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Start Over Author "BOCHDANOVITS, ZOLTAN" Topic genetic predisposition to disease
10 results on '"BOCHDANOVITS, ZOLTAN"'

1. Genome-wide association study confirms extant PD risk loci among the Dutch.

Author

Simón-Sánchez J, van Hilten JJ, van de Warrenburg B, Post B, Berendse HW, Arepalli S, Hernandez DG, de Bie RM, Velseboer D, Scheffer H, Bloem B, van Dijk KD, Rivadeneira F, Hofman A, Uitterlinden AG, Rizzu P, Bochdanovits Z, Singleton AB, and Heutink P

Subjects
ADP-ribosyl Cyclase biosynthesis, Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Antigens, CD biosynthesis, Case-Control Studies, DNA Fingerprinting, Female, GPI-Linked Proteins biosynthesis, GPI-Linked Proteins genetics, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Netherlands, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases biosynthesis, Risk Factors, alpha-Synuclein biosynthesis, tau Proteins biosynthesis, ADP-ribosyl Cyclase genetics, Antigens, CD genetics, Genetic Predisposition to Disease, Intracellular Signaling Peptides and Proteins genetics, Parkinson Disease genetics, Protein Serine-Threonine Kinases genetics, alpha-Synuclein genetics, tau Proteins genetics
Abstract

In view of the population-specific heterogeneity in reported genetic risk factors for Parkinson's disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514,799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P = 1.63 × 10(-5), OR = 1.325 and BST1, rs12502586: P = 1.63 × 10(-3), OR = 1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3' and 5' ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P = 1.22 × 10(-4), OR = 1.51; HLA, rs4248166: P = 4.39 × 10(-5), OR = 1.36; and MAPT, rs3785880: P = 1.9 × 10(-3), OR = 1.19).

Published
2011
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2. 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

3. 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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4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

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