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1. Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Author

Wu, Lesley Yue, Real, Raquel, Martinez-Carrasco, Alejandro, Chia, Ruth, Lawton, Michael A, Shoai, Maryam, Bresner, Catherine, Blauwendraat, Cornelis, Singleton, Andrew B, Ryten, Mina, Abramzon, Yevgeniya, Ahmed, Sarah, Alba, Camille, Albert, Marilyn S, Bacikova, Dagmar, Barrett, Matthew J, Beach, Thomas G, Bennett, David A, Besser, Lilah M, Bigio, Eileen H, Boeve, Bradley F, Bohannan, Ryan C, Caraway, Chad A, Palma, Jose-Alberto, Dalgard, Clifton L, Dickson, Dennis, Ding, Jinhui, Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, Gibbs, J Raphael, Goate, Alison, Goldstein, David, Graff-Radford, Neill R, Hu, Heng-Chen, Hupalo, Daniel, Kaiser, Scott M, Kaufmann, Horacio, Kim, Ronald C, Klein, Gregory, Kukull, Walter, Kuzma, Amanda, Leverenz, James, Lopez, Grisel, Mao, Qinwen, Martinez-McGrath, Elisa, Masliah, Eliezer, Monuki, Ed, Newell, Kathy L, Norcliffe-Kaufmann, Lucy, Perkins, Matthew, Pletnikova, Olga, Renton, Alan E, Resnick, Susan M, Ross, Owen A, Sabir, Marya S, Scherzer, Clemens R, Scholz, Sonja W, Serrano, Geidy, Shakkotai, Vikram, Sidransky, Ellen, Tanaka, Toshiko, Tayebi, Nahid, Traynor, Bryan J, Troncoso, Juan C, Viollet, Coralie, Walton, Ronald L, Woltjer, Randy, Wszolek, Zbigniew K, Black, Sandra E, Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Ferrari, Raffaele, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Reynolds, Regina H, Thomas, Alan J, Tilley, Bension S, Troakes, Claire, Brett, Francesca, Brice, Alexis, and Duyckaerts, Charles

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Genetics, Prevention, Aging, Lewy Body Dementia, Brain Disorders, Dementia, Alzheimer's Disease Related Dementias (ADRD), Parkinson's Disease, Human Genome, Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Neurological, International Lewy Body Dementia Genomics Consortium, APOE, Lewy body diseases, dementia, genome-wide association studies, Clinical sciences, Biological psychology
Abstract

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

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. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author

Kaivola, Karri, Chia, Ruth, Ding, Jinhui, Rasheed, Memoona, Fujita, Masashi, Menon, Vilas, Walton, Ronald L, Collins, Ryan L, Billingsley, Kimberley, Brand, Harrison, Talkowski, Michael, Zhao, Xuefang, Dewan, Ramita, Stark, Ali, Ray, Anindita, Solaiman, Jerez, Pilar Alvarez, Malik, Laksh, Dawson, Ted M, Rosenthal, Liana S, Albert, Marilyn S, Pletnikova, Olga, Troncoso, Juan C, Masellis, Mario, Keith, Julia, Black, Sandra E, Ferrucci, Luigi, Resnick, Susan M, Tanaka, Toshiko, Soltis, Anthony R, Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, Martinez, Elisa McGrath, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N, Adeleye, Adelani, Wilkerson, Matthew D, Pollard, Harvey B, Dalgard, Clifton L, Gan-Or, Ziv, 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, Barrett, Matthew J, Beach, Thomas G, Bekris, Lynn M, Bennett, David A, Boeve, Bradley F, Dickson, Dennis W, Faber, Kelley, Ferman, Tanis, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, and Gibbs, J Raphael

Subjects
Biological Sciences, Genetics, Brain Disorders, Dementia, ALS, Rare Diseases, Neurodegenerative, Neurosciences, Human Genome, Frontotemporal Dementia (FTD), Alzheimer's Disease, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aging, Aetiology, 2.1 Biological and endogenous factors, Neurological, American Genome Center, International LBD Genomics Consortium, International ALS/FTD Consortium, PROSPECT Consortium, Lewy body dementia, amyotrophic lateral sclerosis, case-control study, frontotemporal dementia, genome-wide association study, non–Alzheimer's dementia, resource, structural variant
Abstract

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

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. 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

6. 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

7. 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

8. 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

9. 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 Movement Disorder Society-Endorsed PSP Study Group

Subjects
Movement Disorder Society-Endorsed PSP Study Group, Humans, Supranuclear Palsy, Progressive, Progressive supranuclear palsy, clinical features, clinico-pathological series, diagnosis, systematic review, Prevention, Brain Disorders, Parkinson's Disease, Genetics, Rare Diseases, Neurodegenerative, Clinical Research, Neurosciences, 4.2 Evaluation of markers and technologies, 2.1 Biological and endogenous factors, Neurological, Neurology & Neurosurgery, Clinical Sciences, Human Movement and Sports 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

10. 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

11. 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

12. Genetics of validated Parkinson's disease subtypes in the Oxford Discovery and Tracking Parkinson's cohorts

Author

Lawton, Michael, Tan, Manuela Mx, Ben-Shlomo, Yoav, Baig, Fahd, Barber, Thomas, Klein, Johannes C, Evetts, Samuel G, Millin, Stephanie, Malek, Naveed, Grosset, Katherine, Barker, Roger A, Williams, Nigel, Burn, David J, Foltynie, Thomas, Morris, Huw R, Wood, Nicholas, Grosset, Donald G, Hu, Michele Tao-Ming, Lawton, Michael [0000-0002-3419-0354], Tan, Manuela Mx [0000-0001-5835-669X], Klein, Johannes C [0000-0002-8553-2801], Foltynie, Thomas [0000-0003-0752-1813], Morris, Huw R [0000-0002-5473-3774], Hu, Michele Tao-Ming [0000-0001-6382-5841], and Apollo - University of Cambridge Repository

Subjects
GENETICS, PARKINSON'S DISEASE
Abstract

OBJECTIVES: To explore the genetics of four Parkinson's disease (PD) subtypes that have been previously described in two large cohorts of patients with recently diagnosed PD. These subtypes came from a data-driven cluster analysis of phenotypic variables. METHODS: We looked at the frequency of genetic mutations in glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 against our subtypes. Then we calculated Genetic Risk Scores (GRS) for PD, multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, and Alzheimer's disease. These GRSs were regressed against the probability of belonging to a subtype in the two independent cohorts and we calculated q-values as an adjustment for multiple testing across four subtypes. We also carried out a Genome-Wide Association Study (GWAS) of belonging to a subtype. RESULTS: A severe disease subtype had the highest rates of patients carrying GBA mutations while the mild disease subtype had the lowest rates (p=0.009). Using the GRS, we found a severe disease subtype had a reduced genetic risk of PD (p=0.004 and q=0.015). In our GWAS no individual variants met genome wide significance (

Published
2022

13. Polygenic Parkinson's Disease Genetic Risk Score as Risk Modifier of Parkinsonism in Gaucher Disease.

Author

Blauwendraat, Cornelis, Tayebi, Nahid, Woo, Elizabeth Geena, Lopez, Grisel, Fierro, Luca, Toffoli, Marco, Limbachiya, Naomi, Hughes, Derralynn, Pitz, Vanessa, Patel, Dhairya, Vitale, Dan, Koretsky, Mathew J., Hernandez, Dena, Real, Raquel, Alcalay, Roy N., Nalls, Mike A., Morris, Huw R., Schapira, Anthony H.V., Balwani, Manisha, and Sidransky, Ellen

Abstract

Background: Biallelic pathogenic variants in GBA1 are the cause of Gaucher disease (GD) type 1 (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. Heterozygous GBA1 variants are also a common genetic risk factor for Parkinson's disease (PD). GD manifests with considerable clinical heterogeneity and is also associated with an increased risk for PD. Objective: The objective of this study was to investigate the contribution of PD risk variants to risk for PD in patients with GD1. Methods: We studied 225 patients with GD1, including 199 without PD and 26 with PD. All cases were genotyped, and the genetic data were imputed using common pipelines. Results: On average, patients with GD1 with PD have a significantly higher PD genetic risk score than those without PD (P = 0.021). Conclusions: Our results indicate that variants included in the PD genetic risk score were more frequent in patients with GD1 who developed PD, suggesting that common risk variants may affect underlying biological pathways. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Published
2023
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16. 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

17. 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

19. 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

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

Author

Tan, Manuela M X, Malek, Naveed, Lawton, Michael A, Hubbard, Leon, Pittman, Alan M, Joseph, Theresita, Hehir, Jason, Swallow, Diane M A, 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, and Morris, Huw R

Subjects
phenotype, prevalence, Parkinson’s disease, genetics, heterogeneity, nervous system diseases
Abstract

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 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.2,262 participants were recruited to the Tracking Parkinson’s study. 424 had young-onset Parkinson’s disease (age at onset ≤ 50) and 1,799 had late onset Parkinson’s disease. 2005 patients were genotyped with a range of methods. 302 young-onset patients were fully genotyped with Multiplex Ligation-dependent Probe Amplification and either Sanger and/or exome sequencing. 1701 late-onset patients were genotyped with the LRRK2 ‘Kompetitive’ allele-specific polymerase chain reaction assay and/or exome sequencing. We identified 29 (1.4%) patients carrying pathogenic mutations. 18 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, P113Xfs, R275W, G430D and R33X. In PINK1, 2 patients carried deletions in exon 1 and 5, and the W90Xfs point mutation.Eighteen percent 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 bi-allelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried a 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 early 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

21. 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

22. 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, Sabir, Marya S., Blauwendraat, Cornelis, Adarmes-Gómez, Astrid D., Bernal-Bernal, Inmaculada, Toribio, Marta Bonilla, Buiza-Rueda, Dolores, Carrillo, Fátima, Carrión-Claro, Mario, Gómez-Garre, Pilar, Jesús, Silvia, Labrador-Espinosa, Miguel A., Macias, Daniel, Méndez-del-Barrio, Carlota, Periñán-Tocino, Teresa, Tejera-Parrado, Cristina, Vargas-González, Laura, Diez-Fairen, Monica, Alvarez, Ignacio, Tartari, Juan Pablo, Buongiorno, María Teresa, Aguilar, Miquel, Gorostidi, Ana, Bergareche, Jesús Alberto, Mondragon, Elisabet, Ruiz-Martínez, Javier, Dols-Icardo, Oriol, Kulisevsky, Jaime, Marín-Lahoz, Juan, Pagonabarraga, Javier, Pascual-Sedano, Berta, Ezquerra, Mario, Cámara, Ana, Compta, Yaroslau, Fernández, Manel, Fernández-Santiago, Rubén, Muñoz, Esteban, Tolosa, Eduard, Valldeoriola, Francesc, Gonzalez-Aramburu, Isabel, Rodriguez, Antonio Sanchez, Sierra, María, Menéndez-González, Manuel, Blazquez, Marta, Garcia, Ciara, Martin, Esther Suarez-San, García-Ruiz, Pedro, Martínez-Castrillo, Juan Carlos, Vela-Desojo, Lydia, Ruz, Clara, Barrero, Francisco Javier, Escamilla-Sevilla, Francisco, Mínguez-Castellanos, Adolfo, Cerdan, Debora, Tabernero, Cesar, Heredia, Maria Jose Gomez, Errazquin, Francisco Perez, Romero-Acebal, Manolo, Feliz, Cici, Lopez-Sendon, Jose Luis, Mata, Marina, Torres, Irene Martínez, Kim, Jonggeol Jeffrey, Brooks, Janet, Saez-Atienzar, Sara, Gibbs, J Raphael, Jorda, Rafael, Botia, Juan A., Bonet-Ponce, Luis, Morrison, Karen E, Clarke, Carl, Tan, Manuela, Morris, Huw, Edsall, Connor, Hernandez, Dena, Simon-Sanchez, Javier, Nalls, Mike A, Scholz, Sonja W., Jimenez-Escrig, Adriano, Duarte, Jacinto, Vives, Francisco, Duran, Raquel, Hoenicka, Janet, Alvarez, Victoria, Infante, Jon, Marti, Maria José, Clarimón, Jordi, de Munain, Adolfo López, Pastor, Pau, Mir, Pablo, and Singleton, Andrew

Subjects
Genetics, 0303 health sciences, education.field_of_study, Haplotype, Population, Genome-wide association study, Disease, Runs of Homozygosity, Heritability, Biology, Genetic architecture, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, education, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

BackgroundThe 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.ObjectivesTo perform the largest Parkinson disease (PD) genome-wide association study (GWAS) restricted to a single country.MethodsWe performed a GWAS for both risk of PD and age-at-onset (AAO) 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.ResultsWe identified a novel population-specific GWAS signal atPARK2associated with AAO. We replicated four genome-wide independent signals associated with PD risk, includingSNCA, LRRK2, KANSL1/MAPTandHLA-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 via two-sample Mendelian randomization in expression and methylation datasets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.ConclusionsOur 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 toPARK2as a major hallmark of PD etiology in Spain.

Published
2019
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23. 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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24. 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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25. 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

26. 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

27. 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

28. Penetrance of Parkinson's Disease in LRRK2 p.G2019S Carriers Is Modified by a Polygenic Risk Score.

Author

Iwaki, Hirotaka, Blauwendraat, Cornelis, Makarious, Mary B., Bandrés‐Ciga, Sara, Leonard, Hampton L., Gibbs, J. Raphael, Hernandez, Dena G., Scholz, Sonja W., Faghri, Faraz, Nalls, Mike A., Singleton, Andrew B., Noyce, Alastair J, Kaiyrzhanov, Rauan, Middlehurst, Ben, Kia, Demis A, Tan, Manuela, Houlden, Henry, Morris, Huw R, Plun‐Favreau, Helene, and Holmans, Peter

Subjects
GENETIC mutation, SEQUENCE analysis, GENETIC carriers, PARKINSON'S disease, RESEARCH funding, PHENOTYPES
Abstract

Background: Although the leucine-rich repeat kinase 2 p.G2019S mutation has been demonstrated to be a strong risk factor for PD, factors that contribute to penetrance among carriers, other than aging, have not been well identified.Objectives: To evaluate whether a cumulative genetic risk identified in the recent genome-wide study is associated with penetrance of PD among p.G2019S mutation carriers.Methods: We included p.G2019S heterozygote carriers with European ancestry in three genetic cohorts in which the mutation carriers with and without PD were selectively recruited. We also included the carriers from two data sets: one from a case-control setting without selection of mutation carriers and the other from a population sampling. Associations between polygenic risk score constructed from 89 variants reported recently and PD were tested and meta-analyzed. We also explored the interaction of age and PRS.Results: After excluding eight homozygotes, 833 p.G2019S heterozygote carriers (439 PD and 394 unaffected) were analyzed. Polygenic risk score was associated with a higher penetrance of PD (odds ratio: 1.34; 95% confidence interval: [1.09, 1.64] per +1 standard deviation; P = 0.005). In addition, associations with polygenic risk score and penetrance were stronger in the younger participants (main effect: odds ratio 1.28 [1.04, 1.58] per +1 standard deviation; P = 0.022; interaction effect: odds ratio 0.78 [0.64, 0.94] per +1 standard deviation and + 10 years of age; P = 0.008).Conclusions: Our results suggest that there is a genetic contribution for penetrance of PD among p.G2019S carriers. These results have important etiological consequences and potential impact on the selection of subjects for clinical trials. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Published
2020
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29. 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

30. Genetic comorbidities in Parkinson's disease

Author

Nalls, Mike A, Saad, Mohamad, Morris, Huw R, Mudanohwo, Ese, O'Sullivan, Sean S, Pearson, Justin, Perlmutter, Joel S, Pétursson, Hjörvar, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Williams, Nigel, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Ryten, Mina, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Sidransky, Ellen, Gasser, Thomas, Smith, Colin, Spencer, Chris C A, Stefánsson, Hreinn, Steinberg, Stacy, Stockton, Joanna D, Strange, Amy, Talbot, Kevin, Tanner, Carlie M, Tashakkori-Ghanbaria, Avazeh, Tison, François, Heutink, Peter, Trabzuni, Daniah, Traynor, Bryan J, Uitterlinden, André G, Velseboer, Daan, Vidailhet, Marie, Walker, Robert, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams-Gray, Caroline H, Wood, Nick, Winder-Rhodes, Sophie, Stefánsson, Kári, Martinez, Maria, Hardy, John, Brice, Alexis, Singleton, Andrew B, Wood, Nicholas W, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, N. A., Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Su, Zhan, Vukcevic, Damjan, Consortium, International Parkinson's Disease Genomics, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, 2, Wellcome Trust Case Control Consortium, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Noyce, Alastair J, Consortium, North American Brain Expression, McCarthy, Mark I, Cookson, Mark R, Consortium, United Kingdom Brain Expression, Gibbs, J Raphael, Hernandez, Dena G, Dillman, Allissa, Nalls, Michael A, Zonderman, Alan B, Arepalli, Sampath, Ferrucci, Luigi, Johnson, Robert, Longo, Dan L, O'Brien, Richard, Nalls, Mike, Traynor, Bryan, Troncoso, Juan, van der Brug, Marcel, Zielke, Ronald H, Weale, Michael E, Ramasamy, Adaikalavan, Plagnol, Vincent, Walker, Rober, Sharma, Manu, Sheerin, Una-Marie, Simón-Sánchez, Javier, Schulte, Claudia, Keller, Margaux F, Lesage, Suzanne, Sveinbjörnsdóttir, Sigurlaug, Barker, Roger, Ben-Shlomo, Yoav, Berendse, Henk W, Berg, Daniela, Bhatia, Kailash, de Bie, Rob M A, Biffi, Alessandro, Schrag, Anette, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Bras, Jose M, Brockmann, Kathrin, Brooks, Janet, Burn, David J, Charlesworth, Gavin, Chen, Honglei, Chinnery, Patrick F, Bestwick, Jonathan P, Chong, Sean, Clarke, Carl E, Cooper, J Mark, Corvol, Jean Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean-François, Deuschl, Günther, Dexter, David T, van Dijk, Karin D, Durif, Frank, Dürr, Alexandra, Evans, Jonathan R, Foltynie, Thomas, Gao, Jianjun, Gardner, Michelle, Goate, Alison, Guerreiro, Rita, Gústafsson, Ómar, Harris, Clare, van Hilten, Jacobus J, Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Huber, Heiko, Hudson, Gavin, Huttenlocher, Johanna, Illig, Thomas, Jónsson, Pálmi V, Lambert, Jean-Charles, Lees, Andrew, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, McNeill, Alisdair, Moorby, Catriona, Moore, Matthew, Morrison, Karen E, ANS - Amsterdam Neuroscience, Neurology, Graduate School, and Erasmus MC other

Subjects
genetics [Crohn Disease], epidemiology [Schizophrenia], Single-nucleotide polymorphism, Genome-wide association study, Disease, Comorbidity, Biology, Bioinformatics, Inflammatory bowel disease, Polymorphism, Single Nucleotide, Crohn Disease, genetics [Parkinson Disease], Risk Factors, ddc:570, Mendelian randomization, mental disorders, Genetics, medicine, Humans, Genetic Predisposition to Disease, genetics [Schizophrenia], Molecular Biology, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Genetics (clinical), Genetic association, epidemiology [Crohn Disease], Association Studies Articles, Parkinson Disease, General Medicine, DNA Methylation, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, Schizophrenia, CpG Islands, epidemiology [Parkinson Disease], Genome-Wide Association Study
Abstract

Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain.

Published
2014

31. Analysis of Genome-Wide Association Studies of Alzheimer Disease and of Parkinson Disease to Determine If These 2 Diseases Share a Common Genetic Risk

Author

Moskvina, Valentina, Harold, Denise, Nicolaou, Nayia, Simón-Sánchez, Javier, Gibbs, J Raphael, Schulte, Claudia, Durr, Alexandra, Guerreiro, Rita, Hernandez, Dena, Brice, Alexis, Stefánsson, Hreinn, Majamaa, Kari, Russo, GianCarlo, Gasser, Thomas, Heutink, Peter, Wood, Nick, Martinez, Maria, Singleton, Andrew B, Nalls, Michael A, Hardy, John, Owen, Michael J, O'Donovan, Michael C, Williams, Julie, Vedernikov, Alexey, Morris, Huw R, Williams, Nigel M, Investigators, IPDGC and GERAD, Dillman, Allissa, Brooks, Janet, Chong, Sean, Cookson, Mark R, Moore, Matthew, Keller, Margaux F, Sharma, Manu, Traynor, Bryan J, Arepalli, Sampath, Charlesworth, Gavin, Plagnol, Vincent, Ryten, Mina, Trabzuni, Daniah, Bras, Jose M, Saad, Mohamed, Sheerin, Una-Marie, Bhatia, Kailash, Saad, Mohamad, Bochdanovits, Zoltan, Rizzu, Patrizia, Vidailhet, Marie, Holmans, Peter, Corvol, Jen-Christophe, Curie, Pierre et Marie, Barker, Roger, Hunt, Sarah E, Gray, Emma, Edkins, Sarah, Tashakkori-Ghanbaria, Avazeh, Barrett, Jeffrey, Deloukasm, Panagiotis, Potter, Simon, Ben-Shlomo, Yoav, van Dijk, Karin D, Berendse, Henk W, Velseboer, Daan, de Bie, Rob M A, Biffi, Alessandro, Bloem, Bas, van deWarrenburg, Bart, Post, Bart, Bettella, Francesco, Riess, Olaf, Bonin, Michael, Burn, David J, Human genetics, NCA - neurodegeneration, Graduate School, ANS - Amsterdam Neuroscience, and Neurology

Subjects
Adult, Male, statistics & numerical data [Databases, Factual], Databases, Factual, Genotype, genetics [Alzheimer Disease], Single-nucleotide polymorphism, Genome-wide association study, Disease, In Vitro Techniques, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, Gene Frequency, genetics [Parkinson Disease], Alzheimer Disease, Risk Factors, medicine, Humans, Dementia, Genetic Predisposition to Disease, ddc:610, genetics [Genetic Predisposition to Disease], Allele, Allele frequency, Aged, Genetic association, Aged, 80 and over, Genetics, Parkinson Disease, Middle Aged, medicine.disease, United States, Europe, Meta-analysis, genetics [Polymorphism, Single Nucleotide], Female, Neurology (clinical), Genome-Wide Association Study
Abstract

Importance Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders. Objective To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD. Design Combined GWA analysis. Setting Data sets from the United Kingdom, Germany, France, and the United States. Participants Thousands of patients with AD or PD and their controls. Main Outcomes and Measures Meta-analysis of GWA studies of AD and PD. Methods To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies. We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD. Results Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD. Conclusions and Relevance Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be “downstream” of the primary susceptibility genes that increase the risk of each disease.

Published
2013

32. Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease

Author

Keller, Margaux F, Saad, Mohamad, Schulte, Claudia, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, McNeill, Alisdair, Moorby, Catriona, Moore, Matthew, Morris, Huw R, Morrison, Karen E, Mudanohwo, Ese, O'Sullivan, Sean S, Moskvina, Valentina, Pearson, Justin, Perlmutter, Joel S, Pétursson, Hjörvar, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Durr, Alexandra, Rizzu, Patrizia, Ryten, Mina, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Sidransky, Ellen, Smith, Colin, Spencer, Chris C A, Holmans, Peter, Stefánsson, Hreinn, Steinberg, Stacy, Stockton, Joanna D, Strange, Amy, Talbot, Kevin, Tanner, Carlie M, Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J, Kilarski, Laura L, Uitterlinden, André G, Velseboer, Daan, Vidailhet, Marie, Walker, Robert, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H, Winder-Rhodes, Sophie, Stefánsson, Kári, Guerreiro, Rita, Martinez, Maria, Sabatier, Paul, Hardy, John, Brice, Alexis, Singleton, Andrew B, Wood, Nicholas W, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Hernandez, Dena G, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Ylikotila, Pauli, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Bras, Jose, Majamaa, Kari, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Gasser, Thomas, Heutink, Peter, Nalls, Michael A, Bettella, Francesco, Consortium, International Parkinson's Disease Genomics, 2, Wellcome Trust Case Control Consortium, Plagnol, Vincent, Sheerin, Una-Marie, Simón-Sánchez, Javier, Lesage, Suzanne, Sveinbjörnsdóttir, Sigurlaug, Nicolaou, Nayia, Arepalli, Sampath, 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, Mittag, Florian, Cooper, J Mark, Corvol, Jean Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean-François, Segalen, Victor, Deuschl, Günther, Dexter, David T, van Dijk, Karin D, Büchel, Finja, Dillman, Allissa, Durif, Frank, Montpied, Gabriel, Evans, Jonathan R, Foltynie, Thomas, Gao, Jianjun, Gardner, Michelle, Gibbs, J Raphael, Goate, Alison, Sharma, Manu, Gústafsson, Omar, Harris, Clare, van Hilten, Jacobus J, Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Huber, Heiko, Hudson, Gavin, Huttenlocher, Johanna, Illig, Thomas, Jónsson, Pálmi V, Lambert, Jean-Charles, Lees, Andrew, Lichtner, Peter, ANS - Amsterdam Neuroscience, Neurology, ACS - Amsterdam Cardiovascular Sciences, Graduate School, Human genetics, and NCA - Neurodegeneration

Subjects
Adult, Male, medicine.medical_specialty, Multifactorial Inheritance, Parkinson's disease, Functional Neurogenomics Human Movement & Fatigue [DCN 2], Single-nucleotide polymorphism, Genome-wide association study, Quantitative trait locus, Biology, Genome, White People, 03 medical and health sciences, Quantitative Trait, Heritable, 0302 clinical medicine, genetics [Parkinson Disease], Missing heritability problem, Molecular genetics, ddc:570, medicine, Genetics, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), Aged, 030304 developmental biology, Genetic association, Aged, 80 and over, 0303 health sciences, Association Studies Articles, Genetic Variation, Family aggregation, Parkinson Disease, General Medicine, Middle Aged, Heritability, medicine.disease, Corrigenda, 3. Good health, genetics [European Continental Ancestry Group], Human Movement & Fatigue [DCN MP - Plasticity and memory NCEBP 10], Female, Trait analysis, 030217 neurology & neurosurgery, Imputation (genetics), Genome-Wide Association Study
Abstract

Contains fulltext : 110130.pdf (Publisher’s version ) (Closed access) Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.

Published
2012

33. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies

Author

Consortium, International Parkinson Disease Genomics, Nalls, Michael A, Sveinbjörnsdóttir, Sigurlaug, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Ryten, Mina, Sawcer, Stephen, Stefánsson, Kári, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Sidransky, Ellen, Smith, Colin, Spencer, Chris C A, Stefánsson, Hreinn, Steinberg, Stacy, Stockton, Joanna D, Martinez, Maria, Strange, Amy, Talbot, Kevin, Tanner, Carlie M, Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J, Utterlinden, André G, Velseboer, Daan, Vidailhet, Marie, Hardy, John, Walker, Robert, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H, Winder-Rhodes, Sophie, Heutink, Peter, Brice, Alexis, Gasser, Thomas, Singleton, Andrew B, Wood, Nicholas W, Plagnol, Vincent, Hernandez, Dena G, Sheerin, Una-Marie, Saad, Mohamad, Simón-Sánchez, Javier, Schulte, Claudia, Lesage, Suzanne, Arepalli, Sampath, Barker, Roger, Ben-Shlomo, Yoav, Berendse, Henk W, Berg, Daniela, Bhatia, Kailash, de Bie, Rob M A, Biffi, Alessandro, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Bras, Jose M, Sharma, Manu, Brockmann, Kathrin, Brooks, Janet, Burn, David J, Charlesworth, Gavin, Chen, Honglei, Chinnery, Patrick F, Chong, Sean, Clarke, Carl E, Cookson, Mark R, Cooper, Mark, Corvol, Jean Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean-François, Deloukas, Panos, Deuschl, Günther, Dexter, David T, van Dijk, Karin D, Dillman, Alissa, Durif, Frank, Dürr, Alexandra, Edkins, Sarah, Evans, Jonathan R, Foltynie, Thomas, Gao, Jianjun, Gardner, Michelle, Gibbs, J Raphael, Goate, Alison, Gray, Emma, Guerreiro, Rita, Simón-Sánchez, J., Gústafsson, Ómar, Harris, Clare, van Hilten, Jacobus J, Hofman, Albert, Hollenbeck, Albert, Hu, Michele, Huang, Xuemei, Huber, Heiko, 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, Mudanohwo, Ese, O'Sullivan, Sean, Pearson, Justin, Perlmutter, Joel S, Pétursson, Hjörvar, ANS - Amsterdam Neuroscience, Neurology, ACS - Amsterdam Cardiovascular Sciences, Graduate School, Human genetics, Anatomy and neurosciences, NCA - Neurodegeneration, Pollak, Pierre, and Neuroscience Campus Amsterdam - Neurodegeneration

Subjects
Male, Genome-wide association study, Genomic disorders and inherited multi-system disorders Functional Neurogenomics [IGMD 3], 0302 clinical medicine, genetics [Parkinson Disease], Parkinson Disease/genetics, Age of Onset, genetics [Genetic Predisposition to Disease], Genetics, 0303 health sciences, Genetic Predisposition to Disease/genetics, Parkinson Disease, General Medicine, Middle Aged, Polymorphism, Single Nucleotide/genetics, LRRK2, genetics [Genetic Variation], 3. Good health, Genetic Variation/genetics, Meta-analysis, Genetic Loci/genetics, genetics [Polymorphism, Single Nucleotide], Female, Functional Neurogenomics [DCN 2], Sequence Analysis, Adult, Genotype, Single-nucleotide polymorphism, genetics [Genetic Loci], Biology, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, Humans, Genetic Predisposition to Disease, ddc:610, Alleles, 030304 developmental biology, Aged, Genetic Variation, Odds ratio, nervous system diseases, ddc:616.8, Genetic Loci, Age of onset, 030217 neurology & neurosurgery, Imputation (genetics), Genome-Wide Association Study
Abstract

Item does not contain fulltext BACKGROUND: Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. METHODS: We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. FINDINGS: The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p

Published
2011

34. Web-Based Genome-Wide Association Study Identifies Two Novel Loci and a Substantial Genetic Component for Parkinson's Disease

Author

Consortium, International Parkinson's Disease Genomics, 2, Wellcome Trust Case Control Consortium, Schulte, Claudia, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Sidransky, Ellen, de Silva, Rohan, Smith, Colin, Spencer, Chris C A, Stefánsson, Hreinn, Lesage, Suzanne, Steinberg, Stacy, Stockton, Joanna D, Strange, Amy, Su, Zhan, Talbot, Kevin, Tanner, Carlie M, Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J, Sveinbjörnsdóttir, Sigurlaug, Uitterlinden, André G, Vandrovcova, Jana, Velseboer, Daan, Vidailhet, Marie, Vukcevic, Damjan, Walker, Robert, van de Warrenburg, Bart, Weale, Michael E, Williams, Nigel, Williams-Gray, Caroline H, Amouyel, Philippe, Wickremaratchi, Mirdhu, Winder-Rhodes, Sophie, Stefánsson, Kári, Martinez, Maria, Donnelly, Peter, Singleton, Andrew B, Hardy, John, Heutink, Peter, Brice, Alexis, Gasser, Thomas, Arepalli, Sampath, Wood, Nicholas W, Band, Gavin, Barker, Roger A, Bellinguez, Céline, Ben-Shlomo, Yoav, Berendse, Henk W, Plagnol, Vincent, Berg, Daniela, Bhatia, Kailash, de Bie, Rob M A, Biffi, Alessandro, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Brockmann, Kathrin, Brooks, Janet, Burn, David J, Nalls, Michael A, 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, Bras, Jose M, 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, Hernandez, Dena G, Foltynie, Thomas, Freeman, Colin, Gao, Jianjun, Gardner, Michelle, Gibbs, J Raphael, Goate, Alison, Gray, Emma, Guerreiro, Rita, Gústafsson, Ómar, Harris, Clare, Sharma, Manu, Hellenthal, Garrett, van Hilten, Jacobus J, Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Huber, Heiko, Hudson, Gavin, Hunt, Sarah E, Sheerin, Una-Marie, Huttenlocher, Johanna, Illig, Thomas, Jónsson, Pálmi V, Langford, Cordelia, Lees, Andrew, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, McNeill, Alisdair, Saad, Mohamad, Moorby, Catriona, Moore, Matthew, Morris, Huw, Morrison, Karen E, Mudanohwo, Ese, O'Sullivan, Sean S, Pearson, Justin, Pearson, Richard, Perlmutter, Joel S, Pétursson, Hjörvar, Simón-Sánchez, Javier, Pirinen, Matti, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Ryten, Mina, Neuroscience Campus Amsterdam - Neurodegeneration, Pollak, Pierre, Human genetics, Neurology, Anatomy and neurosciences, NCA - Neurodegeneration, ANS - Amsterdam Neuroscience, ACS - Amsterdam Cardiovascular Sciences, and Graduate School

Subjects
Cancer Research, Candidate gene, Genome-wide association study, QH426-470, 0302 clinical medicine, genetics [Parkinson Disease], Parkinson Disease/genetics, Genetics (clinical), Genetics, 0303 health sciences, education.field_of_study, Brain, Parkinson Disease, Polymorphism, Single Nucleotide/genetics, Genetic Loci/genetics, genetics [Polymorphism, Single Nucleotide], Research Article, Population, Single-nucleotide polymorphism, genetics [Genetic Loci], Biology, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, Genome-Wide Association Studies, Brain/metabolism, Humans, Genetic Predisposition to Disease, ddc:610, education, Molecular Biology, Genotyping, QH426, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Genetic association, GPNMB, Gene Expression Profiling, Haplotype, DNA Methylation, ddc:616.8, Gene Expression Regulation, metabolism [Brain], Genetic Loci, Genetics of Disease, RC0321, 030217 neurology & neurosurgery, Neuroscience, Genome-Wide Association Study
Abstract

A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p, Author Summary This paper describes the largest case-control analysis of Parkinson's disease to date, with a combined sample set of over 12,000 cases and 21,000 controls. After combining our findings with an independent replication dataset of more than 3,000 cases and 29,000 controls, we found five additional PD risk loci in addition to the 11 loci previously identified in earlier consortium efforts. This successful study further demonstrates the power of the GWA scan experimental design to find new loci contributing to disease risk, even in the context of complex disorders like Parkinson's disease. These new findings provide insights into the etiology of PD and will promote a better understanding of its pathogenesis.

Published
2011

35. Early Onset Parkinson's Disease in a family of Moroccan origin caused by a p.A217D mutation in PINK1: a case report.

Author

Norman, Brendan P., Lubbe, Steven J., Tan, Manuela, Warren, Naomi, and Morris, Huw R.

Subjects
GENETIC mutation, GENETICS, CONSANGUINITY, PARKINSONIAN disorders, AGE factors in disease, ENZYMES, PROTEIN kinases, PHENOTYPES, SEQUENCE analysis, GENOTYPES
Abstract

Background: Bi-allelic mutations in the genes Parkin (PARK2), PINK1 (PARK6) and DJ-1 (PARK7) are established causes of autosomal recessive early-onset Parkinson's Disease (EOPD). PINK1 mutations are the second commonest cause of EOPD. Specific mutations may be relatively common in certain populations because of a founder effect. Homozygous p.A217D PINK1 mutations were previously shown to cause EOPD in a large Sudanese kindred.Case Presentation: Here we report the segregation of homozygous PINK1 p.A217D mutations in a family originating in Morocco with a history of parental consanguinity. From the clinical information available for the index case, the phenotype of mild, slowly-progressive Parkinsonism is consistent with previous reports of p.A217D disease and of PINK1 disease phenotype more generally. The reported features of early prominent lower-limb symptoms and gait disturbance with asymmetrical onset are more frequent among PINK1 disease cases.Conclusions: Together, reports of p.A217D in families of Moroccan and Sudanese origin suggest that p.A217D is a North African mutation due to a founder effect. Wider genetic analyses of EOPD in North Africa would be useful to estimate the prevalence of Parkinsonism caused by PINK1 p.A217D. In the absence of bi-allelic Parkin mutations, PINK1 mutations should be considered in cases with evidence of autosomal recessive inheritance of EOPD and presentation of atypical features such as early lower-limb symptoms and gait disturbance with asymmetrical onset, which appear to be common in Mendelian EOPD. [ABSTRACT FROM AUTHOR]

Published
2017
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36. Genetic risk and age in Parkinson's disease: Continuum not stratum.

Author

Nalls, Mike A., Escott‐Price, Valentina, Williams, Nigel M., Lubbe, Steven, Keller, Margaux F., Morris, Huw R., and Singleton, Andrew B.

Abstract

Background Recent genomewide association study meta-analyses have identified 28 loci associated with risk of Parkinson's disease (PD). We sought to investigate whether these genetic risk factors are associated with PD age at onset. Methods Genetic risk scores from these loci were calculated for 6,249 cases. Linear regression tested associations between cumulative genetic risk and PD age at onset. Results Increasing genetic risk scores were associated with earlier age at onset (beta = -0.10, P = 2.92 × 10−8, adjusted r2 = 0.27). Single standard deviation increase in genetic risk score is associated with 37.44 d earlier age at onset. Highest genetic risk was found at 31 to 60 y, onset slightly below average age at onset (AAO). Conclusions Common genetic risk factors have a small but consistent association with AAO in PD. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Published
2015
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37. Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum.

Author

Peall, Kathryn J, Lumsden, Daniel, Kneen, Rachel, Madhu, Rajesh, Peake, Deirdre, Gibbon, Frances, Lewis, Hilary, Hedderly, Tammy, Meyer, Esther, Robb, Stephanie A, Lynch, Bryan, King, Mary D, Lin, Jean‐Pierre, Morris, Huw R, Jungbluth, Heinz, and Kurian, Manju A

Subjects
CHOREA, TRANSCRIPTION factors, GENETIC mutation, OBSESSIVE-compulsive disorder, SKELETAL abnormalities, MUSCLE hypotonia, PEDIATRIC neurology, MOVEMENT disorders in children, GENETICS
Abstract

Aim Benign hereditary chorea is a dominantly inherited, childhood-onset hyperkinetic movement disorder characterized by non-progressive chorea and variable degrees of thyroid and respiratory involvement. Loss-of-function mutations in NKX2.1, a gene vital to the normal development and function of the brain, lungs, and thyroid, have been identified in a number of individuals. Method Clinical data from individuals with benign hereditary chorea identified through paediatric neurology services were collected in a standardized format. The NKX2.1 gene was analysed by Sanger sequencing, multiplex ligation-dependent probe amplification, and microarray analysis. Results Six of our cohort were female and four male, median age at assessment was 8 years 6 months (range 1y 6mo-18y). We identified 10 probands with NKX2.1 mutations; nine of these mutations are novel (including two whole-gene deletions) and one has been previously reported. Of the 10 individuals, eight presented with muscle hypotonia and four had evidence of hypothyroidism or respiratory involvement. Only three out of the 10 individuals had the full triad of 'brain-lung-thyroid syndrome' symptoms. Additional clinical characteristics occurring in individual participants included growth hormone deficiency, pes cavus, kyphosis, duplex kidney, and obsessive-compulsive disorder. Interpretation Our data suggest that the neurological phenotype is prominent in this condition and that many patients with benign hereditary chorea do not have the classic triad of brain-lung-thyroid syndrome. The extended phenotype may include obsessive-compulsive disorder and skeletal abnormalities. [ABSTRACT FROM AUTHOR]

Published
2014
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38. Parkinson's Disease - the Debate on the Clinical Phenomenology, Aetiology, Pathology and Pathogenesis.

Author

Jenner, Peter, Morris, Huw R., Robbins, Trevor W., Goedert, Michel, Hardy, John, Ben-Shlomo, Yoav, Bolam, Paul, Burn, David, Hindle, John V., and Brooks, David

Subjects
*PARKINSON'S disease, *PATHOLOGY, *GENETICS, *DOPAMINE, *ANXIETY
Abstract

The definition of Parkinson's disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article - widening the definition of PD/LBD/synucleinopathies and the heterogeneity that exists within PD itself from a clinical, pathological and genetic perspective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include - Parkinson's syndrome, Parkinson's syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA). [ABSTRACT FROM AUTHOR]

Published
2013
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39. The Genetic and Pathological Classification of Familial Frontotemporal Dementia.

Author

Morris, Huw R., Khan, M. Nadeem, Janssen, John C., Brown, Jeremy M., Perez-Tur, Jordi, Baker, Matthew, Ozansoy, Mehmet, Hardy, John, Hutton, Michael, Wood, Nicholas W., Lees, Andrew J., Revesz, Tamas, Lantos, Peter, and Rossor, Martin N.

Subjects
DEMENTIA, TEMPORAL lobe diseases, FAMILIAL diseases, GENETICS
Abstract

Background: Frontotemporal dementia (FTD) is an important cause of neurodegenerative dementia, particularly in younger patients. TAU has been identified as the gene responsible for FTD linked to chromosome 17, but it is likely that there is pathological and genetic heterogeneity among families with FTD. Objective: To explore the genetic and pathological basis of familial FTD. Design: Clinical case series with genetic analysis of each family, and pathological confirmation of diagnosis where possible. Setting: Specialist dementia research group, particularly recruiting patients with young-onset dementia. Patients: Twenty-two families with an index member with FTD, meeting Lund-Manchester criteria, and a family history of other affected members with dementia were ascertained. Results: Half of the families had mutations in the TAU gene (TAU exon 10 +14, +16, and P301S), and pathological diagnoses were available in 17 of 22 families. Three main pathological diagnoses were made: FTD with neuronal and glial tau deposition, FTD with ubiquitin inclusions, and FTD with neuronal loss and spongiosis but without intracellular inclusions. No cases of familial Pick disease were identified. With the use of the pathological diagnoses, each family with FTD with neuronal and glial tau deposition had a TAU mutation, whereas TAU mutations were not identified in families in the other 2 diagnostic groups. Conclusions: This study illustrates the value of TAU sequencing in FTD and suggests that around one half of individuals with familial FTD have TAU mutations and dementia with tau pathological findings. Furthermore, these data suggest that there are at least 2 additional genes to be identified among families with autosomal dominant FTD. [ABSTRACT FROM AUTHOR]

Published
2001
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40. Ethnic Differences in Atypical Parkinsonism—is South Asian PSP Different?

Author

Balint, Bettina, Neo, Shermyn, Magrinelli, Francesca, Mulroy, Eoin, Latorre, Anna, Stamelou, Maria, Morris, Huw R., Batla, Amit, and Bhatia, Kailash P.

Subjects
*PROGRESSIVE supranuclear palsy, *SYMPTOMS, *BEHAVIOR disorders, *ETHNIC differences, *MEDICAL records
Abstract

Background Objectives Methods Results Conclusions Progressive supranuclear palsy (PSP) is a progressive atypical parkinsonian condition that results in severe disability. There are few studies of PSP in patients of non‐white European ancestry.We aim to perform deep phenotyping in a South Asian PSP cohort to uncover possible ethnic differences in disease characteristics.Consecutive PSP patients had their clinical records reviewed for clinical features operationalized in the Movement Disorder Society (MDS)‐PSP diagnostic criteria and relevant investigations, including imaging and genetic tests. Clinical variables were summarized by descriptive statistics and Kaplan–Meier curves were generated for survival analysis.Twenty‐seven patients, comprising Indians (78%), Pakistanis (11%) and Sri Lankans (11%) were included. Mean age of symptom onset was 63.8 ± 7.0 years and 22% of patients had an early age of onset (<60 years). The most common presenting symptom was parkinsonism (56%), followed by cognitive dysfunction (37%), falls (33%) and dysarthria (26%). The predominance types at final review were distributed across PSP‐RS (67%), PSP‐PGF (15%), PSP‐P (15%) and PSP‐F (4%). Atypical clinical features like cerebellar signs (33%), REM‐sleep behavior disorder (RBD) (55%), visual hallucinations (22%), and a family history of parkinsonism (20%) were evident in a proportion of patients.We present a South Asian cohort of PSP patients with a higher than previously reported percentages of early‐onset disease, family history and atypical clinical manifestations. These patients do not fit easily into the PSP phenotypes defined by the current MDS criteria. Dedicated clinicopathological and genetic tests are needed in this population to dissect the pathogenesis of clinically‐defined PSP. [ABSTRACT FROM AUTHOR]

Published
2024
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41. 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, and Morris, Huw R

Subjects
Adult, Aged, 80 and over, Male, Genotype, phenotype, prevalence, Parkinson Disease, Mendelian Randomization Analysis, Middle Aged, United Kingdom, nervous system diseases, 3. Good health, Cohort Studies, Population Surveillance, Mutation, Parkinson’s disease, Humans, genetics, Female, Genetic Testing, Prospective Studies, heterogeneity, Aged
Abstract

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.

42. Genome-Wide Association Studies of Cognitive and Motor Progression in Parkinson's Disease

Author

Tan, Manuela MX, Lawton, Michael A, Jabbari, Edwin, Reynolds, Regina H, Iwaki, Hirotaka, Blauwendraat, Cornelis, Kanavou, Sofia, Pollard, Miriam I, Hubbard, Leon, Malek, Naveed, Grosset, Katherine A, Marrinan, Sarah L, Bajaj, Nin, Barker, Roger A, Burn, David J, Bresner, Catherine, Foltynie, Thomas, Wood, Nicholas W, Williams-Gray, Caroline H, Hardy, John, Nalls, Michael A, Singleton, Andrew B, Williams, Nigel M, Ben-Shlomo, Yoav, Hu, Michele TM, Grosset, Donald G, Shoai, Maryam, and Morris, Huw R

Subjects
genome-wide association study, Cognition, Parkinson's disease, Disease Progression, Humans, genetics, Parkinson Disease, progression, Biomarkers, 3. Good health
Abstract

BACKGROUND: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies have identified variants associated with disease risk, but not progression. The objective of the current study was to identify genetic variants associated with PD progression. METHODS: We analyzed 3 large longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntington's disease, in which we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analyzed in linear regression in genome-wide association studies. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis. RESULTS: There was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE ε4 tagging variant, rs429358, was significantly associated with composite and cognitive progression in PD. Conditional analysis revealed several independent signals in the APOE locus for cognitive progression. No single variants were associated with motor progression. However, in gene-based analysis, ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (P = 5.3 × 10-6 ). CONCLUSIONS: We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE ε4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts are needed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

43. Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study.

Author

Jabbari, Edwin, Koga, Shunsuke, Valentino, Rebecca R, Reynolds, Regina H, Ferrari, Raffaele, Tan, Manuela M X, Rowe, James B, Dalgard, Clifton L, Scholz, Sonja W, Dickson, Dennis W, Warner, Thomas T, Revesz, Tamas, Höglinger, Günter U, Ross, Owen A, Ryten, Mina, Hardy, John, Shoai, Maryam, Morris, Huw R, and PSP Genetics Group

Subjects
*PROGRESSIVE supranuclear palsy, *PROPORTIONAL hazards models, *PARKINSONIAN disorders, *BRAIN banks, *SINGLE nucleotide polymorphisms, *PARKINSON'S disease, *DATABASES, *CHROMOSOMES, *RESEARCH, *SEQUENCE analysis, *GENETICS, *RESEARCH methodology, *GENETIC polymorphisms, *RNA, *EVALUATION research, *MEDICAL cooperation, *COMPARATIVE studies, *KAPLAN-Meier estimator, *AGE factors in disease, *DISEASE susceptibility, *SURVIVAL analysis (Biometry), *RESEARCH funding
Abstract

Background: The genetic basis of variation in the progression of primary tauopathies has not been determined. We aimed to identify genetic determinants of survival in progressive supranuclear palsy (PSP).Methods: In stage one of this two stage genome-wide association study (GWAS), we included individuals with PSP, diagnosed according to pathological and clinical criteria, from two separate cohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic (Jacksonville, FL, USA) and in Munich (Germany), and the University College London PSP cohort, from brain banks and the PROSPECT study, a UK-wide longitudinal study of patients with atypical parkinsonian syndromes. Individuals were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death or to the date of censoring, Dec 1, 2019, if individuals were alive), and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data were used to do a survival GWAS using a Cox proportional hazards model. In stage two, data from additional individuals from the Mayo Clinic brain bank, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the expression quantitative trait loci (eQTL) profile of variants that passed genome-wide significance in our GWAS using the Functional Mapping and Annotation of GWAS platform, and did colocalisation analyses using the eQTLGen and PsychENCODE datasets.Findings: Data were collected and analysed between Aug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of white European ancestry with PSP in stage one. We found a genome-wide significant association with survival at chromosome 12 (lead single nucleotide polymorphism rs2242367, p=7·5 × 10-10, hazard ratio 1·42 [95% CI 1·22-1·67]). rs2242367 was associated with survival in the individuals added in stage two (n=238; p=0·049, 1·22 [1·00-1·48]) and in the pooled analysis of both stages (n=1239; p=1·3 × 10-10, 1·37 [1·25-1·51]). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and two long intergenic non-coding RNAs (lncRNAs), LINC02555 and AC079630.4, in whole blood. Although we did not detect a colocalisation signal for LRRK2, analysis of the PSP survival signal and eQTLs for LINC02555 in the eQTLGen blood dataset revealed a posterior probability of hypothesis 4 of 0·77, suggesting colocalisation due to a single shared causal variant.Interpretation: Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association might be through a lncRNA-regulated effect on LRRK2 expression because LINC02555 has previously been shown to regulate LRRK2 expression. LRRK2 has been associated with sporadic and familial forms of Parkinson's disease, and our finding suggests a genetic overlap with PSP. Further functional studies will be important to assess the potential of LRRK2 modulation as a disease-modifying therapy for PSP and related tauopathies.Funding: PSP Association, CBD Solutions, Medical Research Council (UK). [ABSTRACT FROM AUTHOR]

Published
2021
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44. Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

Author

Henry Houlden, Valentina Cipriani, Evan Reid, Alkyoni Athanasiou-Fragkouli, Patrick F. Chinnery, Arianna Tucci, Nicholas W. Wood, Raquel Real, Huw R. Morris, Victoria Harrison, Damian Smedley, Thomas Bourinaris, Isabella Sheikh, Jana Vandrovcova, 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, Adolescent, Hereditary spastic paraplegia, Degenerative Disorder, 45/23, Biology, Brief Communication, Genome, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Genetics research, Genetics, medicine, Juvenile, Humans, 692/699/375, Child, Gene, Genetics (clinical), 030304 developmental biology, Aged, 0303 health sciences, Spastic Paraplegia, Hereditary, Parkinsonism, brief-communication, 692/308/2056, 45/77, Middle Aged, medicine.disease, Phenotype, Mutation, Identification (biology), Female, Carrier Proteins, 82/1, 030217 neurology & neurosurgery, Neurological disorders
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
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45. Genome-wide association studies of cognitive and motor progression in Parkinsons disease

Author

Naveed Malek, Michele T.M. Hu, Miriam I Pollard, Hirotaka Iwaki, Mike A. Nalls, Sofia Kanavou, Caroline H. Williams-Gray, Catherine Bresner, Cornelis Blauwendraat, Yoav Ben-Shlomo, Roger A. Barker, John Hardy, Sarah L Marrinan, Manuela Tan, Donald G. Grosset, Katherine A Grosset, David J. Burn, Michael A Lawton, Leon Hubbard, Edwin Jabbari, Nin Bajaj, Andrew B. Singleton, Huw R. Morris, Nigel Williams, Thomas Foltynie, Maryam Shoai, Regina H. Reynolds, Nicholas W. Wood, Tan, Manuela MX [0000-0001-5835-669X], Jabbari, Edwin [0000-0001-6844-882X], Iwaki, Hirotaka [0000-0002-8982-7885], Foltynie, Thomas [0000-0003-0752-1813], Williams-Gray, Caroline H [0000-0002-2648-9743], Morris, Huw R [0000-0002-5473-3774], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Apolipoprotein E, Oncology, medicine.medical_specialty, Movement disorders, Parkinson's disease, Genome-wide association study, Disease, 03 medical and health sciences, Cognition, 0302 clinical medicine, Internal medicine, Humans, Medicine, genetics, Allele, Cognitive impairment, 030304 developmental biology, Genetic association, 0303 health sciences, genome-wide association study, business.industry, Parkinson Disease, medicine.disease, 3. Good health, 030104 developmental biology, Neurology, Disease Progression, Disease risk, progression, Neurology (clinical), medicine.symptom, business, Biomarkers, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Background There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies have identified variants associated with disease risk, but not progression. The objective of the current study was to identify genetic variants associated with PD progression. Methods We analyzed 3 large longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntington's disease, in which we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analyzed in linear regression in genome-wide association studies. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis. Results There was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE e4 tagging variant, rs429358, was significantly associated with composite and cognitive progression in PD. Conditional analysis revealed several independent signals in the APOE locus for cognitive progression. No single variants were associated with motor progression. However, in gene-based analysis, ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (P = 5.3 × 10-6 ). Conclusions We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE e4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts are needed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2020
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46. Tau acts as an independent genetic risk factor in pathologically proven PD

Author

Charlesworth, Gavin, Gandhi, Sonia, Bras, Jose M., Barker, Roger A., Burn, David J., Chinnery, Patrick F., Gentleman, Stephen M., Guerreiro, Rita, Hardy, John, Holton, Janice L., Lees, Andrew, Morrison, Karen, Sheerin, Una-Marie, Williams, Nigel, Morris, Huw, Revesz, Tamas, and Wood, Nicholas W.

Subjects
*TAU proteins, *PARKINSON'S disease, *NEUROLOGICAL disorders, *PSEUDOBULBAR paralysis, *BRAIN diseases, *MEDICAL research
Abstract

Abstract: MAPT has been repeatedly linked with Parkinson''s disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association. [Copyright &y& Elsevier]

Published
2012
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47. The chromosome 9 ALS and FTD locus is probably derived from a single founder

Author

Mok, Kin, Traynor, Bryan J., Schymick, Jennifer, Tienari, Pentti J., Laaksovirta, Hannu, Peuralinna, Terhi, Myllykangas, Liisa, Chiò, Adriano, Shatunov, Aleksey, Boeve, Bradley F., Boxer, Adam L., DeJesus-Hernandez, Mariely, Mackenzie, Ian R., Waite, Adrian, Williams, Nigel, Morris, Huw R., Simón-Sánchez, Javier, van Swieten, John C., Heutink, Peter, and Restagno, Gabriella

Subjects
*CHROMOSOMES, *AMYOTROPHIC lateral sclerosis, *SINGLE nucleotide polymorphisms, *HAPLOTYPES, *LINKAGE (Genetics), *FAMILIES
Abstract

Abstract: We and others have recently reported an association between amyotrophic lateral sclerosis (ALS) and single nucleotide polymorphisms on chromosome 9p21 in several populations. Here we show that the associated haplotype is the same in all populations and that several families previously shown to have genetic linkage to this region also share this haplotype. The most parsimonious explanation of these data are that there is a single founder for this form of disease. [Copyright &y& Elsevier]

Published
2012
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