauopathies

Author

Respondek, Gesine, Grimm, Max‐Joseph, Piot, Ines, Arzberger, Thomas, Compta, Yaroslau, Englund, Elisabet, Ferguson, Leslie W., Gelpi, Ellen, Roeber, Sigrun, Giese, Armin, Grossman, Murray, Irwin, David J., Meissner, Wassilios G., Nilsson, Christer, Pantelyat, Alexander, Rajput, Alex, Swieten, John C., Troakes, Claire, Höglinger, Günter U., Aiba, Ikuko, Antonini, Angelo, Barone, Paolo, Bhatia, Kailash P., Boxer, Adam K., Colosimo, Carlo, Corvol, Jean Christophe, Dickson, Dennis W., Golbe, Lawrence I., Hopfner, Franziska, Josephs, Keith A., Kassubek, Jan, Kovacs, Gabor G., Lang, Anthony E., Levin, Johannes, Litvan, Irene, Höllerhage, Matthias, McFarland, Nikolaus, Morris, Huw R., Müller, Ulrich, Oertel, Wolfgang H., Rowe, James B., Sakakibara, Ruji, Schellenberg, Gerard, Stamelou, Maria, Eimeren, Thilo, Wenning, Gregor K., Whitwell, Jennifer L., and Neurology

Subjects
0301 basic medicine, Male, pathology [Tauopathies], Pediatrics, medicine.medical_specialty, pathology [Supranuclear Palsy, Progressive], Disease, pathology [Parkinsonian Disorders], Progressive supranuclear palsy, 03 medical and health sciences, 0302 clinical medicine, Atrophy, pathology [Brain], medicine, pathology [Multiple System Atrophy], Diagnostic biomarker, Corticobasal degeneration, Humans, ddc:610, Aged, corticobasal degeneration, diagnostic criteria, Four-repeat tauopathies, progressive supranuclear palsy, business.industry, Frontotemporal lobar degeneration, Middle Aged, medicine.disease, Therapeutic trial, pathology [Parkinson Disease], 030104 developmental biology, Neurology, Clinical diagnosis, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

The Movement Disorder Society criteria for progressive supranuclear palsy introduced the category 'probable 4-repeat (4R)-tauopathy' for joint clinical diagnosis of progressive supranuclear palsy and corticobasal degeneration.To validate the accuracy of these clinical criteria for 'probable 4R-tauopathy' to predict underlying 4R-tauopathy pathology.Diagnostic accuracy for 4R-tauopathies according to the established criteria was estimated retrospectively in autopsy-confirmed patients with progressive supranuclear palsy and corticobasal degeneration (grouped as 4R-tauopathies), and Parkinson's disease, multiple system atrophy, and frontotemporal lobar degeneration (grouped as non-4R-tauopathies).We identified 250 cases with progressive supranuclear palsy (N = 195) and corticobasal degeneration (N = 55) and with and non-4R-tauopathies (N = 161). Sensitivity and specificity of 'probable 4R-tauopathy' was 10% and 99% in the first year and 59% and 88% at final record.The new diagnostic category 'probable 4R-tauopathy' showed high specificity and may be suitable for the recruitment of patients with progressive supranuclear palsy and corticobasal degeneration into therapeutic trials targeting 4R-tauopathy. The low sensitivity underpins the need for diagnostic biomarkers. © 2019 International Parkinson and Movement Disorder Society.

Published
2020

21. Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning: Dementia Praecox Revisited

Author

Koutsouleris, Nikolaos, Pantelis, Christos, Kambeitz, Joseph, Toivonen, Anna, Turtonen, Otto, Botterweck, Sonja, Kluthausen, Norman, Antoch, Gerald, Caspers, Julian, Wittsack, Hans-Jörg, Blasi, Giuseppe, Pergola, Giulio, Caforio, Grazia, Salokangas, Raimo K R, Fazio, Leonardo, Quarto, Tiziana, Gelao, Barbara, Romano, Raffaella, Andriola, Ileana, Falsetti, Andrea, Barone, Marina, Passiatore, Roberta, Sangiuliano, Marina, Surmann, Marian, Hietala, Jarmo, Bienek, Olga, Dannlowski, Udo, Solana, Ana Beatriz, Abraham, Manuela, Schirmer, Timo, Ferro, Adele, Re, Marta, Sberna, Maurizio, D'Agostino, Armando, Del Fabro, Lorenzo, Bertolino, Alessandro, Perna, Giampaolo, Nobile, Maria, Balestrieri, Matteo, Bonivento, Carolina, Cabras, Giuseppe, Fabbro, Franco, Delvecchio, Giuseppe, Maggioni, Eleonora, Squarcina, Letizia, Gritti, Davide, Brambilla, Paolo, Rossetti, Maria Gloria, Ferrari, Raffaele, Hernandez, Dena Michelle Godwin, Nalls, Michael, Rohrer, Jonathan, Ramasamy, Adaikalavan, Kwok, John, Dobson-Stone, Carol, Brooks, William, Schofield, Peter, Upthegrove, Rachel, Halliday, Glenda, Hodges, John, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Wood, Stephen J, Cruchaga, Carlos, Cairns, Nigel, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Lencer, Rebekka, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Landqvist Waldö, Maria, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging-Yuek, Mann, David, Borgwardt, Stefan, Grafman, Jordan, Morris, Christopher, Attems, Johannes, McKeith, Ian, Thomas, Alan, Pietrini, Pietro, Huey, Edward, Wassermann, Eric, Baborie, Atik, Jaros, Evelyn, Maj, Carlo, Tierney, Michael, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Velakoulis, Dennis, Nöthen, Markus M., Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James, Schlachetzki, Johannes, Uphill, James, Collinge, John, Degenhardt, Franziska, Mead, Simon, Van Deerlin, Vivianna, Marschhauser, Anke, Regenbrecht, Frank, Thoene-Otto, Angelika, Gordulla, Jannis, Ballarini, Tommaso, Engel, Annerose, Pino, Daniele, Leuthold, Dominique, Polyakova, Maryna, Naumann, Heike, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Van Broeckhofen, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Mueller, Karsten, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Villringer, Arno, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N, Fox, Nick C, Warren, Jason D, Spillantini, Maria Grazia, Morris, Huw R, Rizzu, Patrizia, Heutink, Peter, Danek, Adrian, Snowden, Julie S, Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C, Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Fassbender, Klaus, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W, Graff-Radford, Neill R, Petersen, Ronald C, Knopman, David S, Josephs, Keith A, Fliessbach, Klaus, Boeve, Bradley F, Parisi, Joseph E, Seeley, William W, Miller, Bruce L, Karydas, Anna M, Rosen, Howard, van Swieten, John C, Dopper, Elise Gp, Seelaar, Harro, Pijnenburg, Yolande Al, Jahn, Holger, Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A, Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Kornhuber, Johannes, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B, McGuire, Philip, Landwehrmeyer, Bernhard, Hardy, John, Momeni, Parastoo, Barthel, Henryk, Elisa, Semler, Jolina, Lombardi, Christine, von Arnim, Felix, Oberahauser, Kai, Schumacher, Jan, Lehmbeck, Juan-Manuel, Maler, Anderl-Straub, Sarah, Tanja, Richter-Schmidinger, Anke, Hammer-Kaspereit, Timo, Oberstein, Felix, Müller-Sarnowski, Carola, Roßmeier, Albert, Ludolph, Jan, Kassubek, Anja, Schneider, Johannes, Levin, Prudlo, Johannes, Synofzik, Matthis, Wiltfang, Jens, Riedl, Lina, Diehl-Schmid, Janine, Otto, Markus, Meisenzahl, Eva, Falkai, Peter, Dwyer, Dominic B, Schroeter, Matthias L, Consortium, the PRONIA, Haas, Shalaila, Hasan, Alkomiet, Hoff, Claudius, Khanyaree, Ifrah, Melo, Aylin, Muckenhuber-Sternbauer, Susanna, Köhler, Yanis, Urquijo-Castro, Maria-Fernanda, Öztürk, Ömer, Penzel, Nora, Rangnick, Adrian, von Saldern, Sebastian, Spangemacher, Moritz, Tupac, Ana, Weiske, Johanna, Wosgien, Antonia, Krämer, Camilla, Blume, Karsten, Paul, Riya, Hedderich, Dennis, Julkowski, Dominika, Kaiser, Nathalie, Lichtenstein, Thorsten, Milz, Ruth, Nikolaides, Alexandra, Pilgram, Tanja, Seves, Mauro, Wassen, Martina, Andreou, Christina, Dong, Sen, Egloff, Laura, Harrisberger, Fabienne, Heitz, Ulrike, Lenz, Claudia, Leanza, Letizia, Mackintosh, Amatya, Smieskova, Renata, Studerus, Erich, Walter, Anna, Widmayer, Sonja, Popovic, David, Day, Chris, Lowri Griffiths, Sian, Iqbal, Mariam, Pelton, Mirabel, Mallikarjun, Pavan, Stainton, Alexandra, Lin, Ashleigh, Lalousis, Paris, Denissoff, Alexander, Ellilä, Anu, Oeztuerk, Oemer, From, Tiina, Heinimaa, Markus, Ilonen, Tuula, Jalo, Päivi, Laurikainen, Heikki, Luutonen, Antti, Mäkela, Akseli, Paju, Janina, Pesonen, Henri, Säilä, Reetta-Liina, International FTD-Genetics Consortium (IFGC), German Frontotemporal Lobar Degeneration (FTLD) Consortium, PRONIA Consortium, and International FTD-Genetics Consortium Consortium

Subjects
Adult, Male, Medizin, genetics [Alzheimer Disease], genetics [Psychotic Disorders], Neuropsychological Tests, diagnostic imaging [Frontotemporal Dementia], diagnostic imaging [Psychotic Disorders], Machine Learning, methods [Magnetic Resonance Imaging], Brain, Female, Humans, Magnetic Resonance Imaging, Alzheimer Disease, Frontotemporal Dementia, Psychotic Disorders, Schizophrenia, pathology [Brain], genetics [Schizophrenia], ddc:610, diagnostic imaging [Brain], genetics [Frontotemporal Dementia], Settore MED/25 - Psichiatria, Psychiatry and Mental health, diagnostic imaging [Schizophrenia], diagnostic imaging [Alzheimer Disease]
Abstract

Weitere Nicht-UDE Autoren sind nicht genannt. Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2= 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2= 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.

Published
2022

22. Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

Author

Bourinaris, Thomas, Smedley, Damian, Cipriani, Valentina, Sheikh, Isabella, Athanasiou-Fragkouli, Alkyoni, Chinnery, Patrick, Morris, Huw, Real, Raquel, Harrison, Victoria, Reid, Evan, Wood, Nicholas, Genomics England Research Consortium, Vandrovcova, Jana, Houlden, Henry, Tucci, Arianna, Smedley, Damian [0000-0002-5836-9850], Sheikh, Isabella [0000-0002-3952-371X], Chinnery, Patrick [0000-0002-7065-6617], Morris, Huw [0000-0002-5473-3774], Real, Raquel [0000-0001-8117-742X], Houlden, Henry [0000-0002-2866-7777], Tucci, Arianna [0000-0001-5644-0070], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Phenotype, Adolescent, Spastic Paraplegia, Hereditary, Mutation, Humans, Female, Middle Aged, Carrier Proteins, Child, Aged
Abstract

Hereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

Published
2020

23. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Author

Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS

Subjects
Adult, Male, TDP-43, C9orf72, SLITRK2, amyotrophic lateral sclerosis, frontotemporal dementia, Nerve Tissue Proteins, Settore MED/03 - GENETICA MEDICA, Polymorphism, Single Nucleotide, Cohort Studies, Genes, X-Linked, 80 and over, Medicine, Dementia, Humans, Allele, Age of Onset, Polymorphism, Aged, Aged, 80 and over, biology, C9orf72 Protein, business.industry, Membrane Proteins, MESH: Frontotemporal Lobar Degeneration / epidemiology, Frontotemporal Lobar, Degeneration / genetics, Genes, X-Linked / genetics, Genome-Wide Association Study / methods, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, X-Linked, medicine.disease, Amyotrophic lateral sclerosis, Minor allele frequency, Genes, Immunology, Synaptophysin, biology.protein, Female, MESH: Adult, C9orf72 Protein / genetics, Frontotemporal Lobar Degeneration / diagnosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Neurology (clinical), MESH: Humans, Membrane Proteins / genetics, Nerve Tissue Proteins / genetics, Polymorphism, Single Nucleotide / genetics, Age of onset, Frontotemporal Lobar Degeneration, business, Frontotemporal dementia, Genome-Wide Association Study
Abstract

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Published
2021

24. Neural correlates of early cognitive dysfunction in Parkinson's disease

Author

Weil, Rimona S., Winston, Joel S., Leyland, Louise-Ann, Pappa, Katerina, Mahmood, Ribeya B., Morris, Huw R., and Rees, Geraint

Subjects
Male, Parkinson Disease, Neurosciences. Biological psychiatry. Neuropsychiatry, Middle Aged, Neuropsychological Tests, Gyrus Cinguli, Magnetic Resonance Imaging, behavioral disciplines and activities, Parietal Lobe, Neural Pathways, Humans, Cognitive Dysfunction, Dementia, Female, Perception, Neurology. Diseases of the nervous system, Cognition Disorders, RC346-429, Research Articles, psychological phenomena and processes, Research Article, Aged, RC321-571
Abstract

Objective: \ud Dementia is a common and feared aspect of Parkinson's disease but there are no robust predictors of cognitive outcome. Visuoperceptual deficits are linked to risk of dementia in Parkinson's disease but whether they predict cognitive change is not known, and the neural substrates of visuoperceptual dysfunction in Parkinson's have not yet been identified.\ud \ud Methods: \ud We compared patients with Parkinson's disease and unaffected controls who underwent BOLD fMRI while performing our previously validated visuoperceptual task and tested how functional connectivity between task‐specific regions and the rest of the brain differed between patients who performed well and poorly in the task.\ud \ud Results: \ud We show that task performance at baseline predicts change in cognition in Parkinson's disease after 1 year. Our task‐based fMRI study showed that the performance in this task is associated with activity in the posterior cingulate cortex/precuneus. We found that functional connectivity between this region and dorsomedial prefrontal cortex was reduced in poor performers compared with good performers of this task.\ud \ud Interpretation: \ud Our findings suggest that functional connectivity is reduced between posterior and anterior hubs of the default mode network in Parkinson's patients who are likely to progress to worsening cognitive dysfunction. Our work implicates posterior default mode nodes and their connections as key brain regions in early stages of dementia in Parkinson's disease.

Published
2019

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

Author

Kia, Demis A., Zhang, David, Guelfi, Sebastian, Manzoni, Claudia, Hubbard, Leon, Reynolds, Regina H., Botía, Juan, Ryten, Mina, Ferrari, Raffaele, Lewis, Patrick A., Williams, Nigel, Trabzuni, Daniah, Hardy, John, Wood, Nicholas W., Noyce, Alastair J., Kaiyrzhanov, Rauan, Middlehurst, Ben, Tan, Manuela, Houlden, Henry, Morris, Huw R., Plun-Favreau, Helene, Holmans, Peter, Bras, Jose, PhD, John Quinn, Mok, Kin Y., Kinghorn, Kerri J., Billingsley, Kimberley, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, R'Bibo, Lea, Rizig, Mie, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean-Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, Simón-Sánchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Nicolas, Aude, Cookson, Mark R., Bandres-Ciga, Sara, Blauwendraat, Cornelis, Craig, David W., Faghri, Faraz, Gibbs, J. Raphael, Hernandez, Dena G., Van Keuren-Jensen, Kendall, Shulman, Joshua M., Leonard, Hampton L., Nalls, Mike A., Robak, Laurie, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E., Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W., Reed, Xylena, Alcalay, Roy N., Gan-Or, Ziv, Rouleau, Guy A., Krohn, Lynne, van Hilten, Jacobus J., Marinus, Johan, Adarmes-Gómez, Astrid D., Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Javier Barrero, Francisco, Bergareche Yarza, Jesús A., Bernal-Bernal, Inmaculada, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A., Boungiorno, María T., Buiza-Rueda, Dolores, Càmara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernàndez, Manel, Fernàndez-Santiago, Rubén, Garcia, Ciara, García-Ruiz, Pedro, Gómez-Garre, Pilar, Gomez Heredia, Maria J., Gonzalez-Aramburu, Isabel, Pagola, Ana G., Hoenicka, Janet, Infante, Jon, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A., Lopez-Sendon, Jose Luis, Arregui, Adolfo López de Munain, Macias, Daniel, Torres, Irene Martínez, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Mèndez-del-Barrio, Carlota, González, Manuel Menéndez, Adolfo Mínguez, Marina Mata, Mir, Pablo, Rezola, Elisabet Mondragon, Muñoz, Esteban, Pagonabarraga, Javier, Pastor, Pau, Errazquin, Francisco Perez, Perinán-Tocino, Teresa, Ruiz-Martínez, Javier, Ruz, Clara, Rodriguez, Antonio Sanchez, Sierra, María, Suarez-Sanmartin, Esther, Tabernero, Cesar, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Toft, Mathias, Koks, Sulev, Taba, Pille, Hassin-Baer, Sharon, Weale, Michael, Ramasamy, Adaikalavan, Smith, Colin, Guelfi, Manuel Sebastian, D'sa, Karishma, Forabosco, Paola, Botiá, Juan A., and Universidad de Cantabria

Subjects
Candidate gene, Protein catabolic process, Gene Expression, Genome-wide association study, Computational biology, Biology, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Databases, Genetic, Humans, Online First, 030212 general & internal medicine, Epigenetics, Gene, Genetic Association Studies, Genetic association, Original Investigation, Research, Parkinson Disease, Protein ubiquitination, Neurology (clinical), Candidate Disease Gene, 030217 neurology & neurosurgery, Comments, Genome-Wide Association Study
Abstract

Key Points Question What genes and genomic processes underlie risk of sporadic Parkinson disease? Findings This genetic association study integrated Parkinson disease genome-wide association study data and brain-derived gene regulation data using various complementary bioinformatic tools and identified 11 candidate genes with evidence of disease-associated regulatory changes. Coexpression and protein level analyses of these genes demonstrated a significant functional association with known mendelian Parkinson disease genes. Meaning This study suggests that gene regulation data may be used to identify candidate genes and pathways involved in sporadic Parkinson disease., 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., This genetic association study investigates what genes and genomic processes underlie the risk of sporadic Parkinson disease.

Published
2021

26. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

Author

Chia, Ruth, Sabir, Marya S, Makarious, Mary B, Serrano, Geidy E, Beach, Thomas G, McKeith, Ian G, Thomas, Alan J, Attems, Johannes, Morris, Christopher M, Palmer, Laura, Love, Seth, Troakes, Claire, Al-Sarraj, Safa, Diez-Fairen, Monica, Hodges, Angela K, Aarsland, Dag, Klein, Gregory, Kaiser, Scott M, Woltjer, Randy, Pastor, Pau, Bekris, Lynn M, Leverenz, James B, Besser, Lilah M, Kuzma, Amanda, Portley, Makayla K, Renton, Alan E, Goate, Alison, Bennett, David A, Scherzer, Clemens R, Morris, Huw R, Ferrari, Raffaele, Albani, Diego, Pickering-Brown, Stuart, Faber, Kelley, Kukull, Walter A, Shah, Zalak, Morenas-Rodriguez, Estrella, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Clarimon, Jordi, Nalls, Mike A, Ferrucci, Luigi, Resnick, Susan M, Tanaka, Toshiko, Foroud, Tatiana M, Abramzon, Yevgeniya, Graff-Radford, Neill R, Wszolek, Zbigniew K, Ferman, Tanis, Boeve, Bradley F, Hardy, John A, Topol, Eric J, Torkamani, Ali, Singleton, Andrew B, Ryten, Mina, Dickson, Dennis W, Hernandez, Dena Michelle Godwin, Chiò, Adriano, Ross, Owen A, Gibbs, J Raphael, Dalgard, Clifton L, Traynor, Bryan J, Scholz, Sonja W, Sotis, Anthony R, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, Blauwendraat, Cornelis, Martinez, Elisa McGrath, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N, Adeleye, Adelani, Wilkerson, Matthew D, Pollard, Harvey B, Stone, David J, Eicher, John, Parkkinen, Laura, Bandres-Ciga, Sara, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence S, Marder, Karen, Lemstra, Afina, St George-Hyslop, Peter, Londos, Elisabet, Morgan, Kevin, Lashley, Tammaryn, Warner, Thomas T, Saez-Atienzar, Sara, Jaunmuktane, Zane, Galasko, Douglas, Santana, Isabel, Tienari, Pentti J, Myllykangas, Liisa, Oinas, Minna, Cairns, Nigel J, Morris, John C, Halliday, Glenda M, Van Deerlin, Vivianna M, Reynolds, Regina H, Trojanowski, John Q, Grassano, Maurizio, Calvo, Andrea, Mora, Gabriele, Canosa, Antonio, Floris, Gianluca, Bohannan, Ryan C, Brett, Francesca, Gan-Or, Ziv, Geiger, Joshua T, Gustavsson, Emil, Moore, Anni, May, Patrick, Krüger, Rejko, Goldstein, David S, Lopez, Grisel, Tayebi, Nahid, Sidransky, Ellen, Center, American Genome, Norcliffe-Kaufmann, Lucy, Palma, Jose-Alberto, Walton, Ronald L, Kaufmann, Horacio, Shakkottai, Vikram G, Perkins, Matthew, Newell, Kathy L, Gasser, Thomas, Schulte, Claudia, Landi, Francesco, Salvi, Erika, Cusi, Daniele, Masliah, Eliezer, Ahmed, Sarah, Kim, Ronald C, Caraway, Chad A, Monuki, Edwin S, Brunetti, Maura, Dawson, Ted M, Rosenthal, Liana S, Albert, Marilyn S, Pletnikova, Olga, Troncoso, Juan C, Flanagan, Margaret E, Viollet, Coralie, Mao, Qinwen, Bigio, Eileen H, Rodríguez-Rodríguez, Eloy, Infante, Jon, Lage, Carmen, González-Aramburu, Isabel, Sanchez-Juan, Pascual, Ghetti, Bernardino, Keith, Julia, Black, Sandra E, Ding, Jinhui, Masellis, Mario, Rogaeva, Ekaterina, Duyckaerts, Charles, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Barrett, Matthew J, Tilley, Bension S, Gentleman, Steve, Logroscino, Giancarlo, Neurology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
Genome-wide association study, genetics [Alzheimer Disease], Computational biology, Biology, Polymorphism, Single Nucleotide, DNA sequencing, Article, genetics [Glucosylceramidase], BIN1 protein, human, 03 medical and health sciences, 0302 clinical medicine, genetics [Lewy Body Disease], genetics [Tumor Suppressor Proteins], genetics [Parkinson Disease], ddc:570, genetics [Adaptor Proteins, Signal Transducing], Genetics, medicine, Dementia, Humans, Genetic Predisposition to Disease, SNCA protein, human, GBA protein, human, 030304 developmental biology, Genetic association, Adaptor Proteins, Signal Transducing, Whole genome sequencing, 0303 health sciences, Lewy body, Genome, Human, Gene Expression Profiling, Tumor Suppressor Proteins, Nuclear Proteins, genetics [Nuclear Proteins], medicine.disease, Genetic architecture, Gene expression profiling, Case-Control Studies, genetics [alpha-Synuclein], alpha-Synuclein, Glucosylceramidase, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, Genome-Wide Association Study
Abstract

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Published
2021

27. Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease

Author

Blauwendraat, Cornelis, Iwaki, Hirotaka, Gibbs, Jesse R, Bras, Jose, Guerreiro, Rita, Lubbe, Steven, Troycoco, Timothy, Finkbeiner, Steven, Mencacci, Niccolo E, Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W, Reed, Xylena, Hernandez, Dena Michelle Godwin, Uitti, Ryan J, Ross, Owen A, Grenn, Francis P, Moore, Anni, Alcalay, Roy N, Wszolek, Zbigniew K, Gan-Or, Ziv, Rouleau, Guy A, Krohn, Lynne, Mufti, Kheireddin, Ruskey, Jennifer A, van Hilten, Jacobus J, Marinus, Johan, Adarmes-Gómez, Astrid D, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesús Alberto Bergareche, Bernal-Bernal, Inmaculada, Blazquez, Marta, Pihlstrøm, Lasse, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Toft, Mathias, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Garcia, Ciara, García-Ruiz, Pedro, Gómez-Garre, Pilar, Heredia, Maria Jose Gomez, Gonzalez-Aramburu, Isabel, Pagola, Ana Gorostidi, Hoenicka, Janet, Infante, Jon, Jesús, Silvia, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A, Lopez-Sendon, Jose Luis, de Munain Arregui, Adolfo López, Macias, Daniel, Torres, Irene Martínez, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Méndez-Del-Barrio, Carlota, González, Manuel Menéndez, Schulte, Claudia, Mata, Marina, Mínguez, Adolfo, Mir, Pablo, Rezola, Elisabet Mondragon, Muñoz, Esteban, Pagonabarraga, Javier, Pastor, Pau, Errazquin, Francisco Perez, Periñán-Tocino, Teresa, Ruiz-Martínez, Javier, Brockmann, Kathrin, Ruz, Clara, Rodriguez, Antonio Sanchez, Sierra, María, Suarez-Sanmartin, Esther, Tabernero, Cesar, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Sharma, Manu, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Taba, Pille, Koks, Sulev, Hassin-Baer, Sharon, Majamaa, Kari, Siitonen, Ari, Makarious, Mary B, Tienari, Pentti, Okubadejo, Njideka U, Ojo, Oluwadamilola O, Kaiyrzhanov, Rauan, Shashkin, Chingiz, Zharkinbekova, Nazira, Akhmetzhanov, Vadim, Kaishybayeva, Gulnaz, Karimova, Altynay, Khaibullin, Talgat, Lynch, Timothy L, Eerola-Rautio, Johanna, Tienari, Pentti J, Grosset, Donald G, Lesage, Suzanne, Corvol, Jean-Christophe, Brice, Alexis, Wood, Nick, Hardy, John, Bandres-Ciga, Sara, Heutink, Peter, Gasser, Thomas, Morris, Huw R, Noyce, Alastair J, Nalls, Mike A, Consortium, and the International Parkinson's Disease Genomics, Leonard, Hampton L, Middlehurst, Ben, Kia, Demis A, Tan, Manuela, Houlden, Henry, Storm, Catherine S, Plun-Favreau, Helene, Holmans, Peter, Trabzuni, Daniah, Quinn, John, Bubb, Vivien, Mok, Kin Y, Kinghorn, Kerri J, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian R, Lovering, Ruth, R'Bibo, Lea, Manzoni, Claudia, Lake, Julie, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E, Clarke, Carl, Harvey, Kirsten, Jacobs, Benjamin M, Danjou, Fabrice, Martinez, Maria, Simón-Sánchez, Javier, Rizzu, Patrizia, Schneider, Susanne A, Cookson, Mark R, Craig, David W, Billingsley, Kimberley, Kim, Jonggeol J, Narendra, Derek P, Faghri, Faraz, Gibbs, J Raphael, Van Keuren-Jensen, Kendall, Shulman, Joshua M, Robak, Laurie, Universidad de Cantabria, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, University of Helsinki, Clinicum, Research Programs Unit, and Eija Pirinen / Principal Investigator

Subjects
0301 basic medicine, Male, Genotype, EFFICIENT, Physiology, Genome-wide association study, Disease, Biology, Genetic correlation, 3124 Neurology and psychiatry, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, genetics [Parkinson Disease], Genetic variation, Humans, Genetic Predisposition to Disease, ddc:610, Parkinson Disease/genetics, METAANALYSIS, Research Articles, Genetic association, Aged, RISK, Sex Characteristics, Autosome, 3112 Neurosciences, Parkinson Disease, Heritability, Middle Aged, Genetic architecture, 3. Good health, 030104 developmental biology, Neurology, Female, GENDER, Neurology (clinical), 030217 neurology & neurosurgery, Research Article, Genome-Wide Association Study
Abstract

Methods: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson?s Disease Genomics Consortium and the UK Biobank consisting of 13,020male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWASmeta-analyses to identify distinct patterns of genetic risk contributing to disease inmale versus female PD cases. Results: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%). Interpretation: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. FUNDING: 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. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, and P50NS071674, American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum für Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German Federal Ministry of Education and Research (BMBF) under the funding code 031A430A, the EU Joint Programme - Neurodegenerative Diseases Research (JPND) project under the aegis of JPND -www.jpnd.eu – through Germany, BMBF, funding code 01ED1406 and iMed – the Helmholtz Initiative on Personalized Medicine. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (http://biowulf.nih.gov), and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. People who contributed samples are acknowledged in descriptions of every panel on the repository website. We thank P. Tienari (Molecular Neurology Programme, Biomedicum, University of Helsinki), T. Peuralinna (Department of Neurology, Helsinki University Central Hospital), L. Myllykangas (Folkhalsan Institute of Genetics and Department of Pathology, University of Helsinki), and R. Sulkava (Department of Public Health and General Practice Division of Geriatrics, University of Eastern Finland) for the Finnish controls (Vantaa85+ GWAS data). This study was also funded by the Sigrid Juselius Foundation (KM). We used genomewide association data generated by the Wellcome Trust Case–Control Consortium 2 (WTCCC2) from UK patients with Parkinson’s disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. UK population control data was made available through WTCCC1. As with previous IPDGC efforts, this study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113, 085475, and 090355. This study was also supported by Parkinson’s UK (grants 8047 and J-0804) and the Medical Research Council (G0700943 and G1100643). Sequencing and genotyping done in McGill University was supported by grants from the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) program and Parkinson’s Society Canada. The access to part of the participants at McGill has been made possible thanks to the Quebec Parkinson’s Network (http://rpq-qpn.ca/en). We thank the Quebec Parkinson’s Network (http://rpq-qpn.org) and its members. Harvard NeuroDiscovery Biomarker Study (HBS) is a collaboration of HBS investigators and funded through philanthropy and NIH and Non-NIH funding sources. The HBS Investigators have not participated in reviewing the data analysis or content of the manuscript. PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, the full names of all of the PPMI funding partners can be found at www.ppmi-info.org/ fundingpartners. The PPMI Investigators have not participated in reviewing the data analysis or content of the manuscript. For up-to-date information on the study, visit www.ppmi-info.org. Parkinson’s Disease Biomarker Program (PDBP) consortium is supported by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health. A full list of PDBP investigators can be found at https://pdbp.ninds.nih.gov/ policy. The PDBP Investigators have not participated in reviewing the data analysis or content of the manuscript

Published
2021

28. Identification of sixteen novel candidate genes for late onset Parkinson's disease

Author

Gialluisi, Alessandro, Reccia, Mafalda Giovanna, Modugno, Nicola, Nutile, Teresa, Lombardi, Alessia, Di Giovannantonio, Luca Giovanni, Pietracupa, Sara, Ruggiero, Daniela, Scala, Simona, Gambardella, Stefano, Noyce, Alastair J., Kaiyrzhanov, Rauan, Middlehurst, Ben, Kia, Demis A., Tan, Manuela, Houlden, Henry, Morris, Huw R., Plun-Favreau, Helen, Holmans, Peter, Hardy, John, Trabzuni, Daniah, Quinn, John, Bubb, Vivien, Mok, Kin Y., Kinghorn, Kerri J., Billingsley, Kimberley, Wood, Nicholas W., Lewis, Patrick, Schreglmann, Sebastian, Lovering, Rruth, R'Bibo, Lea, Manzoni, Claudia, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E., Clarke, Carl, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean-Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, Simón-Sánchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Cookson, Mark R., Bandres-Ciga, Sara, Blauwendraat, Cornelis, Craig, David W., Narendra, Derek, Faghri, Faraz, Gibbs, J.Raphael, Hernandez, Dena G., Van Keuren-Jensen, Kendall, Shulman, Joshua M., Iwaki, Hirotaka, Leonard, Hampton L., Nalls, Mike A., Robak, Laurie, Bras, Jose, Guerreiro, Rita, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E., Lungu, Codrin, Singleton, Andrew B., Scholz, Sonja W., Reed, Xylena, Alcalay, Roy N., Gan-Or, Zin, Rouleau, Guy A., Krohn, Lynne, van Hilten, Jacobus J., Marinus, Johan, Adarmes-Gómez, A.D, Aguilar Barberà, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Bergareche Yarza, Jesús Alberto, Bernal-Bernal, Inmaculada, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A., Boungiorno, María Teresa, Buiza-Rueda, Dolores, Carrillo, Fátima, Carrión-Claro, M, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Diez-Fairen, Monica, Dols Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Garcia, Ciara, García-Ruiz, Pedro, Gómez-Garre, Pilar, Gomez Heredia, Maria Jose, Gonzalez-Aramburu, Isabel, Gorostidi Pagola, Ana, Hoenicka, Janet, Infante, Jon, Jesús, Silvia, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A., Lopez-Sendon, Jose Luis, López de Munain Arregui, Adolfo, Macias, Daniel, Martínez Torres, Irene, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Méndez-del-Barrio, Carlota, Menéndez González, Manuel, Mata, Marina, Mínguez, Adolfo, Mir, Pablo, Mondragon Rezola, Elisabet, Muñoz, Esteban, Pagonabarraga Mora, Javier, Pastor, Pau, Perez Errazquin, Francisco, Periñán-Tocino, Teresa, Ruiz-Martínez, Javier, Ruz, Clara, Sanchez Rodriguez, Antonio, Sierra, María, Suarez-Sanmartin, Esther, Tabernero, Cesar, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Toft, Mathias, Koks, Sulev, Taba, Pille, Hassin-Baer, Sharon, Majamaa, Kari, Siitonen, Ari, Okubadejo, Njideka U., Ojo, Oluwadamilola O., Shashkin, Chingiz, Zharkynbekova, Nazira, Akhmetzhanov, Vadim, Aitkulova, Akbota, Zholdybayeva, Elena, Zharmukhanov, Zharkyn, Kaishybayeva, Gulnaz, Karimova, Altynay, Sadykova, Dinara, Iacoviello, Licia, Gianfrancesco, F., Acampora, D., D'Esposito, M., Simeone, A., Ciullo, M., Esposito, T., and Universidad de Cantabria

Subjects
0301 basic medicine, Male, Aging, Candidate gene, Parkinson's disease, Neurodegenerative, Bioinformatics, 0302 clinical medicine, Late onset Parkinson’s disease, Novel candidate genes for Parkinson’s disease, Rare variant burden analysis, Whole exome sequencing, Adult, Age of Onset, Aged, Female, Genetic Predisposition to Disease, Humans, Middle Aged, Parkinson Disease, Pedigree, Whole Exome Sequencing, 2.1 Biological and endogenous factors, Medicine, Novel candidate genes for Parkinson's disease, Aetiology, Exome, Exome sequencing, screening and diagnosis, education.field_of_study, Parkinson's Disease, LRRK2, International Parkinson’s Disease Genomics Consortium, Detection, Neurological, Late onset Parkinson's disease, 4.2 Evaluation of markers and technologies, Research Article, Clinical Sciences, Population, 03 medical and health sciences, Cellular and Molecular Neuroscience, Clinical Research, Exome Sequencing, Genetics, RC346-429, education, Molecular Biology, Neurology & Neurosurgery, business.industry, Genetic heterogeneity, Prevention, RC952-954.6, Neurosciences, PARK7, medicine.disease, Brain Disorders, 030104 developmental biology, Geriatrics, Neurology. Diseases of the nervous system, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

Published
2021

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

Author

Bandres-Ciga, Sara, Ahmed, Sarah, Gómez-Garre, Pilar, Kia, Demis A, Tan, Manuela, Houlden, Henry, Morris, Huw R, Plun-Favreau, Helene, Holmans, Peter, Hardy, John, Trabzuni, Daniah, Bras, Jose, PhD, John Quinn, Jesús, Silvia, Mok, Kin Y, Kinghorn, Kerri J, Billingsley, Kimberley, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, R'Bibo, Lea, Manzoni, Claudia, Labrador-Espinosa, Miguel A, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E, Brice, Alexis, Danjou, Fabrice, Macias, Daniel, Lesage, Suzanne, Corvol, Jean-Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, Simón-Sánchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Méndez-Del-Barrio, Carlota, Nicolas, Aude, Cookson, Mark R, Blauwendraat, Cornelis, Craig, David W, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Keuren-Jensen, Kendall Van, Shulman, Joshua M, Periñán-Tocino, Teresa, Iwaki, Hirotaka, Leonard, Hampton L, Nalls, Mike A, Robak, Laurie, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E, Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W, Tejera-Parrado, Cristina, Reed, Xylena, Alcalay, Roy N, Gan-Or, Ziv, Rouleau, Guy A, Krohn, Lynne, van Hilten, Jacobus J, Marinus, Johan, Adarmes-Gómez, Astrid D, Aguilar, Miquel, Alvarez, Ignacio, Vargas-González, Laura, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesús Alberto Bergareche, Bernal-Bernal, Inmaculada, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Buiza-Rueda, Dolores, Cámara, Ana, Diez-Fairen, Monica, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, de la Casa, Beatríz, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubé, Garcia, Ciara, García-Ruiz, Pedro, Heredia, Maria Jose Gomez, Gonzalez-Aramburu, Isabel, Sabir, Marya S, Tartari, Juan Pablo, Pagola, Ana Gorostidi, Hoenicka, Janet, Infante, Jon, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Lopez-Sendon, Jose Luis, Arregui, Adolfo López de Munain, Buongiorno, Mariateresa, Torres, Irene Martínez, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, González, Manuel Menéndez, Mata, Marina, Mínguez, Adolfo, Mir, Pablo, Rezola, Elisabet Mondragon, Pagonabarraga, Javier, Pascual-Sedano, Berta, Pastor, Pau, Errazquin, Francisco Perez, Ruiz-Martínez, Javier, Ruz, Clara, Rodriguez, Antonio Sanchez, Sierra, María, Suarez-Sanmartin, Esther, Gorostidi, Ana, Tabernero, Cesar, Tolosa, Eduard, Valldeoriola, Francesc, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Bergareche, Jesús Alberto, Toft, Mathias, Koks, Sulev, Taba, Pille, Hassin-Baer, Sharon, Dalgard, Clifton L, Adeleye, Adelani, Soltis, Anthony R, Alba, Camille, Viollet, Coralie, Bacikova, Dagmar, Mondragon, Elisabet, Hupalo, Daniel N, Sukumar, Gauthaman, Pollard, Harvey B, Wilkerson, Matthew D, Martinez, Elisa McGrath, Vinagre-Aragon, Ana, Croitoru, Ioana, Marín-Lahoz, Juan, Fernández-Santiago, Rubén, Muñoz, Esteban, Sanchez Rodriguez, Antonio, Menéndez-González, Manuel, Suarez-San Martin, Esther, Vela-Desojo, Lydia, Mínguez-Castellanos, Adolfo, Gomez Heredia, Maria Jose, Perez Errazquin, Francisco, Romero-Acebal, Manolo, Martínez Torres, Irene, Kim, Jonggeol Jeffrey, Center, American Genome, Brooks, Janet, Saez-Atienzar, Sara, Jorda, Rafael, Botia, Juan A, Bonet-Ponce, Luis, Clarke, Carl, Morris, Huw, Edsall, Connor, Hernandez, Dena, Simon Sanchez, Javier, Marti, Maria José, López de Munain, Adolfo, Singleton, Andrew, Consortium, International Parkinson Disease Genomics, Noyce, Alastair J, Kaiyrzhanov, Rauan, Middlehurst, Ben, National Institutes of Health (US), Department of Defense (US), Michael J. Fox Foundation for Parkinson's Research, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), European Commission, Junta de Andalucía, Sociedad Andaluza de Neurología, Jacques and Gloria Gossweiler Foundation, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, and Universidad de Sevilla

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, Parkinson's disease, age at onset, Machine Learning, 0302 clinical medicine, Cost of Illness, genetics [Parkinson Disease], Population specific, genetics [Genetic Predisposition to Disease], Age of Onset, genetics [Ubiquitin-Protein Ligases], Aged, 80 and over, Age at onset, Chromosome Mapping, Parkinson Disease, Middle Aged, Spanish population, humanities, Neurology, Christian ministry, Female, Adult, Genotype, Ubiquitin-Protein Ligases, Article, risk haplotype, 03 medical and health sciences, Risk score risk haplotype, Political science, polygenic risk score, Humans, Genetic Predisposition to Disease, ddc:610, Risk haplotype, Parkinson's disease, Spanish population, age at onset, polygenic risk score, risk haplotype, Aged, DNA Methylation, 030104 developmental biology, Haplotypes, Spain, Case-Control Studies, Polygenic risk score, Neurology (clinical), Polygenic, Humanities, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

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.

Published
2019

30. The Cortical Basal ganglia Functional Scale (CBFS): Development and preliminary validation

Author

Lang, Anthony E, Stebbins, Glenn T, Wang, Ping, Jabbari, Edwin, Lamb, Ruth, Morris, Huw, Boxer, Adam L, 4RTNI, PROSPECT-M-UK investigators, and Apollo - University of Cambridge Repository

Subjects
Male, Delphi Technique, Psychometrics, Progressive supranuclear palsy, Corticobasal degeneration, 4 repeat tauopathies, Reproducibility of Results, Middle Aged, Outcome measures, Severity of Illness Index, Clinical rating scales, Frontotemporal Dementia, Humans, Female, Longitudinal Studies, Patient Reported Outcome Measures, Supranuclear Palsy, Progressive, Patient reported outcomes
Abstract

OBJECTIVE: To develop a patient/care-giver reported scale capable of easily and reliably assessing functional disability in 4 repeat tauopathies (4RTs). BACKGROUND: 4R tauopathies including progressive supranuclear palsy, corticobasal degeneration and a subset of frontotemporal dementias manifest a range of overlapping clinical phenotypes. No available rating scale is capable of evaluating the functional impact of these complex disorders. METHODS: A multi-staged modified Delphi process was used to propose, evaluate and rank potential scale items providing content validity ratios. Staged cognitive pretesting involving input from examiners, patients and caregivers was followed by validation testing in patients participating in the 4R Tauopathy Neuroimaging Initiative or the PROgressive Supranuclear Palsy CorTico-Basal Syndrome MSA Longitudinal Study. Clinimetric properties were examined using classical test theory and item response methods, assessing data quality, reliability, construct validity, convergent validity and known-group validity. RESULTS: The resultant Cortical Basal ganglia Functional Scale (CBFS) included questions on Motor Experiences in Daily Living (14 items) and Non-Motor Experiences of Daily Living (17 items). Reliability was acceptable for internal consistency, test-retest stability, item discrimination, item-scaling thresholds and item-fit. Examination of construct validity revealed a parsimonious two-factor solution, and concurrent validity demonstrated significant correlations between the CBFS and other measures of disease severity and functional impairment. The CBFS significantly discriminated between all diagnostic groups and controls (all AUCs>90). The CBFS scores demonstrated sensitivity to change over a 12 month follow-up in patients with probable 4RTs. CONCLUSIONS: The CBFS is a patient/care-giver reported outcome measure with excellent clinimetric properties that captures disability correlated with motor, cognitive and psychiatric impairments.

Published
2020
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31. Can neuroimaging predict dementia in Parkinson’s disease?

Author

Lanskey, Juliette H, McColgan, Peter, Schrag, Anette E, Acosta-Cabronero, Julio, Rees, Geraint, Morris, Huw R, and Weil, Rimona S

Subjects
Dopaminergic Neurons, imaging, Brain, Neuroimaging, Parkinson Disease, Review Article, Prognosis, Magnetic Resonance Imaging, Cholinergic Neurons, nervous system diseases, Cognition, Risk Factors, mental disorders, Parkinson’s disease, Disease Progression, Humans, Cognitive Dysfunction, Dementia, MRI
Abstract

Dementia is common in Parkinson’s disease but there is wide variation in severity and timing, and identifying at-risk individuals has proved challenging. Lanskey et al. provide an overview of conventional and emerging neuroimaging techniques with the potential to predict dementia in patients with Parkinson’s disease., Dementia in Parkinson’s disease affects 50% of patients within 10 years of diagnosis but there is wide variation in severity and timing. Thus, robust neuroimaging prediction of cognitive involvement in Parkinson’s disease is important: (i) to identify at-risk individuals for clinical trials of potential new treatments; (ii) to provide reliable prognostic information for individuals and populations; and (iii) to shed light on the pathophysiological processes underpinning Parkinson’s disease dementia. To date, neuroimaging has not made major contributions to predicting cognitive involvement in Parkinson’s disease. This is perhaps unsurprising considering conventional methods rely on macroscopic measures of topographically distributed neurodegeneration, a relatively late event in Parkinson’s dementia. However, new technologies are now emerging that could provide important insights through detection of other potentially relevant processes. For example, novel MRI approaches can quantify magnetic susceptibility as a surrogate for tissue iron content, and increasingly powerful mathematical approaches can characterize the topology of brain networks at the systems level. Here, we present an up-to-date overview of the growing role of neuroimaging in predicting dementia in Parkinson’s disease. We discuss the most relevant findings to date, and consider the potential of emerging technologies to detect the earliest signs of cognitive involvement in Parkinson’s disease.

Published
2018

32. Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease

Author

Robak, Laurie A., Jansen, Iris E., Rooij, Jeroen van, Uitterlinden, André G., Kraaij, Robert, Jankovic, Joseph, Heutink, Peter, Shulman, Joshua M., Nalls, Mike A., Plagnol, Vincent, Hernandez, Dena G., Sharma, Manu, Sheerin, Una Marie, Saad, Mohamad, Simón-Sánchez, Javier, Schulte, Claudia, Lesage, Suzanne, Sveinbjörnsdóttir, Sigurlaug, Arepalli, Sampath, Barker, Roger, Ben, Yoav, Berendse, Henk W., Berg, Daniela, Bhatia, Kailash, de Bie, Rob M.A., Biffi, Alessandro, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Bras, Jose M., Brockmann, Kathrin, Brooks, Janet, Burn, David J., Majounie, Elisa, Charlesworth, Gavin, Lungu, Codrin, Chen, Honglei, Chinnery, Patrick F., Chong, Sean, Clarke, Carl E., Cookson, Mark R., Cooper, J. Mark, Corvol, Jean Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean François, Deloukas, Panos, Deuschl, Günther, Dexter, David T., van Dijk, Karin D., Dillman, Allissa, Durif, Frank, Dürr, Alexandra, Edkins, Sarah, Evans, Jonathan R., Foltynie, Thomas, Dong, Jing, Gardner, Michelle, Gibbs, J. Raphael, Goate, Alison, Gray, Emma, Guerreiro, Rita, Harris, Clare, van Hilten, Jacobus J., Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Wurster, Isabel, Mätzler, Walter, Hudson, Gavin, Hunt, Sarah E., Huttenlocher, Johanna, Illig, Thomas, Jónsson, Pálmi V., Lambert, Jean Charles, Langford, Cordelia, Lees, Andrew, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, McNeill, Alisdair, Moorby, Catriona, Moore, Matthew, Morris, Huw R., Morrison, Karen E., Escott-Price, Valentina, Mudanohwo, Ese, O’sullivan, Sean S., Pearson, Justin, Perlmutter, Joel S., Pétursson, Hjörvar, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Ryten, Mina, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Shulman, Joshua, Sidransky, Ellen, Smith, Colin, Spencer, Chris C.A., Stefánsson, Hreinn, Bettella, Francesco, Stockton, Joanna D., Strange, Amy, Talbot, Kevin, Tanner, Carlie M., Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J., Velseboer, Daan, Vidailhet, Marie, Walker, Robert, Warrenburg, Bart van de, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H., Winder-Rhodes, Sophie, Stefánsson, Kári, Martinez, Maria, Wood, Nicholas W., Hardy, John, Brice, Alexis, Gasser, Thomas, Singleton, Andrew B., Erasmus University Medical Center [Rotterdam] (Erasmus MC), Ctr Life Sci Technol, Div Gen Technol, Tsurumi Ku, RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Neurology, ANS - Neurodegeneration, ANS - Amsterdam Neuroscience, Intensive Care Medicine, ANS - Neuroinfection & -inflammation, Graduate School, ACS - Amsterdam Cardiovascular Sciences, APH - Aging & Later Life, Amsterdam Neuroscience - Neurodegeneration, Human genetics, Internal Medicine, and Erasmus MC other

Subjects
Male, 0301 basic medicine, Parkinson's disease, Acid Ceramidase, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Organic Anion Transporters, ASAH1 protein, human, Disease, CTSD protein, human, Cathepsin D, genetics [Glucosylceramidase], whole exome sequencing, Cohort Studies, 0302 clinical medicine, genetics [Parkinson Disease], Exome, genetics, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Genetics, Symporters, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, genetics [Organic Anion Transporters], Middle Aged, genetics [Lysosomal Storage Diseases], Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Control subjects, sphingomyelin phosphodiesterase 1, human, 3. Good health, sialic acid transport proteins, Sphingomyelin Phosphodiesterase, ASAH1, Glucosylceramidase, Female, Adult, Genotype, Biology, lysosomal storage disorders, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genotyping, Gene, Aged, [SCCO.NEUR]Cognitive science/Neuroscience, Original Articles, medicine.disease, genetics [Symporters], genetics [Acid Ceramidase], nervous system diseases, genetics [Cathepsin D], 030104 developmental biology, Case-Control Studies, Mutation, genetics [Sphingomyelin Phosphodiesterase], Neurology (clinical), Glucocerebrosidase, 030217 neurology & neurosurgery
Abstract

Item does not contain fulltext Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.

Published
2017

33. Analysis of shared heritability in common disorders of the brain

Author

Brainstorm Consortium, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nicholas, Kurth, Tobias, Ligthart, Lannie, Terwindt, Gisela M, Freilinger, Tobias, Ran, Caroline, Gordon, Scott D, Borck, Guntram, Adams, Hieab HH, Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E, Schürks, Markus, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G, Montgomery, Grant W, Kurki, Mitja I, Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfons, Pozo-Rosich, Patricia, Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Metspalu, Andres, Kubisch, Christian, Ferrari, Michel D, Belin, Andrea C, Van Den Maagdenberg, Arn MJM, Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nicholas, Olesen, Jes, Chasman, Daniel I, Nyholt, Dale R, Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell J, Catarino, Claudia B, Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Dennis, Ferraro, Thomas N, French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S, Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S, Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thomas, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M, Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Thomas, G Neil, Visscher, Frank, Whelan, Christopher D, Zara, Federico, Heinzen, Erin L, Marson, Anthony, Becker, Felicitas, Stroink, Hans, Zimprich, Fritz, Gasser, Thomas, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R, Sharma, Manu, Ryten, Mina, Mok, Kin Y, Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thomas, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Boraska Perica, Vesna, Thornton, Laura M, Huckins, Laura M, William Rayner, N, Lewis, Cathryn M, Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I, Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andreas, Mannik, Katrin, Baker, Jessica H, O'Toole, Julie K, Trace, Sara E, Davis, Oliver SP, Helder, Sietske G, Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N, Van Elburg, Annemarie A, Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragiskos, Tziouvas, Konstantinos, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julià, Antonio, Rabionet, Raquel, Dick, Danielle M, Ripatti, Samuli, Andreassen, Ole A, Espeseth, Thomas, Lundervold, Astri J, Steen, Vidar M, Pinto, Dalila, Scherer, Stephen W, Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lars, Padyukov, Leonid, Halmi, Katherine A, Mitchell, James, Strober, Michael, Bergen, Andrew W, Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesús, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D, Banaschewski, Tobias, Franke, Barbara, Buitelaar, Jan K, Arias Vasquez, Alejandro, Doyle, Alysa E, Reif, Andreas, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H, Dalsgaard, Soeren, Børglum, Anders D, Waldman, Irwin, Wilmot, Beth, Molly, Nikolas, Bau, Claiton HD, Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K, McGough, James J, Grevet, Eugenio H, Medland, Sarah E, Robinson, Elise, Weiss, Lauren A, Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M, Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, De-Luca, Daniel Moreno, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thomas, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Rogé, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G, Thompson, Robert C, Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Douglas, McIntosh, Andrew, Bergen, Sarah E, Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B, Reinbold, Céline S, Fullerton, Janice M, Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R, Cichon, Sven, Mühleisen, Thomas W, Degenhardt, Franziska, Schumacher, Johannes, Bauer, Michael, Mitchell, Philip B, Gershon, Elliot S, Rice, John, Potash, James B, Zandi, Peter P, Craddock, Nick, Ferrier, I Nicol, Alda, Martin, Rouleau, Guy A, Turecki, Gustavo, Ophoff, Roel, Pato, Carlos, Anjorin, Adebayo, Stahl, Eli, Leber, Markus, Czerski, Piotr M, Cruceanu, Cristiana, Jones, Ian R, Posthuma, Danielle, Andlauer, Till FM, Forstner, Andreas J, Streit, Fabian, Baune, Bernhard T, Air, Tracy, Sinnamon, Grant, Wray, Naomi R, MacIntyre, Donald J, Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M, Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H, Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S, Nauck, Matthias, Schoevers, Robert A, Beekman, Aartjan Tf, Knowles, James A, Viktorin, Alexander, Arnold, Paul, Barr, Cathy L, Bedoya-Berrio, Gabriel, Bienvenu, O Joseph, Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M, Dietrich, Andrea, Fernandez, Thomas, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L, Hartmann, Andreas, Hirschtritt, Matthew E, Hoekstra, Pieter J, Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J, Macciardi, Fabio, Madruga-Garrido, Marcos, Malaty, Irene A, Maras, Athanasios, McGrath, Lauren, Miguel, Eurípedes C, Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S, Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M, Reus, Victor, Richter, Margaret A, Riddle, Mark A, Robertson, Mary M, Roessner, Veit, Rosário, Maria, Samuels, Jack F, Sandor, Paul, Stein, Dan J, Tsetsos, Fotis, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R, Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S, McLaughlin, Nicole, Nestadt, Paul S, Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A, Cohen, David, Crespo-Facorro, Benedicto, Crowley, James, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Janis, Kučinskas, Vaidutis, Lee Chee Keong, Jimmy, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C, Nenadic, Igor, Van Os, Jim, Pantelis, Christos, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Panos, Sanders, Alan R, Schall, Ulrich, Schwab, Sibylle G, Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, James, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V, Henskens, Frans, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M, Daly, Mark, Dichgans, Martin, Faraone, Stephen V, Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S, Koeleman, Bobby, Mathews, Carol A, Price, Alkes, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W, Cotsapas, Chris, Palotie, Aarno, Smoller, Jordan W, Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M, Schott, Jonathan M, Anney, Richard, Elia, Josephine, Grigoroiu-Serbanescu, Maria, Edenberg, Howard J, Murray, Robin, Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), School of Psychology [Cardiff University], Cardiff University, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), New Jersey Institute of Technology [Newark] (NJIT), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Biotechnologie et Microbiologie Appliquée (LBMA), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Gériatrie générale et aigüe [Paris], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Columbia University [New York], Dpt of Neuroscience [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Washington [Seattle], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Children’s Hospital of Philadelphia (CHOP ), University of Kentucky (UK), School of medicine, Duke University [Durham], College of medicine, Brigham Young University (BYU), Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Department of Neurology, Emory University [Atlanta, GA], Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Health sciences center, The University of New Mexico [Albuquerque], Institute for Memory Impairments and Neurological Disorders [Irvine], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Keck School of Medicine [Los Angeles], University of Southern California (USC), University of South Florida [Tampa] (USF), University of Utah School of Medicine [Salt Lake City], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Perelman School of Medicine, University of Pennsylvania, Dublin City University [Dublin] (DCU), Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Aristotle University of Thessaloniki, Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Dementia Research Centre [London] (DRC), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, MRC Prion Unit [London], Queen's University [Belfast] (QUB), School of Life Sciences, University of Nottingham, UK (UON), Rheinische Friedrich-Wilhelms-Universität Bonn, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), School of Medicine [Dublin], Trinity College Dublin, Department of Medicine, University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), School of Public Health [Boston], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Columbia University Medical Center (CUMC), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Saarland University [Saarbrücken], Universität Leipzig, School of Medicine [Los Angeles], Johannes Kepler Universität Linz - Johannes Kepler University Linz [Autriche] (JKU), Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], School of Medecine, Washington University in Saint Louis (WUSTL), Oslo University Hospital [Oslo], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, 23andMe Inc., Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biological Psychology [Amsterdam], Vrije Universiteit Amsterdam [Amsterdam] (VU), Leiden University Medical Center (LUMC), Universiteit Leiden, University-Hospital Munich-Großhadern [München], Karolinska Institutet [Stockholm], Universität Ulm - Ulm University [Ulm, Allemagne], Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Landspitali National University Hospital of Iceland, VU University Medical Center [Amsterdam], Boston VA Research Institute (BVARI), Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Christian-Albrechts-Universität zu Kiel (CAU), Institute of Clinical Molecular Biology, Kiel University, National Institute for Health and Welfare [Helsinki], Harvard T.H. Chan School of Public Health, Universitat Autònoma de Barcelona (UAB), Vall d'Hebron University Hospital [Barcelona], University of Tartu, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Human and Clinical Genetics, Universiteit Leiden-Universiteit Leiden, University of Copenhagen = Københavns Universitet (UCPH), Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology [Brisbane] (QUT), Discipline of Psychiatry [Dublin], Trinity College Dublin-Trinity College Dublin, Institute of Neurology [London], The University of Hong Kong (HKU), University of Melbourne, Cooper Medical School of Rowan University [Camden] (CMSRU), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), University of Antwerp (UA), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), University of Eastern Finland, Universitätsklinikum Bonn (UKB), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, University Medical Center [Utrecht], Ohio State University [Columbus] (OSU), University of California [San Francisco] (UC San Francisco), University of California (UC), Royal College of Surgeons in Ireland (RCSI), University of Southern Denmark (SDU), United Christian Hospital [Hong Kong] (UCH), University of Cincinnati (UC), University of Cologne, Inselspital Bern, University of Wales, Jefferson University Hospitals, University of Liverpool, Medizinische Universität Wien = Medical University of Vienna, National Institutes of Health [Bethesda] (NIH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Lincoln, University of Newcastle [Callaghan, Australia] (UoN), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Virginia, University of Maryland [Baltimore County] (UMBC), University of Maryland System, Royal Holloway [University of London] (RHUL), University of Edinburgh, Universidade de Lisboa = University of Lisbon (ULISBOA), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), University of Split, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), McLean Hospital [Belmont, Ma.], Norwegian Institute of Public Health [Oslo] (NIPH), Università degli Studi di Salerno = University of Salerno (UNISA), University of Bristol [Bristol], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Utrecht University [Utrecht], Azienda Ospedaliera di Padova, Université de Liège, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Università degli Studi di Perugia = University of Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, National and Kapodistrian University of Athens (NKUA), Charles University [Prague] (CU), SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Flinders University [Adelaide, Australia], Virginia Commonwealth University (VCU), University of Oslo (UiO), University of Bergen (UiB), Weill Medical College of Cornell University [New York], University of North Dakota [Grand Forks] (UND), Oregon Research Institute (ORI), University of California [San Diego] (UC San Diego), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Hospital Universitario Mutua de Terrassa, School of Computer Science and Communication [Stockholm], Royal Institute of Technology [Stockholm] (KTH ), Jefferson (Philadelphia University + Thomas Jefferson University), University Medical Center Göttingen (UMG), Universität Heidelberg [Heidelberg] = Heidelberg University, Radboud University Medical Center [Nijmegen], Universitätsklinikum Frankfurt, Maastricht University [Maastricht], Institute of Psychological Medicine and Clinical Neurosciences, Aarhus University [Aarhus], University of Iowa [Iowa City], Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), The Hospital for sick children [Toronto] (SickKids), Hospital de Clínicas de Porto Alegre (HCPA), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University of British Columbia (UBC), IRCCS Fondazione Stella Maris [Pisa], Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade de Coimbra [Coimbra], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Our Lady's Children's Hospital Crumlin (OLCHC), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Children’s Hospital Los Angeles [Los Angeles], Yale University [New Haven], Brown University, Institute of Neuroscience [Newcastle] (ION), Newcastle University [Newcastle], Department of Medical Epidemiology and Biostatistics (MEB), Division of Medical Genetics [Seattle], University of Illinois [Chicago] (UIC), University of Illinois System, Maine Medical Center Research Institute (MMCRI), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Toulouse Mind & Brain Institut (TMBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Johns Hopkins University School of Medicine [Baltimore], Ludwig Maximilian University [Munich] (LMU), University of Michigan System, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, University of Dundee, National University of Ireland [Galway] (NUI Galway), University Hospital Basel [Basel], Neuroscience Research Australia (NeuRA), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW), University of Chicago, Johns Hopkins University (JHU), Johns Hopkins Bloomberg School of Public Health [Baltimore], Dalhousie University [Halifax], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], State University of New York (SUNY), University Hospital of Cologne [Cologne], University of Adelaide, James Cook University (JCU), Institute for Molecular Bioscience, University of Queensland [Brisbane], Greifswald University Hospital, The University of Sydney, University Medical Center Groningen [Groningen] (UMCG), University of Calgary, University Health Network, Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Universidade de São Paulo = University of São Paulo (USP), Ospedale San Raffaele, University of Amsterdam [Amsterdam] (UvA), University of Groningen [Groningen], Yale School of Medicine [New Haven, Connecticut] (YSM), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Cape Town, Cold Spring Harbor Laboratory (CSHL), Universidad de Sevilla / University of Sevilla, University of Florida [Gainesville] (UF), University of Denver, Purdue University [West Lafayette], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Moscow Institute of Physics and Technology [Moscow] (MIPT), Sunnybrook Health Sciences Centre, Federal Institute of São Paulo (IFSP), Democritus University of Thrace (DUTH), Universiteit Gent = Ghent University (UGENT), Medical University of Warsaw - Poland, Sorbonne Université - Faculté de Médecine - Département d'Enseignement et de Recherche en Médecine Générale, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institute of Mental Health [Singapore], Universidad de Cantabria [Santander], Tel Aviv University (TAU), University College Cork (UCC), University of Rochester [USA], Statens Serum Institut [Copenhagen], Софийски университет = Sofia University, Russian Academy of Sciences [Moscow] (RAS), Latvian Biomedical Research and Study Centre [Rīga], Vilnius University [Vilnius], Nanyang Technological University [Singapour], Department of Life Sciences, Imperial College London, Jena University Hospital [Jena], Oxford University Hospitals NHS Trust, Schizophrenia Research Institute [Sydney], Faculty of Science, Medicine and Health [Wollongong], University of Wollongong [Australia], City University of Hong Kong [Hong Kong] (CUHK), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), This work was supported by grants 1R01MH10764901 and 5U01MH09443203 from the National Institute of Mental Health, as well as the Orion Farmos Research Foundation (V.A.) and the Fannie and John Hertz Foundation (H.K.F.). Consortium specific funding is detailed in the supplementary materials ('Study-specific acknowledgments')., Brainstorm Consortium, University of Kentucky, University of California [Irvine] (UCI), University of California-University of California, University of Pennsylvania [Philadelphia], Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Leipzig [Leipzig], Johannes Kepler University Linz [Linz] (JKU), University of Helsinki-University of Helsinki, University of Helsinki, University of Oxford [Oxford], University of Copenhagen = Københavns Universitet (KU), University of California [San Francisco] (UCSF), University of California, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Newcastle [Australia] (UoN), University of Virginia [Charlottesville], Universidade de Lisboa (ULISBOA), Università degli Studi di Salerno (UNISA), Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Università degli Studi di Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli', Universität Heidelberg [Heidelberg], Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, VU University Amsterdam, Universidade de São Paulo (USP), Yale University School of Medicine, Universidad de Sevilla, Universiteit Gent = Ghent University [Belgium] (UGENT), Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), Tel Aviv University [Tel Aviv], University of Sofia, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K., Walters, Raymond K., Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J., Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A., Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H., Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-Françoi, Duron, Emmanuelle, Vardarajan, Badri N., Reitz, Christiane, Goate, Alison M., Huentelman, Matthew J., Ilyas Kamboh, M., Larson, Eric B., Rogaeva, Ekaterina, George-Hyslop, Peter St, Hakonarson, Hakon, Kukull, Walter A., Farrer, Lindsay A., Barnes, Lisa L., Beach, Thomas G., Yesim Demirci, F., Head, Elizabeth, Hulette, Christine M., Jicha, Gregory A., Kauwe, John S.K., Kaye, Jeffrey A., Leverenz, James B., Levey, Allan I., Lieberman, Andrew P., Pankratz, Vernon S., Poon, Wayne W., Quinn, Joseph F., Saykin, Andrew J., Schneider, Lon S., Smith, Amanda G., Sonnen, Joshua A., Stern, Robert A., Van Deerlin, Vivianna M., Van Eldik, Linda J., Harold, Denise, Russo, Giancarlo, Rubinsztein, David C., Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C., Hampel, Harald, Owen, Michael J., Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M., Rossor, Martin, Lupton, Michelle K., Hoffmann, Per, Kornhuber, Johanne, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C., Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J., De Jager, Philip L., Geschwind, Daniel H., Riemenschneider, Matthia, Riedel-Heller, Steffi, Rotter, Jerome I., Ransmayr, Gerhard, Hyman, Bradley T., Cruchaga, Carlo, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nichola, Kurth, Tobia, Ligthart, Lannie, Terwindt, Gisela M., Freilinger, Tobia, Ran, Caroline, Gordon, Scott D., Borck, Guntram, Adams, Hieab H.H., Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E., Schürks, Marku, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G., Montgomery, Grant W., Kurki, Mitja I., Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfon, Pozo-Rosich, Patricia, Hansen, Thoma, Werge, Thoma, Kaprio, Jaakko, Metspalu, Andre, Kubisch, Christian, Ferrari, Michel D., Belin, Andrea C., Van Den Maagdenberg, Arn M. J. M., Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nichola, Olesen, Je, Chasman, Daniel I., Nyholt, Dale R., Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell, Catarino, Claudia B., Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Denni, Ferraro, Thomas N., French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S., Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S., Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thoma, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M., Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Neil Thomas, G., Visscher, Frank, Whelan, Christopher D., Zara, Federico, Heinzen, Erin L., Marson, Anthony, Becker, Felicita, Stroink, Han, Zimprich, Fritz, Gasser, Thoma, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R., Sharma, Manu, Ryten, Mina, Mok, Kin Y., Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thoma, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Perica, Vesna Boraska, Thornton, Laura M., Huckins, Laura M., William Rayner, N., Lewis, Cathryn M., Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I., Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andrea, Mannik, Katrin, Baker, Jessica H., O'Toole, Julie K., Trace, Sara E., Davis, Oliver S. P., Helder, Sietske G., Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N., Van Elburg, Annemarie A., Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragisko, Tziouvas, Konstantino, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julia, Antonio, Rabionet, Raquel, Dick, Danielle M., Ripatti, Samuli, Andreassen, Ole A., Espeseth, Thoma, Lundervold, Astri J., Steen, Vidar M., Pinto, Dalila, Scherer, Stephen W., Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lar, Padyukov, Leonid, Halmi, Katherine A., Mitchell, Jame, Strober, Michael, Bergen, Andrew W., Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesú, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D., Banaschewski, Tobia, Franke, Barbara, Buitelaar, Jan K., Vasquez, Alejandro Aria, Doyle, Alysa E., Reif, Andrea, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H., Dalsgaard, Soeren, Børglum, Anders D., Waldman, Irwin, Wilmot, Beth, Molly, Nikola, Bau, Claiton H.D., Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K., McGough, James J., Grevet, Eugenio H., Medland, Sarah E., Robinson, Elise, Weiss, Lauren A., Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M., Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, Moreno-De-Luca, Daniel, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thoma, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Roge, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G., Thompson, Robert C., Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Dougla, McIntosh, Andrew, Bergen, Sarah E., Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B., Reinbold, Céline S., Fullerton, Janice M., Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R., Cichon, Sven, Mühleisen, Thomas W., Degenhardt, Franziska, Schumacher, Johanne, Bauer, Michael, Mitchell, Philip B., Gershon, Elliot S., Rice, John, Potash, James B., Zandi, Peter P., Craddock, Nick, Nicol Ferrier, I., Alda, Martin, Rouleau, Guy A., Turecki, Gustavo, Ophoff, Roel, Pato, Carlo, Anjorin, Adebayo, Stahl, Eli, Leber, Marku, Czerski, Piotr M., Cruceanu, Cristiana, Jones, Ian R., Posthuma, Danielle, Andlauer, Till F.M., Forstner, Andreas J., Streit, Fabian, Baune, Bernhard T., Air, Tracy, Sinnamon, Grant, Wray, Naomi R., MacIntyre, Donald J., Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M., Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H., Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S., Nauck, Matthia, Schoevers, Robert A., Beekman, Aartjan TF, Knowles, James A., Viktorin, Alexander, Arnold, Paul, Barr, Cathy L., Bedoya-Berrio, Gabriel, Joseph Bienvenu, O., Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M., Dietrich, Andrea, Fernandez, Thoma, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L., Hartmann, Andrea, Hirschtritt, Matthew E., Hoekstra, Pieter J., Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J., Macciardi, Fabio, Madruga-Garrido, Marco, Malaty, Irene A., Maras, Athanasio, McGrath, Lauren, Miguel, Eurípedes C., Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S., Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M., Reus, Victor, Richter, Margaret A., Riddle, Mark A., Robertson, Mary M., Roessner, Veit, Rosário, Maria, Samuels, Jack F., Sandor, Paul, Stein, Dan J., Tsetsos, Foti, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R., Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S., McLaughlin, Nicole, Nestadt, Paul S., Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A., Cohen, David, Crespo-Facorro, Benedicto, Crowley, Jame, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Jani, Kučinskas, Vaiduti, Keong, Jimmy Lee Chee, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C., Nenadic, Igor, Van Os, Jim, Pantelis, Christo, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Pano, Sanders, Alan R., Schall, Ulrich, Schwab, Sibylle G., Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, Jame, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V., Henskens, Fran, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M., Daly, Mark, Dichgans, Martin, Faraone, Stephen V., Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S., Koeleman, Bobby, Mathews, Carol A., Price, Alke, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W., Cotsapas, Chri, Palotie, Aarno, Smoller, Jordan W., Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M., Epidemiology, Radiology & Nuclear Medicine, Anttila, V, Bulik-Sullivan, B, Finucane, H, Walters, R, Bras, J, Duncan, L, Escott-Price, V, Falcone, G, Gormley, P, Malik, R, Patsopoulos, N, Ripke, S, Wei, Z, Yu, D, Lee, P, Turley, P, Grenier-Boley, B, Chouraki, V, Kamatani, Y, Berr, C, Letenneur, L, Hannequin, D, Amouyel, P, Boland, A, Deleuze, J, Duron, E, Vardarajan, B, Reitz, C, Goate, A, Huentelman, M, Ilyas Kamboh, M, Larson, E, Rogaeva, E, George-Hyslop, P, Hakonarson, H, Kukull, W, Farrer, L, Barnes, L, Beach, T, Yesim Demirci, F, Head, E, Hulette, C, Jicha, G, Kauwe, J, Kaye, J, Leverenz, J, Levey, A, Lieberman, A, Pankratz, V, Poon, W, Quinn, J, Saykin, A, Schneider, L, Smith, A, Sonnen, J, Stern, R, Van Deerlin, V, Van Eldik, L, Harold, D, Russo, G, Rubinsztein, D, Bayer, A, Tsolaki, M, Proitsi, P, Fox, N, Hampel, H, Owen, M, Mead, S, Passmore, P, Morgan, K, Nöthen, M, Rossor, M, Lupton, M, Hoffmann, P, Kornhuber, J, Lawlor, B, Mcquillin, A, Al-Chalabi, A, Bis, J, Ruiz, A, Boada, M, Seshadri, S, Beiser, A, Rice, K, Van Der Lee, S, De Jager, P, Geschwind, D, Riemenschneider, M, Riedel-Heller, S, Rotter, J, Ransmayr, G, Hyman, B, Cruchaga, C, Alegret, M, Winsvold, B, Palta, P, Farh, K, Cuenca-Leon, E, Furlotte, N, Kurth, T, Ligthart, L, Terwindt, G, Freilinger, T, Ran, C, Gordon, S, Borck, G, Adams, H, Lehtimäki, T, Wedenoja, J, Buring, J, Schürks, M, Hrafnsdottir, M, Hottenga, J, Penninx, B, Artto, V, Kaunisto, M, Vepsäläinen, S, Martin, N, Montgomery, G, Kurki, M, Hämäläinen, E, Huang, H, Huang, J, Sandor, C, Webber, C, Muller-Myhsok, B, Schreiber, S, Salomaa, V, Loehrer, E, Göbel, H, Macaya, A, Pozo-Rosich, P, Hansen, T, Werge, T, Kaprio, J, Metspalu, A, Kubisch, C, Ferrari, M, Belin, A, Van Den Maagdenberg, A, Zwart, J, Boomsma, D, Eriksson, N, Olesen, J, Chasman, D, Nyholt, D, Avbersek, A, Baum, L, Berkovic, S, Bradfield, J, Buono, R, Catarino, C, Cossette, P, De Jonghe, P, Depondt, C, Dlugos, D, Ferraro, T, French, J, Hjalgrim, H, Jamnadas-Khoda, J, Kälviäinen, R, Kunz, W, Lerche, H, Leu, C, Lindhout, D, Lo, W, Lowenstein, D, Mccormack, M, Møller, R, Molloy, A, Ng, P, Oliver, K, Privitera, M, Radtke, R, Ruppert, A, Sander, T, Schachter, S, Schankin, C, Scheffer, I, Schoch, S, Sisodiya, S, Smith, P, Sperling, M, Striano, P, Surges, R, Neil Thomas, G, Visscher, F, Whelan, C, Zara, F, Heinzen, E, Marson, A, Becker, F, Stroink, H, Zimprich, F, Gasser, T, Gibbs, R, Heutink, P, Martinez, M, Morris, H, Sharma, M, Ryten, M, Mok, K, Pulit, S, Bevan, S, Holliday, E, Attia, J, Battey, T, Boncoraglio, G, Thijs, V, Chen, W, Mitchell, B, Rothwell, P, Sharma, P, Sudlow, C, Vicente, A, Markus, H, Kourkoulis, C, Pera, J, Raffeld, M, Silliman, S, Perica, V, Thornton, L, Huckins, L, William Rayner, N, Lewis, C, Gratacos, M, Rybakowski, F, Keski-Rahkonen, A, Raevuori, A, Hudson, J, Reichborn-Kjennerud, T, Monteleone, P, Karwautz, A, Mannik, K, Baker, J, O'Toole, J, Trace, S, Davis, O, Helder, S, Ehrlich, S, Herpertz-Dahlmann, B, Danner, U, Van Elburg, A, Clementi, M, Forzan, M, Docampo, E, Lissowska, J, Hauser, J, Tortorella, A, Maj, M, Gonidakis, F, Tziouvas, K, Papezova, H, Yilmaz, Z, Wagner, G, Cohen-Woods, S, Herms, S, Julia, A, Rabionet, R, Dick, D, Ripatti, S, Andreassen, O, Espeseth, T, Lundervold, A, Steen, V, Pinto, D, Scherer, S, Aschauer, H, Schosser, A, Alfredsson, L, Padyukov, L, Halmi, K, Mitchell, J, Strober, M, Bergen, A, Kaye, W, Szatkiewicz, J, Cormand, B, Ramos-Quiroga, J, Sánchez-Mora, C, Ribasés, M, Casas, M, Hervas, A, Arranz, M, Haavik, J, Zayats, T, Johansson, S, Williams, N, Dempfle, A, Rothenberger, A, Kuntsi, J, Oades, R, Banaschewski, T, Franke, B, Buitelaar, J, Vasquez, A, Doyle, A, Reif, A, Lesch, K, Freitag, C, Rivero, O, Palmason, H, Romanos, M, Langley, K, Rietschel, M, Witt, S, Dalsgaard, S, Børglum, A, Waldman, I, Wilmot, B, Molly, N, Bau, C, Crosbie, J, Schachar, R, Loo, S, Mcgough, J, Grevet, E, Medland, S, Robinson, E, Weiss, L, Bacchelli, E, Bailey, A, Bal, V, Battaglia, A, Betancur, C, Bolton, P, Cantor, R, Celestino-Soper, P, Dawson, G, De Rubeis, S, Duque, F, Green, A, Klauck, S, Leboyer, M, Levitt, P, Maestrini, E, Mane, S, Moreno-De-Luca, D, Parr, J, Regan, R, Reichenberg, A, Sandin, S, Vorstman, J, Wassink, T, Wijsman, E, Cook, E, Santangelo, S, Delorme, R, Roge, B, Magalhaes, T, Arking, D, Schulze, T, Thompson, R, Strohmaier, J, Matthews, K, Melle, I, Morris, D, Blackwood, D, Mcintosh, A, Bergen, S, Schalling, M, Jamain, S, Maaser, A, Fischer, S, Reinbold, C, Fullerton, J, Guzman-Parra, J, Mayoral, F, Schofield, P, Cichon, S, Mühleisen, T, Degenhardt, F, Schumacher, J, Bauer, M, Mitchell, P, Gershon, E, Rice, J, Potash, J, Zandi, P, Craddock, N, Nicol Ferrier, I, Alda, M, Rouleau, G, Turecki, G, Ophoff, R, Pato, C, Anjorin, A, Stahl, E, Leber, M, Czerski, P, Cruceanu, C, Jones, I, Posthuma, D, Andlauer, T, Forstner, A, Streit, F, Baune, B, Air, T, Sinnamon, G, Wray, N, Macintyre, D, Porteous, D, Homuth, G, Rivera, M, Grove, J, Middeldorp, C, Hickie, I, Pergadia, M, Mehta, D, Smit, J, Jansen, R, De Geus, E, Dunn, E, Li, Q, Nauck, M, Schoevers, R, Beekman, A, Knowles, J, Viktorin, A, Arnold, P, Barr, C, Bedoya-Berrio, G, Joseph Bienvenu, O, Brentani, H, Burton, C, Camarena, B, Cappi, C, Cath, D, Cavallini, M, Cusi, D, Darrow, S, Denys, D, Derks, E, Dietrich, A, Fernandez, T, Figee, M, Freimer, N, Gerber, G, Grados, M, Greenberg, E, Hanna, G, Hartmann, A, Hirschtritt, M, Hoekstra, P, Huang, A, Huyser, C, Illmann, C, Jenike, M, Kuperman, S, Leventhal, B, Lochner, C, Lyon, G, Macciardi, F, Madruga-Garrido, M, Malaty, I, Maras, A, Mcgrath, L, Miguel, E, Mir, P, Nestadt, G, Nicolini, H, Okun, M, Pakstis, A, Paschou, P, Piacentini, J, Pittenger, C, Plessen, K, Ramensky, V, Ramos, E, Reus, V, Richter, M, Riddle, M, Robertson, M, Roessner, V, Rosário, M, Samuels, J, Sandor, P, Stein, D, Tsetsos, F, Van Nieuwerburgh, F, Weatherall, S, Wendland, J, Wolanczyk, T, Worbe, Y, Zai, G, Goes, F, Mclaughlin, N, Nestadt, P, Grabe, H, Depienne, C, Konkashbaev, A, Lanzagorta, N, Valencia-Duarte, A, Bramon, E, Buccola, N, Cahn, W, Cairns, M, Chong, S, Cohen, D, Crespo-Facorro, B, Crowley, J, Davidson, M, Delisi, L, Dinan, T, Donohoe, G, Drapeau, E, Duan, J, Haan, L, Hougaard, D, Karachanak-Yankova, S, Khrunin, A, Klovins, J, Kučinskas, V, Keong, J, Limborska, S, Loughland, C, Lönnqvist, J, Maher, B, Mattheisen, M, Mcdonald, C, Murphy, K, Nenadic, I, Van Os, J, Pantelis, C, Pato, M, Petryshen, T, Quested, D, Roussos, P, Sanders, A, Schall, U, Schwab, S, Sim, K, So, H, Stögmann, E, Subramaniam, M, Toncheva, D, Waddington, J, Walters, J, Weiser, M, Cheng, W, Cloninger, R, Curtis, D, Gejman, P, Henskens, F, Mattingsdal, M, Oh, S, Scott, R, Webb, B, Breen, G, Churchhouse, C, Bulik, C, Daly, M, Dichgans, M, Faraone, S, Guerreiro, R, Holmans, P, Kendler, K, Koeleman, B, Mathews, C, Price, A, Scharf, J, Sklar, P, Williams, J, Wood, N, Cotsapas, C, Palotie, A, Smoller, J, Sullivan, P, Rosand, J, Corvin, A, Neale, B, Kauwe, John S. K., Mcquillin, Andrew, Adams, Hieab H. H., Mccormack, Mark, Bau, Claiton H. D., Mcgough, James J., Mcintosh, Andrew, Andlauer, Till F. M., Macintyre, Donald J., Mcgrath, Lauren, Mclaughlin, Nicole, Delisi, Lynn, Mcdonald, Colm, Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), RIKEN Center for Integrative Medical Science, Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), University of South Florida (USF), University of Zürich [Zürich] (UZH)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Cardiff University-Medical Research Council, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Johannes Kepler University Linz [linz] (JKU), Washington University in St Louis, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Universitat Autònoma de Barcelona [Barcelona] (UAB), Hôpital Erasme (Bruxelles), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Jagiellonian University [Krakow] (UJ), Technische Universität Dresden (TUD), National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Charles University [Prague], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), University Medicine Goettingen, Università di Bologna [Bologna] (UNIBO), Forschungszentrum Jülich GmbH, UNSW Medicine [Sydney], McGill University, Universidad de Antioquia, University of Florida [Gainesville], Universiteit Gent [Ghent], Service Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], University of Wollongong, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Anttila, Verneri [0000-0002-0073-4675], Finucane, Hilary K [0000-0003-3864-9828], Walters, Raymond K [0000-0001-8422-6530], Duncan, Laramie [0000-0003-1131-661X], Escott-Price, Valentina [0000-0003-1784-5483], Falcone, Guido J [0000-0002-6407-0302], Gormley, Padhraig [0000-0002-8908-6968], Malik, Rainer [0000-0001-9212-2520], Ripke, Stephan [0000-0003-3622-835X], Wei, Zhi [0000-0001-6059-4267], Yu, Dongmei [0000-0001-7901-4365], Lee, Phil H [0000-0003-1770-3100], Breen, Gerome [0000-0003-2053-1792], Bulik, Cynthia M [0000-0001-7772-3264], Daly, Mark [0000-0002-0949-8752], Dichgans, Martin [0000-0002-0654-387X], Faraone, Stephen V [0000-0002-9217-3982], Holmans, Peter [0000-0003-0870-9412], Koeleman, Bobby [0000-0001-7749-182X], Mathews, Carol A [0000-0003-2208-7058], Sklar, Pamela [0000-0001-9715-4943], Williams, Julie [0000-0002-4069-0259], Wood, Nicholas W [0000-0002-9500-3348], Cotsapas, Chris [0000-0002-7772-5910], Smoller, Jordan W [0000-0002-0381-6334], Sullivan, Patrick [0000-0002-6619-873X], Rosand, Jonathan [0000-0002-1014-9138], Corvin, Aiden [0000-0001-6717-4089], Neale, Benjamin M [0000-0003-1513-6077], and Apollo - University of Cambridge Repository

Subjects
Etiology, [SDV]Life Sciences [q-bio], MESH: Brain Diseases, body-mass index, genetics [Mental Disorders], Disorders of the Brain, Risks factors, classification [Mental Disorders], MESH: Quantitative Trait, Heritable, MESH: Risk Factors, Risk Factors, MESH: Genetic Variation, alzheimers-disease, 610 Medicine & health, bipolar disorder, Brain Diseases, deficit hyperactivity disorder, Multidisciplinary, Mental Disorders, genetics [Brain Diseases], Brain Disease, Brain, Genetic Variation, Genome-Wide Association Study, Humans, Phenotype, Quantitative Trait, Heritable, Psychiatric Disorders, anorexia-nervosa, Mental Disorder, Psychiatric Genomics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], long-term survival, Engineering sciences. Technology, Human, General Science & Technology, population-based twin, diagnosis [Mental Disorders], MESH: Phenotype, Neurological Disorders, Quantitative Trait, MD Multidisciplinary, MESH: Mental Disorders, diagnosis [Brain Diseases], Heritable, genetic correlations, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, major depressive disorder, Risk Factor, Brain Diseases/classification, Brain Diseases/diagnosis, Brain Diseases/genetics, Mental Disorders/classification, Mental Disorders/diagnosis, Mental Disorders/genetics, classification [Brain Diseases], Perturbações do Desenvolvimento Infantil e Saúde Mental, ddc:320, MESH: Genome-Wide Association Study, genome-wide association, Brainstorm Consortium, Genetic Factors, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities’ assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer’s disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important “scaffolding” to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders.

Published
2018

34. Genetic analysis of Mendelian mutations in a large UK population-based Parkinson's disease study

Author

Tan, Manuela MX, Malek, Naveed, Lawton, Michael A, Hubbard, Leon, Pittman, Alan M, Joseph, Theresita, Hehir, Jason, Swallow, Diane MA, Grosset, Katherine A, Marrinan, Sarah L, Bajaj, Nin, Barker, Roger A, Burn, David J, Bresner, Catherine, Foltynie, Thomas, Hardy, John, Wood, Nicholas, Ben-Shlomo, Yoav, Grosset, Donald G, Williams, Nigel M, Morris, Huw R, Barker, Roger [0000-0001-8843-7730], and Apollo - University of Cambridge Repository

Subjects
Adult, Aged, 80 and over, Male, Genotype, phenotype, prevalence, Parkinson Disease, Original Articles, Mendelian Randomization Analysis, Middle Aged, United Kingdom, nervous system diseases, Cohort Studies, Population Surveillance, Mutation, Parkinson’s disease, Humans, Female, genetics, Genetic Testing, Prospective Studies, heterogeneity, Aged
Abstract

In a large population-based study, Tan et al. show that pathogenic mutations are present in 1.4% of UK patients with Parkinson’s disease and are more common in those with early-onset or familial disease. Carriers of mutations in PRKN or PINK1 have distinctive clinical features compared to non-carriers., Our objective was to define the prevalence and clinical features of genetic Parkinson’s disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson’s Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson’s study, 424 had young-onset Parkinson’s disease (age at onset ≤ 50) and 1799 had late onset Parkinson’s disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 ‘Kompetitive’ allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson’s disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson’s disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.

Published
2019

35. L-dopa responsiveness in early Parkinson's disease is associated with the rate of motor progression

Author

Malek, Naveed, Kanavou, Sofia, Lawton, Michael A, Pitz, Vanessa, Grosset, Katherine A, Bajaj, Nin, Barker, Roger A, Ben-Shlomo, Yoav, Burn, David J, Foltynie, Tom, Hardy, John, Williams, Nigel M, Wood, Nicholas, Morris, Huw R, Grosset, Donald G, PRoBaND clinical consortium, Barker, Roger [0000-0001-8843-7730], and Apollo - University of Cambridge Repository

Subjects
Male, Parkinson's disease, Parkinson Disease, Middle Aged, Mental Status and Dementia Tests, Severity of Illness Index, Antiparkinson Agents, Levodopa, Treatment Outcome, L-dopa, Disease Progression, Humans, Female, Therapy, Aged
Abstract

BACKGROUND: L-dopa responsiveness in Parkinson's disease (PD) varies, but the clinical correlates and significance of this are ill-defined. METHODS: Patients were assessed before and after their usual morning L-dopa dose, using the MDS Unified PD Rating Scale Part 3 (MDS UPDRS 3), and rated as definite responders (≥24.5% improvement) or limited responders (

Published
2019
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36. Proximity extension assay testing reveals novel diagnostic biomarkers of atypical parkinsonian syndromes

Author

Jabbari, Edwin, Woodside, John, Guo, Tong, Magdalinou, Nadia K, Chelban, Viorica, Athauda, Dilan, Lees, Andrew J, Foltynie, Thomas, Houlden, Henry, Church, Alistair, Hu, Michele Tm, Rowe, James B, Zetterberg, Henrik, Morris, Huw R, Jabbari, Edwin [0000-0001-6844-882X], Rowe, James B [0000-0001-7216-8679], and Apollo - University of Cambridge Repository

Subjects
Immunoassay, Male, Movement Disorders, diagnostic test assessment, multiple system atrophy, Age Factors, Parkinson Disease, progressive supranuclear palsy, Middle Aged, cerebrospinal fluid, Sex Factors, Parkinsonian Disorders, Case-Control Studies, Humans, Female, Biomarkers, corticobasal degeneration, Aged
Abstract

Objective The high degree of clinical overlap between atypical parkinsonian syndromes (APS) and Parkinson’s disease (PD) makes diagnosis challenging. We aimed to identify novel diagnostic protein biomarkers of APS using multiplex proximity extension assay (PEA) testing. Methods Cerebrospinal fluid (CSF) samples from two independent cohorts, each consisting of APS and PD cases, and controls, were analysed for neurofilament light chain (NF-L) and Olink Neurology and Inflammation PEA biomarker panels. Whole-cohort comparisons of biomarker concentrations were made between APS (n=114), PD (n=37) and control (n=34) groups using logistic regression analyses that included gender, age and disease duration as covariates. Results APS versus controls analyses revealed 11 CSF markers with significantly different levels in cases and controls (p Conclusions PEA testing has identified potential novel diagnostic biomarkers of APS.

Published
2019

37. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till F M, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ifgc, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavanramasamy, Kwok, John B. J., Carol, Dobson-Stone, Brooks, William S., Schofield, Peterr., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Laurenbartley, Elizabeth, Thompson, Eric, Haan, Isabel, Hernández, Agustín, Ruiz, Mercè, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigiforloni, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, Jordi, Clarimón, Alberto, Lleó, Rafael, Blesa, Maria Landqvist Waldö, Karinnilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, DavidM. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietrini, P., Huey, Edward D., Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robertperneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, George-Hyslop, Peterst., Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, William, Deschamps, Tim, Vanlangenhove, Marc, Cruts, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle Le Ber, Didier, Hannequin, Véronique, Golfier, Martine, Vercelletto, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuelmayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Annarichardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Fran-cesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Davidknopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, Vanswieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philipscheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolosorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Florencepasquier, Adeline, Rollin, Vincent, Deramecourt, Florence, Lebert, Dimitrioskapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni, Ironside, James W, van Berckel, Bart N M, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel J T, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande A L, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild I A, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, Clarimón, Jordi, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M, Holstege, Henne, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Sociology, The Social Context of Aging (SoCA), Universidad de Cantabria, DESGESCO Dementia Genetics, EADB Alzheimer Dis European, IFGC Int FTD-Genomics, IPDGC Int Parkinson Dis Genomics, RiMod-FTD Risk Modifying, Netherlands Brain Bank NBB, GIFT Genetic Invest, van der Lee, Sven J [0000-0003-1606-8643], Andlauer, Till FM [0000-0002-2917-5889], Tesi, Niccolo [0000-0002-1413-5091], Scheltens, Philip [0000-0002-1046-6408], Holstege, Henne [0000-0002-7688-3087], Apollo - University of Cambridge Repository, Amsterdam Neuroscience - Neurodegeneration, Neurology, Epidemiology and Data Science, Radiology and nuclear medicine, Other Research, Divisions, APH - Societal Participation & Health, APH - Aging & Later Life, Human genetics, Amsterdam Reproduction & Development (AR&D), APH - Personalized Medicine, and APH - Methodology

Subjects
0301 basic medicine, Parkinson's disease, Dementia with Lewy bodies, genetics [Alzheimer Disease], Disease, metabolism [Microglia], Bioinformatics, Neurodegenerative disease, 0302 clinical medicine, genetics [Lewy Body Disease], pathology [Brain], genetics [Parkinson Disease], Missense mutation, genetics [Frontotemporal Dementia], ALZHEIMER’S DISEASE, Brain, Parkinson Disease, purl.org/becyt/ford/3.1 [https], Alzheimer's disease, Phospholipase C Gamma 2, Biobank, 3. Good health, genetics [Amyotrophic Lateral Sclerosis], genetics [Phospholipase C gamma], purl.org/becyt/ford/3 [https], immunology [Brain], Microglia, Alzheimer’s disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Longevity, Multiple sclerosis, PLCG2, Parkinson’s disease, Progressive supranuclear palsy, Lewy Body Disease, Risk, education, Neuroimaging, Pathology and Forensic Medicine, PARKINSON’S DISEASE, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, genetics [Dementia], medicine, Humans, Genetic Predisposition to Disease, ddc:610, Alleles, Original Paper, Phospholipase C gamma, business.industry, genetics [Multiple Sclerosis], medicine.disease, 030104 developmental biology, metabolism [Brain], Mutation, Dementia, Human medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, genetics [Longevity], Genome-Wide Association Study
Abstract

ATENCIÓ: la correcció està també al DDD, cal relacionar??? https://ddd.uab.cat/record/226203 Altres ajuts: The following studies and consortia have contributed to this manuscript. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe): This study/publication is part of the German Research Network on Dementia (KND), the German Research Network on Degenerative Dementia (KNDD; German Study on Ageing, Cognition and Dementia in Primary Care Patients; AgeCoDe), and the Health Service Research Initiative (Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+; AgeQualiDe)) and was funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716; grants Health Service Research Initiative: 01GY1322A, 01GY1322B, 01GY1322C, 01GY1322D, 01GY1322E, 01GY1322F, 01GY1322G). Alfredo Ramirez was partly supported by the ADAPTED consortium: Alzheimer's disease Apolipoprotein Pathology for Treatment Elucidation and Development, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. Brain compendium: This work was funded by the UK Medical Research Council (13044). P.F.C. is a Wellcome Trust principal Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.Clinical AD, Sweden: We would like to thank UCL Genomics for performing the genotyping analyses. Danish data: The studies behind the Danish long-lived cases received funding from The National Program for Research Infrastructure 2007 (grant no. 09-063256), the Danish Agency for Science Technology and Innovation, the Velux Foundation, the US National Institute of Health (P01 AG08761), the Danish Agency for Science, Technology and Innovation/The Danish Council for Independent Research (grant no. 11-107308), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the CERA Foundation (Lyon), the AXA Research Fund, Paris, and The Health Foundation (Helsefonden), Copenhagen, Denmark. The GOYA study was conducted as part of the activities of the Danish Obesity Research Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth Cohort which was established with major funding from the Danish National Research Foundation. Additional support for this cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Fundació ACE (FACE): We would like to thank patients and controls who participated in this project. We are indebted to Trinitat Port-Carbó and her family for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). Agustín Ruiz has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED Grant No. 115975 and by grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- "Una manera de Hacer Europa"), by Fundación bancaria "La Caixa" and Grifols SA (GR@ACE project). Genetics of Healthy Ageing Study (GEHA - NL): The work described in this paper was funded mainly by the EU GEHA Project contract no. LSHM-CT-2004-503-270. Gothenburg Birth Cohort (GBC) Studies: We would like to thank UCL Genomics for performing the genotyping analyses. The studies were supported by The Stena Foundation, The Swedish Research Council (2015-02830, 2013-8717), The Swedish Research Council for Health, Working Life and Wellfare (2013-1202, 2005-0762, 2008-1210, 2013-2300, 2013-2496, 2013-0475), The Brain Foundation, Sahlgrenska University Hospital (ALF), The Alzheimer's Association (IIRG-03-6168), The Alzheimer's Association Zenith Award (ZEN-01-3151), Eivind och Elsa K:son Sylvans Stiftelse, The Swedish Alzheimer Foundation. International FTD-Genomics Consortium (IFGC): International FTD-Genomics Consortium (IFGC): The authors thank the IFGC for providing relevant data to support the analyses presented in this manuscript. Further acknowledgments for IFGC (https://ifgcsite.wordpress.com/), e.g. full members list and affiliations, are found in the online supplementary files. IPDGC (​The International Parkinson Disease Genomics Consortium): We also would like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). See for a complete overview of members, acknowledgements and funding http://pdgenetics.org/partners. Kompetenznetz Multiple Sklerose (KKNMS): This work was supported by the German Ministry for Education and Research (BMBF) as part of the "German Competence Network Multiple Sclerosis" (KKNMS) (grant nos. 01GI0916 and 01GI0917) and the Munich Cluster for Systems Neurology (SyNergy). TA was supported by the BMBF through the Integrated Network IntegraMent, under the auspices of the e:Med Programme (01ZX1614J). BH was supported by the EU Horizon 2020 project MultipleMS.Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. Leiden Longevity Study: This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (Grant 050-060-810), all in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and by Unilever Colworth.Maria Carolina Dalmasso: Georg Forster Research Award (Alexander von Humboldt Foundation). Mayo Clinic AD, DLB, PD, PSP: We thank the patients and their families for their participation, without whom these studies would not have been possible. Funding for this work was supported by National Institute on Aging [RF AG051504 to NET.; U01 AG046139 to NET]; and National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET; P50 NS072187]. The Mayo Clinic is a Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Information and Referral Center and Center for Advanced Research, NINDS Tau Center without Walls (U54-NS100693) and is supported by Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, the Mangurian Foundation for Lewy body research and NINDS R01 NS078086 (to OAR). The PD program at the Mayo Clinic Florida is also supported by the Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, and The Sol Goldman Charitable Trust. Samples included in this study are from the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP The online version of this article (10.1007/s00401-019-02026-8) contains supplementary material, which is available to authorized users.

Published
2019

38. A detailed clinical study of pain in 1957 participants with early/moderate Parkinson's disease

Author

Silverdale, Monty A, Kobylecki, Christopher, Kass-Iliyya, Lewis, Martinez-Martin, Pablo, Lawton, Michael, Cotterill, Sarah, Chaudhuri, K Ray, Morris, Huw, Baig, Fahd, Williams, Nigel, Hubbard, Leon, Hu, Michele T, Grosset, Donald G, UK Parkinson's Pain Study Collaboration, and Parkinson's UK

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Parkinson's disease, Population, Pain, Disease, medicine.disease_cause, Article, Clinical study, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Medicine, Humans, Longitudinal Studies, education, Aged, Pain Measurement, education.field_of_study, business.industry, Poor posture, Parkinson Disease, Pain scale, Central sensitization, Middle Aged, medicine.disease, Peripheral, 030104 developmental biology, Allodynia, Early Diagnosis, Neurology, Musculoskeletal, Parkinson’s disease, Nonmotor, Female, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Introduction The causes of pain in early/moderate Parkinson's disease (PD) are not well understood. Although peripheral factors such as rigidity, reduced joint movements and poor posture may contribute towards the development of pain, central mechanisms including altered nociceptive processing may also be involved. Methods We performed a large clinical study to investigate potential factors contributing towards pain in early/moderate PD. We recruited 1957 PD participants who had detailed assessments of pain, motor and non-motor symptoms. The King's Parkinson's Pain scale was used to quantify different subtypes of pain. Results 85% of participants reported pain (42% with moderate to severe pain). Pain influenced quality of life more than motor symptoms in a multiple regression model. Factors predicting overall pain severity included affective symptoms, autonomic symptoms, motor complications, female gender and younger age, but not motor impairment or disease duration. There was negligible correlation between the severity of motor impairment and the severity of musculoskeletal or dystonic pain as well as between the severity of OFF period motor problems and the severity of OFF period pain or OFF period dystonic pain. Features of central sensitization, including allodynia and altered pain sensation were common in this population. The use of drugs targeting central pain was very low. Conclusions Pain in early/moderate PD cannot be explained by peripheral factors. Central causes may play a much more important role than previously considered. These results should lead to a major shift in the investigation and management of this common and disabling symptom., Highlights • Pain is common in early/moderate PD and impairs quality of life more than motor symptoms • No correlation between mobility problems and musculoskeletal or radicular pain in early/moderate PD • No correlation between OFF motor symptoms and OFF period pain in early/moderate PD • Features of central pain sensitization are common in early/moderate PD • Central factors are a more important cause of pain in early/moderate PD than previously considered

Published
2018

39. Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study

Author

Malek, Naveed, Weil, Rimona S, Bresner, Catherine, Lawton, Michael A, Grosset, Katherine A, Tan, Manuela, Bajaj, Nin, Barker, Roger A, Burn, David J, Foltynie, Thomas, Hardy, John, Wood, Nicholas W, Ben-Shlomo, Yoav, Williams, Nigel W, Grosset, Donald G, Morris, Huw R, PRoBaND Clinical Consortium, Weil, Rimona S [0000-0002-5092-6325], and Apollo - University of Cambridge Repository

Subjects
Male, Heterozygote, Parkinson Disease, Middle Aged, United Kingdom, Cohort Studies, Mutation, Glucosylceramidase, Humans, Cognitive Dysfunction, Dementia, Female, Prospective Studies, Age of Onset, Aged
Abstract

OBJECTIVES: To examine the influence of the glucocerebrosidase (GBA) mutation carrier state on age at onset of Parkinson's disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function. METHODS: We prospectively recruited patients with PD in the Tracking Parkinson's study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson's Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia. RESULTS: We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher's disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage. CONCLUSIONS: Our study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA mutation carriers and non-carriers at baseline, implying that cognitive impairment/dementia, reported in other studies at a later disease stage, is not present in recently diagnosed cases. This offers an important window of opportunity for potential disease-modifying therapy that may protect against the development of dementia in GBA-PD. CLINICAL TRIAL REGISTRATION: NCT02881099; Results.

Published
2018

40. No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease in nine ADHD candidate SNPs

Author

Geissler, Julia M, Romanos, Marcel, Sheerin, Una-Marie, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Sidransky, Ellen, Smith, Colin, Spencer, Chris C A, Stefánsson, Hreinn, Steinberg, Stacy, Stockton, Joanna D, Strange, Amy, Saad, Mohamad, Talbot, Kevin, Tanner, Carlie M, Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J, Uitterlinden, André G, Velseboer, Daan, Vidailhet, Marie, Walker, Robert, Simón-Sánchez, Javier, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H, Winder-Rhodes, Sophie, Stefánsson, Kári, Martinez, Maria, Hardy, John, Heutink, Peter, Brice, Alexis, Schulte, Claudia, Gasser, Thomas, Singleton, Andrew B, Wood, Nicholas W, Lesage, Suzanne, Sveinbjörnsdóttir, Sigurlaug, Arepalli, Sampath, Barker, Roger, Ben-Shlomo, Yoav, Berendse, Henk W, Gerlach, Manfred, Berg, Daniela, Bhatia, Kailash, de Bie, Rob M A, Biffi, Alessandro, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Bras, Jose M, Brockmann, Kathrin, Brooks, Janet, Burn, David J, Charlesworth, Gavin, Chen, Honglei, Chinnery, Patrick F, Chong, Sean, Clarke, Carl E, Cookson, Mark R, Cooper, J Mark, Corvol, Jean Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean-François, Deloukas, Panos, Deuschl, Günther, Dexter, David T, van Dijk, Karin D, Dillman, Allissa, Durif, Frank, Dürr, Alexandra, Edkins, Sarah, members, International Parkinson Disease Genomics Consortium, Evans, Jonathan R, Foltynie, Thomas, Gao, Jianjun, Gardner, Michelle, Gibbs, J Raphael, Goate, Alison, Gray, Emma, Guerreiro, Rita, Gústafsson, Ómar, Harris, Clare, Nalls, Mike, van Hilten, Jacobus J, Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Huber, Heiko, Hudson, Gavin, Hunt, Sarah E, Huttenlocher, Johanna, Plagnol, Vincent, Illig, Thomas, Jónsson, Pálmi V, Lambert, Jean-Charles, Langford, Cordelia, Lees, Andrew, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, McNeill, Alisdair, Hernandez, Dena G, Moorby, Catriona, Moore, Matthew, Morris, Huw R, Morrison, Karen E, Mudanohwo, Ese, O'Sullivan, Sean S, Pearson, Justin, Perlmutter, Joel S, Pétursson, Hjörvar, Pollak, Pierre, Sharma, Manu, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Ryten, Mina, Sawcer, Stephen, Schapira, Anthony, Human genetics, Neurology, Amsterdam Neuroscience - Neurodegeneration, Geissler, Julia M [0000-0003-1878-9647], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Parkinson's disease, Single-nucleotide polymorphism, Genome-wide association study, genetics [Attention Deficit Disorder with Hyperactivity], Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, genetics [Parkinson Disease], medicine, Attention deficit hyperactivity disorder, ADHD, GWAS, Humans, Genetic Predisposition to Disease, ddc:610, genetics [Genetic Predisposition to Disease], Genetic Association Studies, Genetic association, Dopamine transporter, Genetics, TPH2, biology, Parkinson Disease, General Medicine, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Norepinephrine transporter, Attention Deficit Disorder with Hyperactivity, biology.protein, genetics [Polymorphism, Single Nucleotide], Parkinson’s disease, Psychology, 030217 neurology & neurosurgery, CDH13, SNPs
Abstract

Item does not contain fulltext Attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD) involve pathological changes in brain structures such as the basal ganglia, which are essential for the control of motor and cognitive behavior and impulsivity. The cause of ADHD and PD remains unknown, but there is increasing evidence that both seem to result from a complicated interplay of genetic and environmental factors affecting numerous cellular processes and brain regions. To explore the possibility of common genetic pathways within the respective pathophysiologies, nine ADHD candidate single nucleotide polymorphisms (SNPs) in seven genes were tested for association with PD in 5333 cases and 12,019 healthy controls: one variant, respectively, in the genes coding for synaptosomal-associated protein 25 k (SNAP25), the dopamine (DA) transporter (SLC6A3; DAT1), DA receptor D4 (DRD4), serotonin receptor 1B (HTR1B), tryptophan hydroxylase 2 (TPH2), the norepinephrine transporter SLC6A2 and three SNPs in cadherin 13 (CDH13). Information was extracted from a recent meta-analysis of five genome-wide association studies, in which 7,689,524 SNPs in European samples were successfully imputed. No significant association was observed after correction for multiple testing. Therefore, it is reasonable to conclude that candidate variants implicated in the pathogenesis of ADHD do not play a substantial role in PD.

Published
2018
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41. A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia

Author

Mencacci, Niccolo E, Rubio-Agusti, Ignacio, Forabosco, Paola, Hughes, Deborah, Soutar, Marc M P, Peall, Kathryn, Morris, Huw R, Trabzuni, Daniah, Tekman, Mehmet, Stanescu, Horia C, Kleta, Robert, Carecchio, Miryam, Zdebik, Anselm, Zorzi, Giovanna, Nardocci, Nardo, Garavaglia, Barbara, Lohmann, Ebba, Weissbach, Anne, Klein, Christine, Hardy, John, Pittman, Alan M, Foltynie, Thomas, Abramov, Andrey Y, Asmus, Friedrich, Gasser, Thomas, Bhatia, Kailash P, Wood, Nicholas W, Ludtmann, Marthe H R, Ryten, Mina, Plagnol, Vincent, Hauser, Ann-Kathrin, Bandres-Ciga, Sara, and Bettencourt, Conceição

Subjects
genetics [Dystonic Disorders], genetics [Synaptic Transmission], Male, Potassium Channels, genetics [Mutation, Missense], Molecular Sequence Data, pathology [Dystonic Disorders], Mutation, Missense, Synaptic Transmission, ddc:570, genetics [Adaptor Proteins, Signal Transducing], Germany, Report, genetics [Genes, Dominant], genetics [Exome], Genetics, metabolism [Dystonic Disorders], Humans, Exome, Gene Regulatory Networks, Genetics(clinical), Adaptor Proteins, Signal Transducing, Genes, Dominant, Base Sequence, genetics [Potassium Channels], Brain, Chromosome Mapping, Sequence Analysis, DNA, KCTD17 protein, human, United Kingdom, Pedigree, metabolism [Brain], Dystonic Disorders, genetics [Gene Regulatory Networks], Female
Abstract

Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%-50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c. 434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c. 434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D.

Published
2015
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42. A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease

Author

Holmans, Peter, Moskvina, Valentina, Jones, Lesley, Sharma, Manu, Vedernikov, Alexey, Buchel, Finja, Sadd, Mohamad, Bras, Jose M., Bettella, Francesco, Nicolaou, Nayia, Simón-Sánchez, Javier, Mittag, Florian, Gibbs, J. Raphael, Schulte, Claudia, Durr, Alexandra, Guerreiro, Rita, Hernandez, Dena, Brice, Alexis, Stefánsson, Hreinn, Majamaa, Kari, Gasser, Thomas, Heutink, Peter, Wood, Nicholas W., Martinez, Maria, Singleton, Andrew B., Nalls, Michael A., Hardy, John, Morris, Huw R., Williams, Nigel M., Arepalli, Sampath, Barker, Roger, Barrett, Jeffrey, Ben-Shlomo, Yoav, Berendse, Henk W., Berg, Daniela, Bhatia, Kailash, de Bie, Rob M.A., Biffi, Alessandro, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Brockmann, Kathrin, Brooks, Janet, Burn, David J., Charlesworth, Gavin, Chen, Honglei, Chinnery, Patrick F., Chong, Sean, Clarke, Carl E., Cookson, Mark R., Cooper, Jonathan M., Corvol, Jen-Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean Francois, Deloukas, Panagiotis, Deuschl, Günther, Dexter, David T., van Dijk, Karin D., Dillman, Allissa, Durif, Frank, Edkins, Sarah, Evans, Jonathan R., Foltynie, Thomas, Gao, Jianjun, Gardner, Michelle, Goate, Alison, Gray, Emma, Gústafsson, Ómar, Harris, Clare, Hernandez, Dena G., van Hilten, Jacobus J., Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huber, Heiko, Hudson, Gavin, Hunt, Sarah E., Huttenlocher, Johanna, Illig, Thomas, Langford, Cordelia, Lees, Andrew, Lesage, Suzanne, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, McNeill, Alisdair, Moorby, Catriona, Moore, Matthew, Morris, Huw, Morrison, Karen E., Mudanohwo, Ese, Pearson, Justin, Perlmutter, Joel S., Pétursson, Hjörvar, Plagnol, Vincent, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Ryten, Mina, Saad, Mohamad, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Sheerin, Una-Marie, Shoulson, Ira, Sidransky, Ellen, Smith, Colin, Stefánsson, Kári, Steinberg, Stacy, Stockton, Joanna D., Sveinbjornsdottir, Sigurlaug, Talbot, Kevin, Tanner, Carlie M., Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J., Uitterlinden, André G., Velseboer, Daan, Vidailhet, Marie, Walker, Robert, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H., Winder-Rhodes, Sophie, Wood, Nicholas, Internal Medicine, Functional Genomics, Neuroscience Campus Amsterdam - Neurodegeneration, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Human genetics, NCA - Brain mechanisms in health and disease, NCA - neurodegeneration, ANS - Amsterdam Neuroscience, Neurology, Graduate School, and Pollak, Pierre

Subjects
Parkinson's disease, Genome-wide association study, Genome, Parkinson Disease/genetics/immunology/metabolism, 0302 clinical medicine, genetics [Parkinson Disease], HLA Antigens, Genetics (clinical), Genetics, 0303 health sciences, biology, Association Studies Articles, Parkinson Disease, HLA Antigens/genetics, General Medicine, genetics [Metabolic Networks and Pathways], Human Movement & Fatigue [DCN MP - Plasticity and memory NCEBP 10], HMG-CoA reductase, immunology [Metabolic Networks and Pathways], Corrigendum, Metabolic Networks and Pathways, Risk, medicine.medical_specialty, DCN MP - Plasticity and memory, metabolism [Parkinson Disease], Single-nucleotide polymorphism, Locus (genetics), Human leukocyte antigen, Polymorphism, Single Nucleotide, 03 medical and health sciences, Immune system, immunology [Parkinson Disease], SDG 3 - Good Health and Well-being, Molecular genetics, ddc:570, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Allele, Gene, Molecular Biology, Alleles, 030304 developmental biology, Metabolic Networks and Pathways/genetics/immunology, medicine.disease, ddc:616.8, genetics [HLA Antigens], biology.protein, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Item does not contain fulltext Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people >60 and 3-4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 x 10(-16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the 'regulation of leucocyte/lymphocyte activity' and also 'cytokine-mediated signalling' as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.

Published
2013

43. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

Author

Consortium, Coffee and Caffeine Genetics, Cornelis, Marilyn C, Renstrom, Frida, Rasheed, Asif, Mason, Marc A, Zonderman, Alan B, Franke, Lude, Kristal, Bruce S, Consortium, International Parkinson’s Disease Genomics, Consortium, North American Brain Expression, Consortium, UK Brain Expression, Karjalainen, Juha, Reed, Danielle R, Ngwa, Julius S, Westra, Harm-Jan, Evans, Michele K, Saleheen, Danish, Harris, Tamara B, Dedoussis, George, Curhan, Gary, Stumvoll, Michael, Beilby, John, Pasquale, Louis R, Feenstra, Bjarke, Huikari, Ville, Bandinelli, Stefania, Ordovas, Jose M, Chan, Andrew T, Peters, Ulrike, Ohlsson, Claes, Gieger, Christian, Martin, Nicholas G, Waldenberger, Melanie, Siscovick, David S, Raitakari, Olli, Cavadino, Alana, Eriksson, Johan G, Mitchell, Paul, Hunter, David J, Kraft, Peter, Rimm, Eric B, Boomsma, Dorret I, Borecki, Ingrid B, Loos, Ruth Jf, Wareham, Nicholas J, Vollenweider, Peter, Nolte, Ilja M, Caporaso, Neil, Grabe, Hans Jörgen, Neuhouser, Marian L, Wolffenbuttel, Bruce Hr, Hu, Frank B, Hyppönen, Elina, Järvelin, Marjo-Riitta, Cupples, L Adrienne, Franks, Paul W, Ridker, Paul M, Teumer, Alexander, van Duijn, Cornelia M, Heiss, Gerardo, Metspalu, Andres, North, Kari E, Ingelsson, Erik, Nettleton, Jennifer A, van Dam, Rob M, Chasman, Daniel I, Nalls, Michael A, Plagnol, Vincent, Yu, Kai, Hernandez, Dena G, Sharma, Manu, Sheerin, Una-Marie, Saad, Mohamad, Simón-Sánchez, Javier, Schulte, Claudia, Lesage, Suzanne, Sveinbjörnsdóttir, Sigurlaug, Arepalli, Sampath, Barker, Roger, Marques-Vidal, Pedro, Ben-Shlomo, Yoav, Berendse, Henk W, Berg, Daniela, Bhatia, Kailash, de Bie, Rob M A, Biffi, Alessandro, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Bras, M., Rawal, Rajesh, Brockmann, Kathrin, Brooks, Janet, Burn, David J, Charlesworth, Gavin, Chen, Honglei, Chinnery, Patrick F, Chong, Sean, Clarke, Carl E, Cookson, Mark R, Cooper, J Mark, Manichaikul, Ani, Corvol, Jean Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean-François, Deloukas, Panos, Deuschl, Günther, Dexter, David T, van Dijk, Karin D, Dillman, Allissa, Durif, Frank, Byrne, Enda M, Wojczynski, Mary K, Dürr, Alexandra, Edkins, Sarah, Evans, Jonathan R, Foltynie, Thomas, Dong, Jing, Gardner, Michelle, Gibbs, J Raphael, Goate, Alison, Gray, Emma, Guerreiro, Rita, Vink, Jacqueline M, Harris, Clare, van Hilten, Jacobus J, Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Hershey, Milton S, Wurster, Isabel, Mätzler, Walter, Zhao, Jing Hua, Hudson, Gavin, Hunt, Sarah E, Huttenlocher, Johanna, Illig, Thomas, München, Helmholtz Zentrum, Jónsson, Pálmi V, Lambert, Jean-Charles, Langford, Cordelia, Lees, Andrew, Lichtner, Peter, Burlutsky, George, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, McNeill, Alisdair, Moorby, Catriona, Moore, Matthew, Morris, Huw R, Morrison, Karen E, O' Sullivan, Sean S, Lahti, Jari, Pearson, Justin, Perlmutter, Joel S, Pétursson, Hjörvar, Pollak, Pierre, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Mikkilä, Vera, Ryten, Mina, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Sidransky, Ellen, Smith, Colin, Spencer, Chris C A, Stefánsson, Hreinn, Bettella, Francesco, Lemaitre, Rozenn N, Stockton, Joanna D, Strange, Amy, Talbot, Kevin, Tanner, M., Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J, Uitterlinden, André G, Velseboer, Daan, Eriksson, Joel, Vidailhet, Marie, Walker, Robert, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H, Winder-Rhodes, Sophie, Stefánsson, Kári, Martinez, Maria, Sabatier, Paul, Musani, Solomon K, Wood, Nicholas W, Hardy, John, Heutink, Peter, Brice, Alexis, Gasser, Thomas, Singleton, Andrew B, Singleton, Andrew, Cookson, Mark, Hernandez, Dena, Tanaka, Toshiko, Nalls, Michael, Zonderman, Alan, Ferrucci, Luigi, Johnson, Robert, Longo, Dan, O'Brien, Richard, Traynor, Bryan, Troncoso, Juan, Esko, Tõnu, Geller, Frank, van der Brug, Marcel, Zielke, Ronald, Weale, Michael, Ramasamy, Adaikalavan, Box, P. O., Luan, Jian'an, Hui, Jennie, Mägi, Reedik, Dimitriou, Maria, Garcia, Melissa E, Ho, Weang-Kee, Wright, Margaret J, Rose, Lynda M, Magnusson, Patrik Ke, Pedersen, Nancy L, Couper, David, Oostra, Ben A, Ikram, Mohammad Arfan, Tiemeier, Henning W, Uitterlinden, Andre G, van Rooij, Frank Ja, Barroso, Inês, Johansson, Ingegerd, Ganna, Andrea, Xue, Luting, Kaakinen, Marika, Milani, Lili, Power, Chris, Snieder, Harold, Stolk, Ronald P, Baumeister, Sebastian E, Biffar, Reiner, Gu, Fangyi, Bastardot, François, Paynter, Nina, Kutalik, Zoltán, Jacobs, David R, Forouhi, Nita G, Mihailov, Evelin, Lind, Lars, Lindgren, Cecilia, Michaëlsson, Karl, Morris, Andrew, Jensen, Majken, Khaw, Kay-Tee, Monda, Keri L, Luben, Robert N, Wang, Jie Jin, Männistö, Satu, Perälä, Mia-Maria, Kähönen, Mika, Lehtimäki, Terho, Viikari, Jorma, Mozaffarian, Dariush, Mukamal, Kenneth, Psaty, Bruce M, Amin, Najaf, Döring, Angela, Heath, Andrew C, Montgomery, Grant W, Dahmen, Norbert, Carithers, Teresa, Tucker, Katherine L, Boyd, Heather A, Melbye, Mads, Treur, Jorien L, Fischer, Krista, Mellström, Dan, Hottenga, Jouke Jan, Prokopenko, Inga, Tönjes, Anke, Kanoni, Stavroula, Lorentzon, Mattias, Houston, Denise K, Liu, Yongmei, Danesh, John, Biological Psychology, Nutrition and Health, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, The, Coffee, Cornelis, MC, Byrne, Enda, Esko, Tonu, Nalls, MA, Hyppönen, Elina, Chasman, DI, The Coffee and Caffeine Genetics Consortium, International Parkinson's Disease Genomics Consortium (IPDGC), UK Brain Expression Consortium (UKBEC), North American Brain Expression Consortium (NABEC), Epidemiology, Surgery, Public Health, Cell biology, Hematology, Clinical Genetics, Internal Medicine, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), ANS - Amsterdam Neuroscience, Neurology, Graduate School, Pediatric surgery, VU University medical center, NCA - neurodegeneration, Human genetics, NCA - Brain mechanisms in health and disease, and NCA - Neurobiology of mental health

Subjects
INVOLVEMENT, Netherlands Twin Register (NTR), GCKR protein, human, PROTEIN, Genome-wide association study, VARIANTS, genetics [Brain-Derived Neurotrophic Factor], chemistry.chemical_compound, 0302 clinical medicine, Polymorphism (computer science), genetics [Adaptor Proteins, Signal Transducing], BINDING, BRAIN, Genetics, 0303 health sciences, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, Psychiatry and Mental health, Phenotype, genetics [Polymorphism, Single Nucleotide], genetics [Cytochrome P-450 CYP1A2], Caffeine, CAFFEINE, Single-nucleotide polymorphism, Biology, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Cytochrome P-450 CYP1A2, SNP, Humans, ddc:610, Allele, genetics [Basic Helix-Loop-Helix Leucine Zipper Transcription Factors], Molecular Biology, 030304 developmental biology, Adaptor Proteins, Signal Transducing, MLXIPL protein, human, RECEPTOR, Brain-Derived Neurotrophic Factor, Coffea, ta1182, Feeding Behavior, biology.organism_classification, ta3124, BDNF, chemistry, Behavioral medicine, Developmental Psychopathology, 030217 neurology & neurosurgery, GLUCOKINASE, metabolism [Coffea], Genome-Wide Association Study
Abstract

Contains fulltext : 155360.pdf (Publisher’s version ) (Closed access) Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P

Published
2015

44. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing

Author

Jansen, Iris E, Ye, Hui, Gibbs, J Raphael, Illig, Thomas, Jónsson, Pálmi V, Lambert, Jean-Charles, Langford, Cordelia, Lees, Andrew, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, Lungu, Codrin, Nalls, Mike A, McNeill, Alisdair, Moorby, Catriona, Moore, Matthew, Morris, Huw R, Morrison, Karen E, Escott-Price, Valentina, Mudanohwo, Ese, O'Sullivan, Sean S, Pearson, Justin, Perlmutter, Joel S, Ryten, Mina, Pétursson, Hjörvar, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Sawcer, Stephen, Botia, Juan A, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Shulman, Joshua, Sidransky, Ellen, Smith, Colin, Spencer, Chris C A, Stefánsson, Hreinn, Bettella, Francesco, Vandrovcova, Jana, Stockton, Joanna D, Strange, Amy, Talbot, Kevin, Tanner, Carlie M, Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J, Uitterlinden, André G, Velseboer, Daan, Simon Sanchez, Javier, Vidailhet, Marie, Walker, Robert, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H, Winder-Rhodes, Sophie, Stefánsson, Kári, Martinez, Maria, Wood, Nicholas W, Castillo Lizardo, Melissa Gissel, Hardy, John, Heutink, Peter, Brice, Alexis, Gasser, Thomas, Singleton, Andrew B, Rizzu, Patrizia, Blauwendraat, Cornelis, Chouhan, Amit K, Heetveld, Sasja, Li, Yarong, Yogi, Puja, Amin, Najaf, van Duijn, Cornelia M, Consortium, International Parkinson’s Disease Genetics, David, Della C, Nollen, Ellen A, Lechler, Marie C, Jain, Shushant, Shulman, Joshua M, Plagnol, Vincent, Hernandez, Dena G, Sharma, Manu, Sheerin, Una-Marie, Saad, Mohamad, SimónSánchez, Javier, Schulte, Claudia, Michels, Helen, Lesage, Suzanne, Sveinbjörnsdóttir, Sigurlaug, Arepalli, Sampath, Barker, Roger, Ben-Shlomo, Yoav, Berendse, Henk W, Berg, Daniela, Bhatia, Kailash, de Bie, Rob M A, Biffi, Alessandro, Seinstra, Renée I, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Bras, Jose M, Brockmann, Kathrin, Brooks, Janet, Burn, David J, Majounie, Elisa, Lubbe, Steven, Price, Ryan, Lubbe, Steven J, Nicolas, Aude, Charlesworth, Gavin, Chen, Honglei, Chinnery, Patrick F, Chong, Sean, Clarke, Carl E, Cookson, Mark R, Cooper, J Mark, Corvol, Jean Christophe, Drouet, Valérie, Counsell, Carl, Damier, Philippe, Dartigues, Jean-François, Deloukas, Panos, Deuschl, Günther, Dexter, David T, van Dijk, Karin D, Dillman, Allissa, Durif, Frank, Dürr, Alexandra, Edkins, Sarah, Evans, Jonathan R, Foltynie, Thomas, Dong, Jing, Gardner, Michelle, Goate, Alison, Gray, Emma, Guerreiro, Rita, Harris, Clare, van Hilten, Jacobus J, Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Wurster, Isabel, Mätzler, Walter, Hudson, Gavin, Hunt, Sarah E, Huttenlocher, Johanna, Epidemiology, Neurology, Amsterdam Neuroscience - Neurodegeneration, Human genetics, ANS - Neurodegeneration, Graduate School, ANS - Neuroinfection & -inflammation, Botia, Juan A [0000-0002-6992-598X], Chouhan, Amit K [0000-0003-2991-6402], Amin, Najaf [0000-0002-8944-1771], van Duijn, Cornelia M [0000-0002-2374-9204], David, Della C [0000-0001-8597-9470], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Candidate gene, G-PATCH, Parkinson's disease, methods [Sequence Analysis, DNA], Compound heterozygosity, AXON GUIDANCE, Animals, Genetically Modified, DOMAIN-CONTAINING 2, genetics [Parkinson Disease], Exome, Child, Cells, Cultured, Exome sequencing, Genetics, genetics [Drosophila melanogaster], High-Throughput Nucleotide Sequencing, Parkinson Disease, Genomics, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Mitochondria, ALZHEIMERS-DISEASE, Drosophila melanogaster, Whole-exome sequencing, genetics [alpha-Synuclein], alpha-Synuclein, genetics [Caenorhabditis elegans], RNA Interference, Adult, methods [High-Throughput Nucleotide Sequencing], NETWORK ANALYSIS, Adolescent, Biology, Loss-of-function, Young Adult, 03 medical and health sciences, α-synuclein, SDG 3 - Good Health and Well-being, ddc:570, Functional screening, Animals, Humans, Animal model, Genetic Predisposition to Disease, Allele, Caenorhabditis elegans, Parkin, RECEPTOR TYROSINE PHOSPHATASE, Research, RETROMER COMPLEX, Rare variants, Sequence Analysis, DNA, Human genetics, Retromer complex, DROSOPHILA MODEL, Disease Models, Animal, 030104 developmental biology, Case-Control Studies, Parkinson’s disease, CAENORHABDITIS-ELEGANS
Abstract

Background Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson’s disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. Results Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes—GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C—also showed evidence consistent with genetic replication. Conclusions By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1147-9) contains supplementary material, which is available to authorized users.

Published
2017

45. Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations:Evidence for oligogenic inheritance

Author

Lubbe, Steven J, Escott-Price, Valentina, Tomkins, James E, Lewis, Patrick A, Noyce, Alastair J, Lesage, Suzanne, Sharma, Manu, Schiff, Elena R, Levine, Adam P, Brice, Alexis, Gasser, Thomas, Hardy, John, Gibbs, J Raphael, Heutink, Peter, Wood, Nicholas W, Singleton, Andrew B, Williams, Nigel M, Morris, Huw R, Consortium, for International Parkinson’s Disease Genomics, Nalls, Mike A, Bras, Jose, Price, T Ryan, Nicolas, Aude, Jansen, Iris E, Mok, Kin Y, Pittman, Alan M, Human genetics, and Amsterdam Neuroscience - Neurodegeneration

Subjects
Male, Multifactorial Inheritance, Genotype, Association Studies Articles, Parkinson Disease, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, R1, pathology [Parkinson Disease], genetics [Parkinson Disease], Risk Factors, ddc:570, Mutation, Humans, genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2], Female, Genetic Predisposition to Disease, LRRK2 protein, human, Age of Onset, genetics [Multifactorial Inheritance]
Abstract

Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in\ud Parkinson’s (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in\ud individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases\ud and 6,166 controls. An excess (�30%) of cases with a recognised primary genetic cause had�1 additional rare variants in\ud Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our\ud hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional\ud Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for\ud some of the variation in penetrance. About 10% of No Known Mutation-PD cases harbour a rare GBA variant compared to\ud known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest\ud that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause,\ud whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD.\ud The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating\ud relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant\ud to genetic testing and counselling of patients with PD and their families.

Published
2016

46. The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism

Author

Klebe, Stephan, Golmard, Jean-Louis, Charfi, Rim, Edkins, Sarah, Evans, Jonathan R, Foltynie, Thomas, Freeman, Colin, Gao, Jianjun, Gardner, Michelle, Gibbs, Raphael, Goate, Alison, Gray, Emma, Guerreiro, Rita, Klein, Christine, Gústafsson, Omar, Harris, Clare, Hellenthal, Garrett, van Hilten, Jacobus J, Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Huber, Heiko, Hagenah, Johann, Hudson, Gavin, Hunt, Sarah E, Huttenlocher, Johanna, Illig, Thomas, Jónsson, Pálmi V, Langford, Cordelia, Lees, Andrew, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Gasser, Thomas, Lorenz, Delia, McNeill, Alisdair, Moorby, Catriona, Morris, Huw, Morrison, Karen E, Mudanohwo, Ese, O'Sullivan, Sean S, Pearson, Justin, Pearson, Richard, Perlmutter, Joel S, Wurster, Isabel, Pétursson, Hjörvar, Pirinen, Matti, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Lesage, Suzanne, Ryten, Mina, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Sidransky, Ellen, de Silva, Rohan, Smith, Colin, Spencer, Chris Ca, Stefánsson, Hreinn, Steinberg, Stacy, Stockton, Joanna D, Strange, Amy, Su, Zhan, Talbot, Kevin, Tanner, Carlie M, Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Deuschl, Günther, Traynor, Bryan J, Uitterlinden, G., Vandrovcova, Jana, Velseboer, Daan, Vidailhet, Marie, Vukcevic, Damjan, Walker, Robert, van de Warrenburg, Bart, Weale, Michael E, Wickremaratchi, Mirdhu, Durif, Franck, Williams, Nigel, Williams-Gray, Caroline H, Winder-Rhodes, Sophie, Martinez, Maria, Donnelly, Peter, Hardy, John, Heutink, Peter, Brice, Alexis, Wood, Nicholas W, Singleton, Andrew B, Nalls, Michael A, Damier, Philippe, Durr, Alexandra, Amouyel, Philippe, Lambert, Jean-Charles, Tzourio, Christophe, Maubaret, Cécilia, Charbonnier-Beaupel, Fanny, Tahiri, Khadija, Saad, Mohamad, Corvol, Jean-Christophe, Group, French Parkinson's Disease Genetics Study, Consortium, International Parkinson's Disease Genomics, Agid, Y., Anheim, M., Bonnet, A-M, Borg, M., Brice, A., Broussolle, E., Corvol, J-C, Damier, Ph, Destée, A., Durr, A., Durif, F., Klebe, S., Lohmann, E., Martinez, M., Penet, C., Bras, Jose M, Pollak, P., Krack, P., Rascol, O., Tison, F., Tranchant, C., Vérin, M., Viallet, F., Plagnol, Vincent, Hernandez, Dena G, Sharma, Manu, Sheerin, Una-Marie, Simón-Sánchez, Javier, Schulte, Claudia, Sveinbjörnsdóttir, Sigurlaug, Arepalli, Sampath, Band, Gavin, Simon-Sanchez, Javier, Barker, Roger A, Bellinguez, Céline, Ben-Shlomo, Yoav, Berendse, Henk W, Berg, Daniela, Bhatia, Kailash, de Bie, Rob Ma, Biffi, Alessandro, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Brockmann, Kathrin, Brooks, Janet, Burn, David J, Charlesworth, Gavin, Chen, Honglei, Chinnery, Patrick F, Chong, Sean, Clarke, Carl E, Cookson, Mark R, Kuhlenbäumer, Gregor, Cooper, J Mark, Corvol, Jean Christophe, Counsell, Carl, Dartigues, Jean-François, Deloukas, Panos, Dexter, David T, van Dijk, Karin D, Dillman, Allissa, Durif, Frank, INSERM UMR_S9745, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Biostatistiques [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UCL Institute of neurology, UCL Institute of Neurology, Department of Clinical Genetics, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institute of Experimental Medicine, Christian-Albrechts-University, Department of Neurology, University of Lübeck, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, Christian-Albrechts-Universität zu Kiel (CAU), Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Service de neurologie [Univ. Paris VII], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Departamento de Geologia CICESE, Centro de Investigacion Cientifica y de Education Superior de Ensenada [Mexico] (CICESE), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Human genetics, NCA - Brain mechanisms in health and disease, NCA - neurodegeneration, Child and Adolescent Psychiatry / Psychology, ANS - Amsterdam Neuroscience, Neurology, Graduate School, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Département de Neurologie [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-IFR70-CHU Pitié-Salpêtrière [APHP]

Subjects
Male, medicine.medical_specialty, Genotype, DCN MP - Plasticity and memory, [SDV]Life Sciences [q-bio], genetics [Catechol O-Methyltransferase], Neurogenetics, Catechol O-Methyltransferase/genetics, Catechol O-Methyltransferase, Polymorphism, Single Nucleotide, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, Sex Factors, 0302 clinical medicine, genetics [Parkinson Disease], Internal medicine, medicine, Humans, ddc:610, Parkinson Disease/genetics, Age of Onset, Allele, Aged, 030304 developmental biology, Genetics, 0303 health sciences, Movement Disorders, Parkinson's Disease, Catechol-O-methyl transferase, Parkinson Disease, Middle Aged, Polymorphism, Single Nucleotide/genetics, ddc:616.8, Sexual dimorphism, Psychiatry and Mental health, Human Movement & Fatigue [DCN MP - Plasticity and memory NCEBP 10], Endocrinology, Cohort, genetics [Polymorphism, Single Nucleotide], Surgery, Neurology (clinical), Age of onset, Psychology, 030217 neurology & neurosurgery, rs4680
Abstract

Item does not contain fulltext The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1+/-13.9, p=0.03) than the Val/Met (57.4+/-13.9) and the Met/Met genotypes (58.3+/-13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.

Published
2013

47. Increased fractional anisotropy in the motor tracts of Parkinson's disease suggests compensatory neuroplasticity or selective neurodegeneration

Author

Mole, Jilu Princy, Subramanian, Leena, Bracht, Tobias, Morris, Huw, Metzler-Baddeley, Claudia, and Linden, David E. J.

Subjects
Male, Neuronal Plasticity, Parkinson Disease, Middle Aged, Basal Ganglia, Deterministic tractography, Diffusion Magnetic Resonance Imaging, Radiology Nuclear Medicine and imaging, Parkinson’s disease, RC0321, Anisotropy, Humans, Neuroplasticity, Female, Diffusion-weighted imaging, Neuro, Nerve Net, Fractional anisotropy
Abstract

Objective To determine the differences in motor pathways and selected non-motor pathways of the basal ganglia in Parkinson’s disease (PD) patients compared to healthy controls (HCs). Methods We analysed diffusion weighted imaging data of 24 PD patients and 26 HCs. We performed deterministic tractography analysis using the spherical deconvolution-based damped Richardson-Lucy algorithm and subcortical volume analysis. Results We found significantly increased fractional anisotropy (FA) in the motor pathways of PD patients: the bilateral corticospinal tract (right; corrected p = 0.0003, left; corrected p = 0.03), bilateral thalamus-motor cortex tract (right; corrected p = 0.02, left; corrected p = 0.004) and the right supplementary area-putamen tract (corrected p = 0.001). We also found significantly decreased FA in the right uncinate fasiculus (corrected p = 0.01) and no differences of FA in the bilateral supero-lateral medial forebrain bundles (p > 0.05) of PD patients compared to HCs. There were no subcortical volume differences (p > 0.05) between the PD patients and HCs. Conclusion These results can inform biological models of neurodegeneration and neuroplasticity in PD. We suggest that increased FA values in the motor tracts in PD may reflect compensatory reorganization of neural circuits indicative of adaptive or extended neuroplasticity. Key points • Fractional anisotropy was higher in motor pathways of PD patients compared to healthy controls. • Fractional anisotropy was lower in the uncinate fasciculus of PD patients compared to healthy controls. • Increased fractional anisotropy could suggest adaptive neuroplasticity or selective neurodegeneration. Electronic supplementary material The online version of this article (doi:10.1007/s00330-015-4178-1) contains supplementary material, which is available to authorized users.

Published
2016

48. Vascular disease and vascular risk factors in relation to motor features and cognition in early Parkinson's disease

Author

Malek, Naveed, Lawton, Michael A., Swallow, Diane M.A., Grosset, Katherine, Marrinan, Sarah L., Bajaj, Nin, Barker, Roger A., Burn, David J., Hardy, John, Morris, Huw R., Williams, Nigel M., Wood, Nicholas, Ben-Shlomo, Yoav, and Grosset, Donald

Subjects
Male, diabetes, phenotype, Parkinson's disease, Parkinson Disease, Comorbidity, Middle Aged, R1, United Kingdom, cerebrovascular, Risk Factors, gender, Humans, Cognitive Dysfunction, Dementia, Female, Prospective Studies, Vascular Diseases, Research Articles, Gait Disorders, Neurologic, Research Article, Aged
Abstract

Objective The purpose of this study was to examine the relationship between vascular disease (and vascular risk factors), cognition and motor phenotype in Parkinson's disease (PD). Methods Recently diagnosed PD cases were enrolled in a multicenter prospective observational longitudinal cohort study. Montreal cognitive assessment (normal >23, mild cognitive impairment 22 to 23 or lower but without functional impairment, and dementia 21 or less with functional impairment) and Movement Disorder Society Unified PD Rating Scale part 3 (UPDRS 3) scores were analyzed in relation to a history of vascular events and risk factors. Results In 1759 PD cases, mean age 67.5 (standard deviation 9.3) years, mean disease duration 1.3 (standard deviation 0.9) years, 65.2% were men, 4.7% had a history of prior stroke or transient ischemic attack, and 12.5% had cardiac disease (angina, myocardial infarction, heart failure). In cases without a history of vascular disease, hypertension was recorded in 30.4%, high cholesterol 27.3%, obesity 20.7%, diabetes 7.2%, and cigarette smoking in 4.6%. Patients with prior stroke or transient ischemic attack were more likely to have cognitive impairment (42% vs 25%) and postural instability gait difficulty (53.5% vs 39.5%), but these findings were not significant after adjustment for age, sex, and disease duration (P = .075). The presence of more than 2 vascular risks was associated with worse UPDRS 3 motor scores (beta coefficient 4.05, 95% confidence interval 1.48, 6.61, p = .002) and with cognitive impairment (ordinal odds ratio 2.24, 95% confidence interval 1.34, 3.74, p = .002). In 842 patients (47.8%) with structural brain imaging, white matter leukoaraiosis, but not lacunar or territorial infarction, was associated with impaired cognition (p = .006) and postural instability gait difficulty (p = .010). Conclusion Vascular comorbidity is significantly associated with cognitive and gait impairment in patients with early PD, which may have prognostic and treatment implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Published
2016

49. Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data

Author

Mok, Kin Y., Sheerin, Una, Simon-Sanchez, Javier, Salaka, Afnan, Chester, Lucy, Escott-Price, Valentina, Mantripragada, Kiran, Doherty, Karen M., Noyce, Alastair J., Mencacci, Niccolo E., Lubbe, Steven J., Williams-Gray, Caroline H., Barker, Roger A., Dijk, Karin D., Berendse, Henk W., Heutink, Peter, Corvol, Jean-Christophe, Cormier, Florence, Lesage, Suzanne, Brice, Alexis, Brockmann, Kathrin, Schulte, Claudia, Gasser, Thomas, Foltynie, Thomas, Limousin, Patricia, Morrison, Karen E., Clarke, Carl E., Sawcer, Stephen, Warner, Tom T., Lees, Andrew J., Morris, Huw R., Nalls, Mike A., Singleton, Andrew B., Hardy, John, Abramov, Andrey Y., Plagnol, Vincent, Williams, Nigel M., Nicholas Wood, Int Parkinson S Dis, Genomics, Williams-Gray, Caroline [0000-0002-2648-9743], Barker, Roger [0000-0001-8843-7730], Sawcer, Stephen [0000-0001-7685-0974], and Apollo - University of Cambridge Repository

Subjects
Adult, Aged, 80 and over, Male, DNA Copy Number Variations, Parkinson Disease, Comorbidity, Middle Aged, genetics [Parkinson Disease], genetics [DiGeorge Syndrome], DiGeorge Syndrome, epidemiology [DiGeorge Syndrome], Humans, Female, ddc:610, epidemiology [Parkinson Disease], Age of Onset, Aged, Genome-Wide Association Study
Abstract

BACKGROUND: Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2. METHODS: We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients. FINDINGS: We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0-55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5-61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p

Published
2016

50. The Cats‐and‐Dogs test: A tool to identify visuoperceptual deficits in Parkinson's disease

Author

Weil, Rimona S., Pappa, Katerina, Schade, Rachel N., Schrag, Anette E., Bahrami, Bahador, Schwarzkopf, Dietrich S., Crutch, Sebastian J, O'Keeffe, Aidan G., and Morris, Huw R.

Subjects
cognition, Male, vision, Parkinson's disease, Parkinson Disease, Pilot Projects, Neuropsychological Tests, Letters: New Observations, Perceptual Disorders, biomarker, Humans, Female, dementia, Aged
Published
2017

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