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1. 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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2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

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