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1. High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression

Author

Hamshere, Marian L, Langley, Kate, Martin, Joanna, Agha, Sharifah Shameem, Stergiakouli, Evangelia, Anney, Richard JL, Buitelaar, Jan, Faraone, Stephen V, Lesch, Klaus-Peter, Neale, Benjamin M, Franke, Barbara, Sonuga-Barke, Edmund, Asherson, Philip, Merwood, Andrew, Kuntsi, Jonna, Medland, Sarah E, Ripke, Stephan, Steinhausen, Hans-Christoph, Freitag, Christine, Reif, Andreas, Renner, Tobias J, Romanos, Marcel, Romanos, Jasmin, Warnke, Andreas, Meyer, Jobst, Palmason, Haukur, Vasquez, Alejandro Arias, Lambregts-Rommelse, Nanda, Roeyers, Herbert, Biederman, Joseph, Doyle, Alysa E, Hakonarson, Hakon, Rothenberger, Aribert, Banaschewski, Tobias, Oades, Robert D, McGough, James J, Kent, Lindsey, Williams, Nigel, Owen, Michael J, Holmans, Peter, O’Donovan, Michael C, and Thapar, Anita

Subjects
Prevention, Behavioral and Social Science, Human Genome, Genetics, Mental Health, Attention Deficit Hyperactivity Disorder (ADHD), Clinical Research, Brain Disorders, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Mental health, Aggression, Anxiety Disorders, Attention Deficit Disorder with Hyperactivity, Child, Child, Preschool, Comorbidity, Conduct Disorder, Depressive Disorder, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Multifactorial Inheritance, United Kingdom, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

Published
2013

2. Genome-Wide Analysis of Copy Number Variants in Attention Deficit Hyperactivity Disorder: The Role of Rare Variants and Duplications at 15q13.3

Author

Williams, Nigel M, Franke, Barbara, Mick, Eric, Anney, Richard JL, Freitag, Christine M, Gill, Michael, Thapar, Anita, O'Donovan, Michael C, Owen, Michael J, Holmans, Peter, Kent, Lindsey, Middleton, Frank, Zhang-James, Yanli, Liu, Lu, Meyer, Jobst, Nguyen, Thuy Trang, Romanos, Jasmin, Romanos, Marcel, Seitz, Christiane, Renner, Tobias J, Walitza, Susanne, Warnke, Andreas, Palmason, Haukur, Buitelaar, Jan, Rommelse, Nanda, Vasquez, Alejandro Arias, Hawi, Ziarih, Langley, Kate, Sergeant, Joseph, Steinhausen, Hans-Christoph, Roeyers, Herbert, Biederman, Joseph, Zaharieva, Irina, Hakonarson, Hakon, Elia, Josephine, Lionel, Anath C, Crosbie, Jennifer, Marshall, Christian R, Schachar, Russell, Scherer, Stephen W, Todorov, Alexandre, Smalley, Susan L, Loo, Sandra, Nelson, Stanley, Shtir, Corina, Asherson, Philip, Reif, Andreas, Lesch, Klaus-Peter, and Faraone, Stephen V

Subjects
Human Genome, Clinical Research, Mental Health, Genetics, Pediatric, Attention Deficit Hyperactivity Disorder (ADHD), Brain Disorders, Serious Mental Illness, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Attention Deficit Disorder with Hyperactivity, Canada, Causality, Child, Child, Preschool, Female, Gene Dosage, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, In Situ Hybridization, Fluorescence, Inheritance Patterns, Polymorphism, Single Nucleotide, Receptors, Nicotinic, Segmental Duplications, Genomic, United Kingdom, United States, alpha7 Nicotinic Acetylcholine Receptor, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveAttention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology.MethodThe authors performed a genome-wide analysis of large, rare CNVs (100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder.ConclusionsThese findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

Published
2012

4. Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders

Author

Waltes, Regina, Duketis, Eftichia, Knapp, Michael, Anney, Richard J. L., Huguet, Guillaume, Schlitt, Sabine, Jarczok, Tomasz A., Sachse, Michael, Kämpfer, Laura M., Kleinböck, Tina, Poustka, Fritz, Bölte, Sven, Schmötzer, Gabriele, Voran, Anette, Huy, Ellen, Meyer, Jobst, Bourgeron, Thomas, Klauck, Sabine M., Freitag, Christine M., and Chiocchetti, Andreas G.

Published
2014
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6. Genome-wide linkage analysis of families with primary hyperhidrosis

Author

Schote, Andrea B, Schiel, Florian, Schmitt, Benedikt, Winnikes, Ulrike, Frank, Nicole, Gross, Katharina, Croyé, Marie-Anne, Tarragon, Ernesto, Bekhit, Adam, Bobbili, Dheeraj Reddy, May, Patrick, Schick, Christoph, Meyer, Jobst, and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Exome sequencing, Male, Nicotinic Acetylcholine Receptors, Heredity, Transmembrane Receptors, Genetic Linkage, Single Nucleotide Polymorphisms, Science, Cholinergics, Emotions, Social Sciences, Polymorphism, Single Nucleotide, Biochemistry, Germany, Exome Sequencing, Genetics, Humans, Hyperhidrosis, Psychology, Genetic Predisposition to Disease, Alleles, Chromosome Mapping, High-Throughput Nucleotide Sequencing, Biology and Life Sciences, Proteins, Neurochemistry, Neurotransmitters, Cell Biology, Pedigree, Genetic Mapping, Haplotypes, Genetic Loci, Acetylcholine Receptors, Linkage Analysis, Medicine, Female, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Linkage analysis, Genome-Wide Association Study, Research Article, Neuroscience, Signal Transduction
Abstract

Primary focal hyperhidrosis (PFH, OMIM %144110) is a genetically influenced condition characterised by excessive sweating. Prevalence varies between 1.0–6.1% in the general population, dependent on ethnicity. The aetiology of PFH remains unclear but an autosomal dominant mode of inheritance, incomplete penetrance and variable phenotypes have been reported. In our study, nine pedigrees (50 affected, 53 non-affected individuals) were included. Clinical characterisation was performed at the German Hyperhidrosis Centre, Munich, by using physiological and psychological questionnaires. Genome-wide parametric linkage analysis with GeneHunter was performed based on the Illumina genome-wide SNP arrays. Haplotypes were constructed using easyLINKAGE and visualised via HaploPainter. Whole-exome sequencing (WES) with 100x coverage in 31 selected members (24 affected, 7 non-affected) from our pedigrees was achieved by next generation sequencing. We identified four genome-wide significant loci, 1q41-1q42.3, 2p14-2p13.3, 2q21.2-2q23.3 and 15q26.3-15q26.3 for PFH. Three pedigrees map to a shared locus at 2q21.2-2q23.3, with a genome-wide significant LOD score of 3.45. The chromosomal region identified here overlaps with a locus at chromosome 2q22.1-2q31.1 reported previously. Three families support 1q41-1q42.3 (LOD = 3.69), two families share a region identical by descent at 2p14-2p13.3 (LOD = 3.15) and another two families at 15q26.3 (LOD = 3.01). Thus, our results point to considerable genetic heterogeneity. WES did not reveal any causative variants, suggesting that variants or mutations located outside the coding regions might be involved in the molecular pathogenesis of PFH. We suggest a strategy based on whole-genome or targeted next generation sequencing to identify causative genes or variants for PFH.

Published
2020

8. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Author

Demontis, Ditte, Walters, Raymond K., Martin, Joanna, Mattheisen, Manuel, Als, Thomas D., Agerbo, Esben, Baldursson, Gisli, Belliveau, Rich, Bybjerg-Grauholm, Jonas, Baekvad-Hansen, Marie, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dumont, Ashley, Eriksson, Nicholas, Gandal, Michael, Goldstein, Jacqueline I., Grasby, Katrina L., Grove, Jakob, Gudmundsson, Olafur O., Hansen, Christine S., Hauberg, Mads Engel, Hollegaard, Mads V., Howrigan, Daniel P., Huang, Hailiang, Maller, Julian B., Martin, Alicia R., Martin, Nicholas G., Moran, Jennifer, Pallesen, Jonatan, Palmer, Duncan S., Pedersen, Carsten Bocker, Pedersen, Marianne Giortz, Poterba, Timothy, Poulsen, Jesper Buchhave, Ripke, Stephan, Robinson, Elise B., Satterstrom, F. Kyle, Stefansson, Hreinn, Stevens, Christine, Turley, Patrick, Walters, G. Bragi, Won, Hyejung, Wright, Margaret J., Andreassen, Ole A., Asherson, Philip, Burton, Christie L., Boomsma, Dorret I., Cormand, Bru, Dalsgaard, Soren, Franke, Barbara, Gelernter, Joel, Geschwind, Daniel, Hakonarson, Hakon, Haavik, Jan, Kranzler, Henry R., Kuntsi, Jonna, Langley, Kate, Lesch, Klaus-Peter, Middeldorp, Christel, Reif, Andreas, Rohde, Luis Augusto, Roussos, Panos, Schachar, Russell, Sklar, Pamela, Sonuga-Barke, Edmund J. S., Sullivan, Patrick F., Thapar, Anita, Tung, Joyce Y., Waldman, Irwin D., Medland, Sarah E., Stefansson, Kari, Nordentoft, Merete, Hougaard, David M., Werge, Thomas, Mors, Ole, Mortensen, Preben Bo, Daly, Mark J., Faraone, Stephen V., Borglum, Anders D., Neale, Benjamin M., Albayrak, Ozgur, Anney, Richard J. L., Arranz, Maria Jesus, Banaschewski, Tobias J., Bau, Claiton, Biederman, Joseph, Buitelaar, Jan K., Casas, Miguel, Charach, Alice, Crosbie, Jennifer, Dempfle, Astrid, Doyle, Alysa E., Ebstein, Richard P., Elia, Josephine, Freitag, Christine, Focker, Manuel, Gill, Michael, Grevet, Eugenio, Hawi, Ziarih, Hebebrand, Johannes, Herpertz-Dahlmann, Beate, Hervas, Amaia, Hinney, Anke, Hohmann, Sarah, Holmans, Peter, Hutz, Mara, Ickowitz, Abel, Johansson, Stefan, Kent, Lindsey, Kittel-Schneider, Sarah, Lambregts-Rommelse, Nanda, Lehmkuhl, Gerd, Loo, Sandra K., McGough, James J., Meyer, Jobst, Mick, Eric, Middletion, Frank, Miranda, Ana, Mota, Nina Roth, Mulas, Fernando, Mulligan, Aisling, Nelson, Freimer, Nguyen, T. Trang, Oades, Robert D., O'Donovan, Michael C., Owen, Michael J., Palmason, Haukur, Ramos-Quiroga, Josep Antoni, Renner, Tobias J., Ribases, Marta, Rietschel, Marcella, Rivero, Olga, Romanos, Jasmin, Romanos, Marcel, Rothenberger, Aribert, Royers, Herbert, Sanchez-Mora, Christina, Scherag, Andre, Schimmelmann, Benno G., Schafer, Helmut, Sergeant, Joseph, Sinzig, Judith, Smalley, Susan L., Steinhausen, Hans-Christoph, Thompson, Margaret, Todorov, Alexandre, Vasquez, Alejandro Arias, Walitza, Susanne, Wang, Yufeng, Warnke, Andreas, Williams, Nigel, Witt, Stephanie H., Yang, Li, Zayats, Tetyana, Zhang-James, Yanli, Smith, George Davey, Davies, Gareth E., Ehli, Erik A., Evans, David M., Fedko, Iryna O., Greven, Corina U., Groen-Blokhuis, Maria M., Guxens, Monica, Hammerschlag, Anke R., Hartman, Catharina A., Heinrich, Joachim, Hottenga, Jouke Jan, Hudziak, James, Jugessur, Astanand, Kemp, John P., Krapohl, Eva, Murcia, Mario, Myhre, Ronny, Nolte, Ilja M., Nyholt, Dale R., Ormel, Johan, Ouwens, Klaasjan G., Pappa, Irene, Pennell, Craig E., Plomin, Robert, Ring, Susan, Standl, Marie, Stergiakouli, Evie, St Pourcain, Beate, Stoltenberg, Camilla, Sunyer, Jordi, Thiering, Elisabeth, Tiemeier, Henning, Tiesler, Carla M. T., Timpson, Nicholas J., Trzaskowski, Maciej, van der Most, Peter Johannes, Vilor-Tejedor, Natalia, Wang, Carol A., Whitehouse, Andrew J. O., Zhao, Huiying, Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Hinds, David A., Hromatka, Bethann S., Huber, Karen E., Kleinman, Aaron, Litterman, Nadia K., McIntyre, Matthew H., Mountain, Joanna L., Northover, Carrie A. M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Vacic, Vladimir, Wilson, Catherine H., Demontis, Ditte, Walters, Raymond K., Martin, Joanna, Mattheisen, Manuel, Als, Thomas D., Agerbo, Esben, Baldursson, Gisli, Belliveau, Rich, Bybjerg-Grauholm, Jonas, Baekvad-Hansen, Marie, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dumont, Ashley, Eriksson, Nicholas, Gandal, Michael, Goldstein, Jacqueline I., Grasby, Katrina L., Grove, Jakob, Gudmundsson, Olafur O., Hansen, Christine S., Hauberg, Mads Engel, Hollegaard, Mads V., Howrigan, Daniel P., Huang, Hailiang, Maller, Julian B., Martin, Alicia R., Martin, Nicholas G., Moran, Jennifer, Pallesen, Jonatan, Palmer, Duncan S., Pedersen, Carsten Bocker, Pedersen, Marianne Giortz, Poterba, Timothy, Poulsen, Jesper Buchhave, Ripke, Stephan, Robinson, Elise B., Satterstrom, F. Kyle, Stefansson, Hreinn, Stevens, Christine, Turley, Patrick, Walters, G. Bragi, Won, Hyejung, Wright, Margaret J., Andreassen, Ole A., Asherson, Philip, Burton, Christie L., Boomsma, Dorret I., Cormand, Bru, Dalsgaard, Soren, Franke, Barbara, Gelernter, Joel, Geschwind, Daniel, Hakonarson, Hakon, Haavik, Jan, Kranzler, Henry R., Kuntsi, Jonna, Langley, Kate, Lesch, Klaus-Peter, Middeldorp, Christel, Reif, Andreas, Rohde, Luis Augusto, Roussos, Panos, Schachar, Russell, Sklar, Pamela, Sonuga-Barke, Edmund J. S., Sullivan, Patrick F., Thapar, Anita, Tung, Joyce Y., Waldman, Irwin D., Medland, Sarah E., Stefansson, Kari, Nordentoft, Merete, Hougaard, David M., Werge, Thomas, Mors, Ole, Mortensen, Preben Bo, Daly, Mark J., Faraone, Stephen V., Borglum, Anders D., Neale, Benjamin M., Albayrak, Ozgur, Anney, Richard J. L., Arranz, Maria Jesus, Banaschewski, Tobias J., Bau, Claiton, Biederman, Joseph, Buitelaar, Jan K., Casas, Miguel, Charach, Alice, Crosbie, Jennifer, Dempfle, Astrid, Doyle, Alysa E., Ebstein, Richard P., Elia, Josephine, Freitag, Christine, Focker, Manuel, Gill, Michael, Grevet, Eugenio, Hawi, Ziarih, Hebebrand, Johannes, Herpertz-Dahlmann, Beate, Hervas, Amaia, Hinney, Anke, Hohmann, Sarah, Holmans, Peter, Hutz, Mara, Ickowitz, Abel, Johansson, Stefan, Kent, Lindsey, Kittel-Schneider, Sarah, Lambregts-Rommelse, Nanda, Lehmkuhl, Gerd, Loo, Sandra K., McGough, James J., Meyer, Jobst, Mick, Eric, Middletion, Frank, Miranda, Ana, Mota, Nina Roth, Mulas, Fernando, Mulligan, Aisling, Nelson, Freimer, Nguyen, T. Trang, Oades, Robert D., O'Donovan, Michael C., Owen, Michael J., Palmason, Haukur, Ramos-Quiroga, Josep Antoni, Renner, Tobias J., Ribases, Marta, Rietschel, Marcella, Rivero, Olga, Romanos, Jasmin, Romanos, Marcel, Rothenberger, Aribert, Royers, Herbert, Sanchez-Mora, Christina, Scherag, Andre, Schimmelmann, Benno G., Schafer, Helmut, Sergeant, Joseph, Sinzig, Judith, Smalley, Susan L., Steinhausen, Hans-Christoph, Thompson, Margaret, Todorov, Alexandre, Vasquez, Alejandro Arias, Walitza, Susanne, Wang, Yufeng, Warnke, Andreas, Williams, Nigel, Witt, Stephanie H., Yang, Li, Zayats, Tetyana, Zhang-James, Yanli, Smith, George Davey, Davies, Gareth E., Ehli, Erik A., Evans, David M., Fedko, Iryna O., Greven, Corina U., Groen-Blokhuis, Maria M., Guxens, Monica, Hammerschlag, Anke R., Hartman, Catharina A., Heinrich, Joachim, Hottenga, Jouke Jan, Hudziak, James, Jugessur, Astanand, Kemp, John P., Krapohl, Eva, Murcia, Mario, Myhre, Ronny, Nolte, Ilja M., Nyholt, Dale R., Ormel, Johan, Ouwens, Klaasjan G., Pappa, Irene, Pennell, Craig E., Plomin, Robert, Ring, Susan, Standl, Marie, Stergiakouli, Evie, St Pourcain, Beate, Stoltenberg, Camilla, Sunyer, Jordi, Thiering, Elisabeth, Tiemeier, Henning, Tiesler, Carla M. T., Timpson, Nicholas J., Trzaskowski, Maciej, van der Most, Peter Johannes, Vilor-Tejedor, Natalia, Wang, Carol A., Whitehouse, Andrew J. O., Zhao, Huiying, Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Hinds, David A., Hromatka, Bethann S., Huber, Karen E., Kleinman, Aaron, Litterman, Nadia K., McIntyre, Matthew H., Mountain, Joanna L., Northover, Carrie A. M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Vacic, Vladimir, and Wilson, Catherine H.

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Published
2019

9. A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder

Author

Martin, Joanna, Walters, Raymond K., Demontis, Ditte, Mattheisen, Manuel, Lee, S. Hong, Robinson, Elise, Brikell, Isabell, Ghirardi, Laura, Larsson, Henrik, Lichtenstein, Paul, Eriksson, Nicholas, Werge, Thomas, Mortensen, Preben Bo, Pedersen, Marianne Giørtz, Mors, Ole, Nordentoft, Merete, Hougaard, David M., Bybjerg-Grauholm, Jonas, Wray, Naomi R., Franke, Barbara, Faraone, Stephen V., O'Donovan, Michael, Thapar, Anita, Børglum, Anders D., Neale, Benjamin M., Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Hinds, David A., Hromatka, Bethann S., Huber, Karen E., Kleinman, Aaron, Litterman, Nadia K., McIntyre, Matthew H., Mountain, Joanna L., Northover, Carrie A.M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Vacic, Vladimir, Wilson, Catherine H., Albayrak, Özgür, Anney, Richard J. L., Vasquez, Alejandro Arias, Arranz, Maria Jesús, Asherson, Philip, Banaschewski, Tobias, Banaschewski, Tobias J., Bau, Claiton, Biederman, Joseph, Buitelaar, Jan K., Casas, Miguel, Charach, Alice, Cormand, Bru, Crosbie, Jennifer, Dalsgaard, Soeren, Daly, Mark J., Dempfle, Astrid, Doyle, Alysa E., Ebstein, Richard P., Elia, Josephine, Föcker, Manuel, Freitag, Christine, Gelernter, Joel, Gill, Michael, Grevet, Eugenio, Haavik, Jan, Hakonarson, Hakon, Hawi, Ziarih, Hebebrand, Johannes, Herpertz-Dahlmann, Beate, Hervas, Amaia, Hinney, Anke, Hohmann, Sarah, Holmans, Peter, Hutz, Mara, Ickowitz, Abel, Johansson, Stefan, Kent, Lindsey, Kittel-Schneider, Sarah, Kranzler, Henry, Kuntsi, Jonna, Lambregts-Rommelse, Nanda, Langley, Kate, Lehmkuhl, Gerd, Lesch, Klaus-Peter, Loo, Sandra K., McGough, James J., Medland, Sarah E., Meyer, Jobst, Mick, Eric, Middletion, Frank, Miranda, Ana, Mulas, Fernando, Mulligan, Aisling, Nelson, Stan F., Nguyen, T. Trang, Oades, Robert D., Palmason, Haukur, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Renner, Tobias J., Rhode, Luis, Ribasés, Marta, Rietschel, Marcella, Ripke, Stephan, Rivero, Olga, Sánchez-Mora, Cristina, Schachar, Russell, Schäfer, Helmut, Scherag, André, Schimmelmann, Benno G., Sergeant, Joseph, Sinzig, Judith, Smalley, Susan L., Sonuga-Barke, Edmund J.S., Steinhausen, Hans-Christoph, Sullivan, Patrick F., Thompsom, Margaret, Todorov, Alexandre, Waldman, Irwin, Walitza, Susanne, Wang, Yufeng, Warnke, Andreas, Williams, Nigel, Witt, Stephanie H., Yang, Li, Zayats, Tetyana, Zhang-James, Yanli, Agerbo, Esben, Damm Als, Thomas, Bækved-Hansen, Marie, Belliveau, Rich, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dalsgaard, Søren, Dumont, Ashley, Goldstein, Jacqueline, Grove, Jakob, Hansen, Christine S., Engel Hauberg, Mads, Hollegaard, Mads V., Howrigan, Daniel P., Huang, Hailiang, Maller, Julian, Martin, Alicia R., Moran, Jennifer, Pallesen, Jonatan, Palmer, Duncan S., Pedersen, Carsten Bøcker, Poterba, Timothy, Poulson, Jesper Buchhave, Robinson, Elise B., Satterstrom, F. Kyle, Stevens, Christine, and Turley, Patrick

Abstract

Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish populationregister data (N=77,905 cases, N=1,874,637 population controls). Results Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that females with ADHD may be at especially high risk of certain comorbid developmental conditions (i.e. autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score (PRS) analysis did not support a higher burden of ADHD common risk variants in female cases (OR=1.02 [0.98-1.06], p=0.28). In contrast, epidemiological sibling analyses revealed that the siblings of females with ADHD are at higher familial risk of ADHD than siblings of affected males (OR=1.14, [95% CI: 1.11-1.18], p=1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.

Published
2018

10. Basal Levels of Salivary Alpha-Amylase Are Associated with Preference for Foods High in Sugar and Anthropometric Markers of Cardiovascular Risk

Author

Tarragon Cros, Ernesto, Stein, Jakob, Meyer, Jobst, Tarragon Cros, Ernesto, Stein, Jakob, and Meyer, Jobst

Abstract

Salivary alpha-amylase (sAA) influences the perception of taste and texture, features both relevant in acquiring food liking and, with time, food preference. However, no studies have yet investigated the relationship between basal activity levels of sAA and food preference. We collected saliva from 57 volunteers (63% women) who we assessed in terms of their preference for different food items. These items were grouped into four categories according to their nutritional properties: high in starch, high in sugar, high glycaemic index, and high glycaemic load. Anthropometric markers of cardiovascular risk were also calculated. Our findings suggest that sAA influences food preference and body composition in women. Regression analysis showed that basal sAA activity is inversely associated with subjective but not self-reported behavioural preference for foods high in sugar. Additionally, sAA and subjective preference are associated with anthropometric markers of cardiovascular risk. We believe that this pilot study points to this enzyme as an interesting candidate to consider among the physiological factors that modulate eating behaviour., Trier University/German Research Foundation (DFG), Alexander von Humboldt Foundation, Depto. de Psicobiología y Metodología en Ciencias del Comportamiento, Fac. de Psicología, TRUE, pub

Published
2018

12. Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: Genome-wide association study of both common and rare variants

Author

Yang, Li, Neale, Benjamin M., Liu, Lu, Lee, S. Hong, Wray, Naomi R., Ji, Ning, Li, Haimei, Qian, Qiujin, Wang, Dongliang, Li, Jun, Faraone, Stephen V., Wang, Yufeng, Doyle, Alysa, Reif, Andreas, Rothenberger, Aribert, Franke, Barbara, Sonuga-Barke, Edmund J.S., Steinhausen, Hans-Christoph, Buitelaar, Jan K, Kuntsi, Jonna, Biederman, Joseph, Lesch, Klaus Peter, Kent, Lindsey, Asherson, Philip, Oades, Robert D., Loo, Sandra K., Nelson, Stanley F., Smalley, Susan L., Banaschewski, Tobias, Vasquez, Alejandro Arias, Todorov, Alexandre, Charach, A., Miranda, Ana, Warnke, Andreas, Thapar, Anita, Cormand, B., Freitag, Christine, Mick, Eric, Mulas, Fernando, Middleton, Frank, Hakonarson, Hakon, Pálmason, Haukur, Schäfer, Helmut, Roeyers, Herbert, McGough, James J., Romanos, Jasmin, Crosbie, J., Meyer, Jobst, Ramos-Qiroga, J.A., Sergeant, Joseph A, Elia, Josephine, Langely, Kate, Nisenbaum, Laura, Romanos, Marcel, Daly, Mark, Ribases, M., Gill, Michael, O’Donovan, Michael, Owen, Michael, Casas, M., Bayes, M., Lambregts-Rommelse, Nanda, Williams, Nigel, Holmans, Peter, Anney, Richard J.L., Ebstein, Richard, Schachar, R., Medland, Sarah E., Ripke, Stephan, Walitza, Susanne, Nguyen, Thuy Trang, Renner, Tobias J., Hu, Xiaolan, Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, RS: MHeNs School for Mental Health and Neuroscience, Yang, Li, Neale, Benjamin M, Liu, Lu, Lee, S Hong, Wray, Naomi R, Ji, Ning, Li, Haimei, Qian, Qiujin, Wang, Dongliang, Li, Jun, Faraone, Stephen V, Wang, Yufeng, and Psychiatric GWAS Consortium: ADHD Subgroup

Subjects
Male, Adolescent, DCN MP - Plasticity and memory, Medizin, SNP, Single-nucleotide polymorphism, Genome-wide association study, DCN PAC - Perception action and control, Biology, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Correlation, single nucleotide polymorphisms, Cellular and Molecular Neuroscience, Polymorphism (computer science), attention-deficit hyperactivity disorder, mental disorders, medicine, ddc:61, Humans, ADHD, GWAS, Attention deficit hyperactivity disorder, Genetic Predisposition to Disease, DCN PAC - Perception action and control NCEBP 9 - Mental health, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Copy-number variation, Child, Genetics (clinical), Genetics & Heredity, Psychiatry, Genetics, neurodevelopment, pathway, Case-control study, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], medicine.disease, genetic architecture, Genetic architecture, Psychiatry and Mental health, polygenic disorders, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Female, Genome-Wide Association Study
Abstract

Attention-deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case-control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM-IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome-wide association analyses were performed using PLINK. SNP-heritability and SNP-genetic correlations with ADHD in Caucasians were estimated with genome-wide complex trait analysis (GCTA). Pathway analyses were performed using the Interval enRICHment Test (INRICH), the Disease Association Protein-Protein Link Evaluator (DAPPLE), and the Genomic Regions Enrichment of Annotations Tool (GREAT). We did not find genome-wide significance for single SNPs but did find an increased burden of large, rare CNVs in the ADHD sample (P=0.038). SNP-heritability was estimated to be 0.42 (standard error, 0.13, P=0.0017) and the SNP-genetic correlation with European Ancestry ADHD samples was 0.39 (SE 0.15, P=0.0072). The INRICH, DAPPLE, and GREAT analyses implicated several gene ontology cellular components, including neuron projections and synaptic components, which are consistent with a neurodevelopmental pathophysiology for ADHD. This study suggested the genetic architecture of ADHD comprises both common and rare variants. Some common causal variants are likely to be shared between Han Chinese and Caucasians. Complex neurodevelopmental networks may underlie ADHD's etiology. (c) 2013 Wiley Periodicals, Inc. Refereed/Peer-reviewed

Published
2013

13. Mutational Analysis of the SOX9 Gene in Campomelic Dysplasia and Autosomal Sex Reversal: Lack of Genotype/Phenotype Correlations

Author

Meyer, Jobst, Südbeck, Peter, Held, Marika, Wagner, Thomas, Schmitz, M. Lienhard, Dagna Bricarelli, Franca, Eggermont, Ephrem, Friedrich, Ursula, Haas, Oskar A., Kobelt, Albrecht, Leroy, Jules G., Van Maldergem, Lionel, Michel, Erik, Mitulla, Beate, Pfeiffer, Rudolf A., Schinzel, Albert, Schmidt, Heinrich, Scherer, Gerd, Meyer, Jobst, Südbeck, Peter, Held, Marika, Wagner, Thomas, Schmitz, M. Lienhard, Dagna Bricarelli, Franca, Eggermont, Ephrem, Friedrich, Ursula, Haas, Oskar A., Kobelt, Albrecht, Leroy, Jules G., Van Maldergem, Lionel, Michel, Erik, Mitulla, Beate, Pfeiffer, Rudolf A., Schinzel, Albert, Schmidt, Heinrich, and Scherer, Gerd

Abstract

It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations

Published
2017

15. Splitting Schizophrenia: Periodic Catatonia--Susceptibility Locus on Chromosome 15q15

Author

Stober, Gerald, Saar, Kathrin, Ruschendorf, Franz, Meyer, Jobst, Nurnberg, Gudrun, Jatzke, Susanne, Franzek, Ernst, Reis, Andre, Lesch, Klaus-Peter, Wienker, Thomas F., and Beckmann, Helmut

Subjects
Genetic research -- Analysis, Human genetics -- Research, Genetic disorders -- Research, Schizophrenia -- Genetic aspects, Biological sciences
Published
2000

16. Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder

Author

Jarick, Ivonne, Volckmar, Anna-Lena, Pütter, Carolin, Pechlivanis, Sonali, Nguyen, Trang T., Dauvermann, Maria R., Beck, Sebastian, Albayrak, Özgür, Scherag, Susann, Gilsbach, Susanne, Cichon, Sven, Hoffmann, Per, Degenhardt, Franziska, Nöthen, Markus Maria, Schreiber, Stefan, Wichmann, Heinz Erich, Jöckel, Karl-Heinz, Heinrich, Joachim, Tiesler, Carla Marie Thérèse, Faraone, Stephen V., Walitza, Susanne, Sinzig, Judith, Freitag, Christine M., Meyer, Jobst, Herpertz-Dahlmann, Beate, Lehmkuh, Gerd, Renner, Tobias J., Warnke, Andreas, Romanos, Marcel, Lesch, Klaus-Peter J., Reif, Andreas, Schimmelmann, Benno G., Hebebrand, Johannes, Scherag, André, Hinney, Anke, Jarick, Ivonne, Volckmar, Anna-Lena, Pütter, Carolin, Pechlivanis, Sonali, Nguyen, Trang T., Dauvermann, Maria R., Beck, Sebastian, Albayrak, Özgür, Scherag, Susann, Gilsbach, Susanne, Cichon, Sven, Hoffmann, Per, Degenhardt, Franziska, Nöthen, Markus Maria, Schreiber, Stefan, Wichmann, Heinz Erich, Jöckel, Karl-Heinz, Heinrich, Joachim, Tiesler, Carla Marie Thérèse, Faraone, Stephen V., Walitza, Susanne, Sinzig, Judith, Freitag, Christine M., Meyer, Jobst, Herpertz-Dahlmann, Beate, Lehmkuh, Gerd, Renner, Tobias J., Warnke, Andreas, Romanos, Marcel, Lesch, Klaus-Peter J., Reif, Andreas, Schimmelmann, Benno G., Hebebrand, Johannes, Scherag, André, and Hinney, Anke

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

Published
2015

17. Variants of the Monoamine Oxidase A Gene (MAOA) predict free-riding behavior in women in a strategic public goods experiment

Author

Mertins, Vanessa, Schote, Andrea B., and Meyer, Jobst

Subjects
conditional cooperation, C72, player type, public good, C91, ddc:330, H41, gene, experimental economics, D87
Abstract

Laboratory experiments have documented substantial heterogeneity in social preferences, but little is known about the origins of such behavior. Previous research on public goods experiments suggests that individual-level demographic and psychological variables correlate with player types. However, the key question about biological sources of variation in these preferences remains open. The aim of this study is to uncover genetic variations that influence differences in cooperative behavior. For this reason, we identify types of players within a strategic public goods experiment. We explicitly test for an association between individual variance in strategy choice and the functional promoter-region repeat of the monoamine oxidase A gene (MAOA). Our experimental findings suggest a link between MAOA and the occurrence of free-riding in females. Females with MAOA-L are less likely to behave like weak free-riders than MAOA-H carriers, whereas among males, our results did not support a significant relation between genotype and player type. Furthermore, MAOA-L female carriers contribute more than MAOA-H subjects to the public good if they know that others contribute nothing, and they showed slightly lower scores on the Machiavellianism scale. This is the first piece of evidence that genotype might predict player type within a public goods setting. It contributes to our understanding of biological drivers of economic decision-making and points to the need for further exploration.

Published
2013

18. Erratum: DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders (Neuropsychopharmacology (2011) 36 (2318-2327) DOI: 10.1038/npp.2011.120)

Author

Reif, Andreas, Nguyen, T. Trang, Weißflog, Lena, Jacob, Christian P., Romanos, Marcel, Renner, Tobias J., Buttenschon, Henriette N., Kittel-Schneider, Sarah, Gessner, Alexandra, Weber, Heike, Neuner, Maria, Gross-Lesch, Silke, Zamzow, Karin, Kreiker, Susanne, Walitza, Susanne, Meyer, Jobst, Freitag, Christine M., Bosch, Rosa, Casas, Miquel, Gómez, Nuria, Ribasès, Marta, Bayès, Mónica, Buitelaar, Jan K., Kiemeney, Lambertus Alm, Kooij, Jj Sandra, Kan, Cees C., Hoogman, Martine, Johansson, Stefan, Jacobsen, Kaya K., Knappskog, Per M., Fasmer, Ole B., Asherson, Phil, Warnke, Andreas, Grabe, Hans Jörgen, Mahler, Jessie, Teumer, Alexander, Völzke, Henry, Mors, Ole N., Schäfer, Helmut, Psychiatry, and APH - Mental Health

Published
2012

19. Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD

Author

Stergiakouli, Evangelia, Hamshere, Marian, Holmans, Peter, Langley, Kate, Zaharieva, Irina, Hawi, Ziarah, Kent, Lindsey, Gill, Michael, Williams, Nigel, Owen, Michael J., O'Donovan, Michael, Thapar, Anita, Faraone, Stephen V., Neale, Benjamin M., Ripke, Stephan, Daly, Mark, Medland, Sarah E., Asherson, Philip, Franke, Barbara, Steinhausen, Hans-Christoph, Lesch, Klaus-Peter, Freitag, Christine, Reif, Andreas, Renner, Tobias J., Nguyen, Thuy Trang, Romanos, Marcel, Romanos, Jasmin, Walitza, Susanne, Schäfer, Helmut, Warnke, Andreas, Meyer, Jobst, Palmason, Haukur, Buitelaar, Jan, Vasquez, Alejandro Arias, Lambregts-Rommelse, Nanda, Anney, Richard J. L., Sergeant, Joseph, Roeyers, Herbert, Mick, Eric, Biederman, Joseph, Doyle, Alysa, Smalley, Susan, Loo, Sandra, Hakonarson, Hakon, Elia, Josephine, Todorov, Alexandre, Miranda, Ana, Mulas, Fernando, Ebstein, Richard, Rothenberger, Aribert, Banaschewski, Tobias, Oades, Robert D., Sonuga-Barke, Edmund, McGough, James, Nisenbaum, Laura, Middleton, Frank, Hu, Xiaolan, and Nelson, Stan

Subjects
Medizin
Published
2012

20. Joint Analysis of Psychiatric Disorders Increases Accuracy of Risk Prediction for Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

Author

Maier, Robert, primary, Moser, Gerhard, additional, Chen, Guo-Bo, additional, Ripke, Stephan, additional, Coryell, William, additional, Potash, James B., additional, Scheftner, William A., additional, Shi, Jianxin, additional, Weissman, Myrna M., additional, Hultman, Christina M., additional, Landén, Mikael, additional, Levinson, Douglas F., additional, Kendler, Kenneth S., additional, Smoller, Jordan W., additional, Wray, Naomi R., additional, Lee, S. Hong, additional, Absher, Devin, additional, Agartz, Ingrid, additional, Akil, Huda, additional, Amin, Farooq, additional, Andreassen, Ole A., additional, Anjorin, Adebayo, additional, Anney, Richard, additional, Arking, Dan E., additional, Asherson, Philip, additional, Azevedo, Maria H., additional, Backlund, Lena, additional, Badner, Judith A., additional, Bailey, Anthony J., additional, Banaschewski, Tobias, additional, Barchas, Jack D., additional, Barnes, Michael R., additional, Barrett, Thomas B., additional, Bass, Nicholas, additional, Battaglia, Agatino, additional, Bauer, Michael, additional, Bayés, Mònica, additional, Bellivier, Frank, additional, Bergen, Sarah E., additional, Berrettini, Wade, additional, Betancur, Catalina, additional, Bettecken, Thomas, additional, Biederman, Joseph, additional, Binder, Elisabeth B., additional, Black, Donald W., additional, Blackwood, Douglas H.R., additional, Bloss, Cinnamon S., additional, Boehnke, Michael, additional, Boomsma, Dorret I., additional, Breen, Gerome, additional, Breuer, René, additional, Bruggeman, Richard, additional, Buccola, Nancy G., additional, Buitelaar, Jan K., additional, Bunney, William E., additional, Buxbaum, Joseph D., additional, Byerley, William F., additional, Caesar, Sian, additional, Cahn, Wiepke, additional, Cantor, Rita M., additional, Casas, Miguel, additional, Chakravarti, Aravinda, additional, Chambert, Kimberly, additional, Choudhury, Khalid, additional, Cichon, Sven, additional, Cloninger, C. Robert, additional, Collier, David A., additional, Cook, Edwin H., additional, Coon, Hilary, additional, Cormand, Bru, additional, Cormican, Paul, additional, Corvin, Aiden, additional, Coryell, William H., additional, Craddock, Nicholas, additional, Craig, David W., additional, Craig, Ian W., additional, Crosbie, Jennifer, additional, Cuccaro, Michael L., additional, Curtis, David, additional, Czamara, Darina, additional, Daly, Mark J., additional, Datta, Susmita, additional, Dawson, Geraldine, additional, Day, Richard, additional, De Geus, Eco J., additional, Degenhardt, Franziska, additional, Devlin, Bernie, additional, Djurovic, Srdjan, additional, Donohoe, Gary J., additional, Doyle, Alysa E., additional, Duan, Jubao, additional, Dudbridge, Frank, additional, Duketis, Eftichia, additional, Ebstein, Richard P., additional, Edenberg, Howard J., additional, Elia, Josephine, additional, Ennis, Sean, additional, Etain, Bruno, additional, Fanous, Ayman, additional, Faraone, Stephen V., additional, Farmer, Anne E., additional, Ferrier, I. Nicol, additional, Flickinger, Matthew, additional, Fombonne, Eric, additional, Foroud, Tatiana, additional, Frank, Josef, additional, Franke, Barbara, additional, Fraser, Christine, additional, Freedman, Robert, additional, Freimer, Nelson B., additional, Freitag, Christine M., additional, Friedl, Marion, additional, Frisén, Louise, additional, Gallagher, Louise, additional, Gejman, Pablo V., additional, Georgieva, Lyudmila, additional, Gershon, Elliot S., additional, Geschwind, Daniel H., additional, Giegling, Ina, additional, Gill, Michael, additional, Gordon, Scott D., additional, Gordon-Smith, Katherine, additional, Green, Elaine K., additional, Greenwood, Tiffany A., additional, Grice, Dorothy E., additional, Gross, Magdalena, additional, Grozeva, Detelina, additional, Guan, Weihua, additional, Gurling, Hugh, additional, De Haan, Lieuwe, additional, Haines, Jonathan L., additional, Hakonarson, Hakon, additional, Hallmayer, Joachim, additional, Hamilton, Steven P., additional, Hamshere, Marian L., additional, Hansen, Thomas F., additional, Hartmann, Annette M., additional, Hautzinger, Martin, additional, Heath, Andrew C., additional, Henders, Anjali K., additional, Herms, Stefan, additional, Hickie, Ian B., additional, Hipolito, Maria, additional, Hoefels, Susanne, additional, Holmans, Peter A., additional, Holsboer, Florian, additional, Hoogendijk, Witte J., additional, Hottenga, Jouke-Jan, additional, Hultman, Christina M., additional, Hus, Vanessa, additional, Ingason, Andrés, additional, Ising, Marcus, additional, Jamain, Stéphane, additional, Jones, Ian, additional, Jones, Lisa, additional, Kähler, Anna K., additional, Kahn, René S., additional, Kandaswamy, Radhika, additional, Keller, Matthew C., additional, Kelsoe, John R., additional, Kendler, Kenneth S., additional, Kennedy, James L., additional, Kenny, Elaine, additional, Kent, Lindsey, additional, Kim, Yunjung, additional, Kirov, George K., additional, Klauck, Sabine M., additional, Klei, Lambertus, additional, Knowles, James A., additional, Kohli, Martin A., additional, Koller, Daniel L., additional, Konte, Bettina, additional, Korszun, Ania, additional, Krabbendam, Lydia, additional, Krasucki, Robert, additional, Kuntsi, Jonna, additional, Kwan, Phoenix, additional, Långström, Niklas, additional, Lathrop, Mark, additional, Lawrence, Jacob, additional, Lawson, William B., additional, Leboyer, Marion, additional, Ledbetter, David H., additional, Lee, Phil H., additional, Lencz, Todd, additional, Lesch, Klaus-Peter, additional, Levinson, Douglas F., additional, Lewis, Cathryn M., additional, Li, Jun, additional, Lichtenstein, Paul, additional, Lieberman, Jeffrey A., additional, Lin, Dan-Yu, additional, Linszen, Don H., additional, Liu, Chunyu, additional, Lohoff, Falk W., additional, Loo, Sandra K., additional, Lord, Catherine, additional, Lowe, Jennifer K., additional, Lucae, Susanne, additional, MacIntyre, Donald J., additional, Madden, Pamela A.F., additional, Maestrini, Elena, additional, Magnusson, Patrik K.E., additional, Mahon, Pamela B., additional, Maier, Wolfgang, additional, Malhotra, Anil K., additional, Mane, Shrikant M., additional, Martin, Christa L., additional, Martin, Nicholas G., additional, Mattheisen, Manuel, additional, Matthews, Keith, additional, Mattingsdal, Morten, additional, McCarroll, Steven A., additional, McGhee, Kevin A., additional, McGough, James J., additional, McGrath, Patrick J., additional, McGuffin, Peter, additional, McInnis, Melvin G., additional, McIntosh, Andrew, additional, McKinney, Rebecca, additional, McLean, Alan W., additional, McMahon, Francis J., additional, McMahon, William M., additional, McQuillin, Andrew, additional, Medeiros, Helena, additional, Medland, Sarah E., additional, Meier, Sandra, additional, Melle, Ingrid, additional, Meng, Fan, additional, Meyer, Jobst, additional, Middeldorp, Christel M., additional, Middleton, Lefkos, additional, Milanova, Vihra, additional, Miranda, Ana, additional, Monaco, Anthony P., additional, Montgomery, Grant W., additional, Moran, Jennifer L., additional, Moreno-De-Luca, Daniel, additional, Morken, Gunnar, additional, Morris, Derek W., additional, Morrow, Eric M., additional, Moskvina, Valentina, additional, Mowry, Bryan J., additional, Muglia, Pierandrea, additional, Mühleisen, Thomas W., additional, Müller-Myhsok, Bertram, additional, Murtha, Michael, additional, Myers, Richard M., additional, Myin-Germeys, Inez, additional, Neale, Benjamin M., additional, Nelson, Stan F., additional, Nievergelt, Caroline M., additional, Nikolov, Ivan, additional, Nimgaonkar, Vishwajit, additional, Nolen, Willem A., additional, Nöthen, Markus M., additional, Nurnberger, John I., additional, Nwulia, Evaristus A., additional, Nyholt, Dale R., additional, O’Donovan, Michael C., additional, O’Dushlaine, Colm, additional, Oades, Robert D., additional, Olincy, Ann, additional, Oliveira, Guiomar, additional, Olsen, Line, additional, Ophoff, Roel A., additional, Osby, Urban, additional, Owen, Michael J., additional, Palotie, Aarno, additional, Parr, Jeremy R., additional, Paterson, Andrew D., additional, Pato, Carlos N., additional, Pato, Michele T., additional, Penninx, Brenda W., additional, Pergadia, Michele L., additional, Pericak-Vance, Margaret A., additional, Perlis, Roy H., additional, Pickard, Benjamin S., additional, Pimm, Jonathan, additional, Piven, Joseph, additional, Posthuma, Danielle, additional, Potash, James B., additional, Poustka, Fritz, additional, Propping, Peter, additional, Purcell, Shaun M., additional, Puri, Vinay, additional, Quested, Digby J., additional, Quinn, Emma M., additional, Ramos-Quiroga, Josep Antoni, additional, Rasmussen, Henrik B., additional, Raychaudhuri, Soumya, additional, Rehnström, Karola, additional, Reif, Andreas, additional, Ribasés, Marta, additional, Rice, John P., additional, Rietschel, Marcella, additional, Roeder, Kathryn, additional, Roeyers, Herbert, additional, Rossin, Lizzy, additional, Rothenberger, Aribert, additional, Rouleau, Guy, additional, Ruderfer, Douglas, additional, Rujescu, Dan, additional, Sanders, Alan R., additional, Sanders, Stephan J., additional, Santangelo, Susan L., additional, Schachar, Russell, additional, Schalling, Martin, additional, Schatzberg, Alan F., additional, Scheftner, William A., additional, Schellenberg, Gerard D., additional, Scherer, Stephen W., additional, Schork, Nicholas J., additional, Schulze, Thomas G., additional, Schumacher, Johannes, additional, Schwarz, Markus, additional, Scolnick, Edward, additional, Scott, Laura J., additional, Sergeant, Joseph A., additional, Shilling, Paul D., additional, Shyn, Stanley I., additional, Silverman, Jeremy M., additional, Sklar, Pamela, additional, Slager, Susan L., additional, Smalley, Susan L., additional, Smit, Johannes H., additional, Smith, Erin N., additional, Smoller, Jordan W., additional, Sonuga-Barke, Edmund J.S., additional, St Clair, David, additional, State, Matthew, additional, Steffens, Michael, additional, Steinhausen, Hans-Christoph, additional, Strauss, John S., additional, Strohmaier, Jana, additional, Stroup, T. Scott, additional, Sullivan, Patrick F., additional, Sutcliffe, James, additional, Szatmari, Peter, additional, Szelinger, Szabocls, additional, Thapar, Anita, additional, Thirumalai, Srinivasa, additional, Thompson, Robert C., additional, Todorov, Alexandre A., additional, Tozzi, Federica, additional, Treutlein, Jens, additional, Tzeng, Jung-Ying, additional, Uhr, Manfred, additional, van den Oord, Edwin J.C.G., additional, Van Grootheest, Gerard, additional, Van Os, Jim, additional, Vicente, Astrid M., additional, Vieland, Veronica J., additional, Vincent, John B., additional, Visscher, Peter M., additional, Walsh, Christopher A., additional, Wassink, Thomas H., additional, Watson, Stanley J., additional, Weiss, Lauren A., additional, Weissman, Myrna M., additional, Werge, Thomas, additional, Wienker, Thomas F., additional, Wiersma, Durk, additional, Wijsman, Ellen M., additional, Willemsen, Gonneke, additional, Williams, Nigel, additional, Willsey, A. Jeremy, additional, Witt, Stephanie H., additional, Wray, Naomi R., additional, Xu, Wei, additional, Young, Allan H., additional, Yu, Timothy W., additional, Zammit, Stanley, additional, Zandi, Peter P., additional, Zhang, Peng, additional, Zitman, Frans G., additional, and Zöllner, Sebastian, additional

Published
2015
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21. Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder

Author

Jarick, Ivonne, Volckmar, Anna-Lena, Pütter, Carolin, Pechlivanis, Sonali, Nguyen, Trang T, Dauvermann, Maria R, Beck, Sebastian, Albayrak, Özgür, Scherag, Susann, Gilsbach, Susanne, Cichon, Sven, Hoffmann, Per, Degenhardt, Franziska, Nöthen, Markus M, Schreiber, Stefan, Wichmann, H-Erich, Jöckel, Karl-Heinz, Heinrich, Joachim, Tiesler, Carla M T, Faraone, Stephen V, Walitza, Susanne; https://orcid.org/0000-0002-8161-8683, Sinzig, Judith, Freitag, Christine, Meyer, Jobst, Herpertz-Dahlmann, Beate, Lehmkuhl, Gerd, Renner, Tobias J, Warnke, Andreas, Romanos, Marcel, Lesch, Klaus-Peter, Reif, Andreas, Schimmelmann, Benno G, Hebebrand, Johannes, Scherag, André, Hinney, Anke, Jarick, Ivonne, Volckmar, Anna-Lena, Pütter, Carolin, Pechlivanis, Sonali, Nguyen, Trang T, Dauvermann, Maria R, Beck, Sebastian, Albayrak, Özgür, Scherag, Susann, Gilsbach, Susanne, Cichon, Sven, Hoffmann, Per, Degenhardt, Franziska, Nöthen, Markus M, Schreiber, Stefan, Wichmann, H-Erich, Jöckel, Karl-Heinz, Heinrich, Joachim, Tiesler, Carla M T, Faraone, Stephen V, Walitza, Susanne; https://orcid.org/0000-0002-8161-8683, Sinzig, Judith, Freitag, Christine, Meyer, Jobst, Herpertz-Dahlmann, Beate, Lehmkuhl, Gerd, Renner, Tobias J, Warnke, Andreas, Romanos, Marcel, Lesch, Klaus-Peter, Reif, Andreas, Schimmelmann, Benno G, Hebebrand, Johannes, Scherag, André, and Hinney, Anke

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency 1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

Published
2014

23. Association of a polymorphism in the H6PD gene and basal cortisol secretion, body fat mass and leptin level

Author

Bellingrath, Silja, Kumsta, Robert, Meyer, Jobst, Moser, Dirk, Federenko, Ilona S., Hellhammer, Dirk H., and Wüst, Stefan

Subjects
endocrine system, Psychologie, hormones, hormone substitutes, and hormone antagonists
Abstract

The hypothalamus-pituitary-adrenal (HPA) axix is vital for an organism's response to physical or psychosocial stimulation. Chronic dysregulation of HPA axis activity is related to several psychiatric and psychosomatic disorders. Cortisol, the end product of this endocrine system, affects a multitude of systems in the body, including the HPA axis itself and it also has an influence on behavior. The intracellular availability of cortisol is crucial for the regulation of this endocrine system. The enzyme hexose-6-phosphat-dehydrogenase (H6PDH) affects cortisol availability via its influenec on 11β-hydroxysteroid dehydrogenase type I (11β-HSDI)-activity, which regenerates cortisol from inactive cortisone. 116 healthy males (33 monozygotic & 25 dizygotic twin pairs) were studied to estimate the association between a polymorphism in the exon 5 of the H6PD gene (R435Q, GA) and adrenocortical responses to psychosocial stress, basal salivary cortisol levels and body composition. Compared with subjects with the more frequent H6PD genotypers the homozygous AA-carriers displayed a significantly decreased cortisol awakening rise (CAR) as well as lower daytime cortisol levels. In response to stress, the AA-carriers exhibited a trend towards lower cortisol and ACH responses compared with GG- and GA-carriers. In addition, significantly higher levels of leptin and amount of body fat were observed in AA-carriers. We hypothesize that the R453Q polymorphism in the H6PD gene might influence intracellular cortisol availability and thus affect HPA axis regulation.

Published
2005

25. The chromosome 15q14 locus for bipolar disorder and schizophrenia: Is C15orf53 a major candidate gene?

Author

Kranz, Thorsten M., Ekawardhani, Savira, Lin, Michelle K., Witzmann, Simone, Streit, Fabian, Schuelter, Ulrike, Bauer, Hans, Henseler, Darja, Turner, Jonathan D., Muller, Claude P., Reif, Andreas, Schote, Andrea B., Meyer, Jobst, Kranz, Thorsten M., Ekawardhani, Savira, Lin, Michelle K., Witzmann, Simone, Streit, Fabian, Schuelter, Ulrike, Bauer, Hans, Henseler, Darja, Turner, Jonathan D., Muller, Claude P., Reif, Andreas, Schote, Andrea B., and Meyer, Jobst

Published
2012
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26. A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD

Author

Jain, Mahim, Vélez, Jorge I, Acosta, Maria T, Palacio, Louis Guillermo, Balog, Joan, Roessler, Erich, Pineda, David, Londoño, Ana C, Palacio, Juan Davis, Arbelaez, Andres, Lopera, Francisco, Elia, Josephine, Hakonarson, Hakon, Seitz, Christiane, Freitag, Christine M, Palmason, Haukur, Meyer, Jobst, Romanos, Marcel, Walitza, Susanne; https://orcid.org/0000-0002-8161-8683, Hemminger, Uwe, Warnke, Andreas, Romanos, Jasmin, Renner, Tobias, Jacob, Christian, Lesch, Klaus-Peter, Swanson, James, Castellanos, Francisco Xavier, Bailey-Wilson, Joan E, Arcos-Burgos, Mauricio, Muenke, Maximilian, Jain, Mahim, Vélez, Jorge I, Acosta, Maria T, Palacio, Louis Guillermo, Balog, Joan, Roessler, Erich, Pineda, David, Londoño, Ana C, Palacio, Juan Davis, Arbelaez, Andres, Lopera, Francisco, Elia, Josephine, Hakonarson, Hakon, Seitz, Christiane, Freitag, Christine M, Palmason, Haukur, Meyer, Jobst, Romanos, Marcel, Walitza, Susanne; https://orcid.org/0000-0002-8161-8683, Hemminger, Uwe, Warnke, Andreas, Romanos, Jasmin, Renner, Tobias, Jacob, Christian, Lesch, Klaus-Peter, Swanson, James, Castellanos, Francisco Xavier, Bailey-Wilson, Joan E, Arcos-Burgos, Mauricio, and Muenke, Maximilian

Abstract

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.

Published
2012

27. Genome-Wide Association Study in German Patients With Attention Deficit/Hyperactivity Disorder

Author

Hinney, Anke, Scherag, Andre, Jarick, Ivonne, Albayrak, Oezguer, Puetter, Carolin, Pechlivanis, Sonali, Dauvermann, Maria R., Beck, Sebastian, Weber, Heike, Scherag, Susann, Nguyen, Trang T., Volckmar, Anna-Lena, Knoll, Nadja, Faraone, Stephen V., Neale, Benjamin M., Franke, Barbara, Cichon, Sven, Hoffmann, Per, Noethen, Markus M., Schreiber, Stefan, Joeckel, Karl-Heinz, Wichmann, H. -Erich, Freitag, Christine, Lempp, Thomas, Meyer, Jobst, Gilsbach, Susanne, Herpertz-Dahlmann, Beate, Sinzig, Judith, Lehmkuhl, Gerd, Renner, Tobias J., Warnke, Andreas, Romanos, Marcel, Lesch, Klaus-Peter, Reif, Andreas, Schimmelmann, Benno G., Hebebrand, Johannes, Hinney, Anke, Scherag, Andre, Jarick, Ivonne, Albayrak, Oezguer, Puetter, Carolin, Pechlivanis, Sonali, Dauvermann, Maria R., Beck, Sebastian, Weber, Heike, Scherag, Susann, Nguyen, Trang T., Volckmar, Anna-Lena, Knoll, Nadja, Faraone, Stephen V., Neale, Benjamin M., Franke, Barbara, Cichon, Sven, Hoffmann, Per, Noethen, Markus M., Schreiber, Stefan, Joeckel, Karl-Heinz, Wichmann, H. -Erich, Freitag, Christine, Lempp, Thomas, Meyer, Jobst, Gilsbach, Susanne, Herpertz-Dahlmann, Beate, Sinzig, Judith, Lehmkuhl, Gerd, Renner, Tobias J., Warnke, Andreas, Romanos, Marcel, Lesch, Klaus-Peter, Reif, Andreas, Schimmelmann, Benno G., and Hebebrand, Johannes

Abstract

The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 x 10(-7)) have potential relevance for ADHD (e. g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values <= 7.57 x 10(-5)) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD. (C) 2011 Wiley Periodicals, Inc.

Published
2011

28. Adenosine A2A receptor gene (ADORA2A) variants may increase autistic symptoms and anxiety in autism spectrum disorder

Author

Freitag, Christine M., Agelopoulos, Konstantin, Huy, Ellen, Rothermundt, Matthias, Krakowitzky, Petra, Meyer, Jobst, Deckert, Jürgen, Gontard, Alexander, Hohoff, Christa, Freitag, Christine M., Agelopoulos, Konstantin, Huy, Ellen, Rothermundt, Matthias, Krakowitzky, Petra, Meyer, Jobst, Deckert, Jürgen, Gontard, Alexander, and Hohoff, Christa

Abstract

Autism spectrum disorders (ASDs) are heterogeneous disorders presenting with increased rates of anxiety. The adenosine A2A receptor gene (ADORA2A) is associated with panic disorder and is located on chromosome 22q11.23. Its gene product, the adenosine A2A receptor, is strongly expressed in the caudate nucleus, which also is involved in ASD. As autistic symptoms are increased in individuals with 22q11.2 deletion syndrome, and large 22q11.2 deletions and duplications have been observed in ASD individuals, in this study, 98 individuals with ASD and 234 control individuals were genotyped for eight single-nucleotide polymorphisms in ADORA2A. Nominal association with the disorder was observed for rs2236624-CC, and phenotypic variability in ASD symptoms was influenced by rs3761422, rs5751876 and rs35320474. In addition, association of ADORA2A variants with anxiety was replicated for individuals with ASD. Findings point toward a possible mediating role of ADORA2A variants on phenotypic expression in ASD that need to be replicated in a larger sample.

Published
2010

29. DIRAS2 is Associated with Adult ADHD, Related Traits, and Co-Morbid Disorders

Author

Reif, Andreas, primary, Nguyen, T Trang, additional, Weißflog, Lena, additional, Jacob, Christian P, additional, Romanos, Marcel, additional, Renner, Tobias J, additional, Buttenschon, Henriette N, additional, Kittel-Schneider, Sarah, additional, Gessner, Alexandra, additional, Weber, Heike, additional, Neuner, Maria, additional, Gross-Lesch, Silke, additional, Zamzow, Karin, additional, Kreiker, Susanne, additional, Walitza, Susanne, additional, Meyer, Jobst, additional, Freitag, Christine M, additional, Bosch, Rosa, additional, Casas, Miquel, additional, Gómez, Nuria, additional, Ribasès, Marta, additional, Bayès, Mónica, additional, Buitelaar, Jan K, additional, Kiemeney, Lambertus A L M, additional, Kooij, J J Sandra, additional, Kan, Cees C, additional, Hoogman, Martine, additional, Johansson, Stefan, additional, Jacobsen, Kaya K, additional, Knappskog, Per M, additional, Fasmer, Ole B, additional, Asherson, Phil, additional, Warnke, Andreas, additional, Grabe, Hans-Jörgen, additional, Mahler, Jessie, additional, Teumer, Alexander, additional, Völzke, Henry, additional, Mors, Ole N, additional, Schäfer, Helmut, additional, Ramos-Quiroga, Josep Antoni, additional, Cormand, Bru, additional, Haavik, Jan, additional, Franke, Barbara, additional, and Lesch, Klaus-Peter, additional

Published
2011
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32. Rare variants of the gene encoding the potassium chloride co-transporter 3 are associated with bipolar disorder

Author

Meyer, Jobst, primary, Johannssen, Kirsten, additional, Freitag, Christine M., additional, Schraut, Kerstin, additional, Teuber, Isabel, additional, Hahner, Astrid, additional, Mainhardt, Christian, additional, Mössner, Rainald, additional, Volz, Hans-Peter, additional, Wienker, Thomas F., additional, McKeane, Darleen, additional, Stephan, Dietrich A., additional, Rouleau, Guy, additional, Reif, Andreas, additional, and Lesch, Klaus-Peter, additional

Published
2005
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33. Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations

Author

Meyer, Jobst, Südbeck, Peter, Held, Marika, Wagner, Thomas, Schmitz, M Lienhard, Bricarelli, Franca Dagna, Eggermont, Ephrem, Friedrich, Ursula, Haas, Oskar A, Kobelt, Albrecht, Leroy, Jules G, Van Maldergem, Lionel, Michel, Erik, Mitulla, Beate, Pfeiffer, Rudolph A, Schinzel, Albert, Schmidt, Heinrich, Scherer, Gerd, Meyer, Jobst, Südbeck, Peter, Held, Marika, Wagner, Thomas, Schmitz, M Lienhard, Bricarelli, Franca Dagna, Eggermont, Ephrem, Friedrich, Ursula, Haas, Oskar A, Kobelt, Albrecht, Leroy, Jules G, Van Maldergem, Lionel, Michel, Erik, Mitulla, Beate, Pfeiffer, Rudolph A, Schinzel, Albert, Schmidt, Heinrich, and Scherer, Gerd

Abstract

It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations.

Published
1997

38. Novel 5′-regulatory region polymorphisms of the 5-HT2C receptor gene: association study with panic disorder

Author

Deckert, Jürgen, primary, Meyer, Jobst, additional, Catalano, Marco, additional, Bosi, Monica, additional, Sand, Philipp, additional, DiBella, Daniela, additional, Ortega, Gabriela, additional, Stöber, Gerald, additional, Franke, Petra, additional, Nöthen, Markus M., additional, Fritze, Jürgen, additional, Maier, Wolfgang, additional, Beckmann, Helmut, additional, Propping, Peter, additional, Bellodi, Laura, additional, and Lesch, Klaus-Peter, additional

Published
2000
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41. Transcriptional control of the human glucocorticoid receptor: identification and analysis of alternative promoter regions.

Author

Lei Cao-Lei, Leija, Salomon Carlos, Kumsta, Robert, Wüst, Stefan, Meyer, Jobst, Turner, Jonathan D., and Muller, Claude P.

Subjects
GLUCOCORTICOID receptors, EXONS (Genetics), REPORTER genes, CELL lines, CELL culture
Abstract

Glucocorticoid receptor levels are thought to be controlled by multiple alternative first exons. Seven of these exons are located in an upstream CpG island. In this study, we investigated the promoter activity of the intronic regions between these exons, and their susceptibility to CpG methylation and sequence variability. The seven promoters were cloned into luciferase reporter genes, and their activity measured in ten cell lines. CpG islands of 221 donors were genotyped and the effects of these SNPs were investigated in a reporter gene assay. We showed that each of the first exons was independently controlled by a unique promoter located directly upstream. Promoter activities were cell type-specific, and varied considerably between cell types. Irrespective of the cell type, in vitro methylation effectively silenced all reporter constructs. Eleven SNPs were observed within the CpG island of 221 donors, and a new promoter-specific haplotype was revealed. Four of the minor alleles reduced the reporter gene activity, with cell type specific effects. This complexity within the CpG island helps to explain the variable, tissue-specific transcriptional control of the GR, and provides insight into the mechanisms underlying tissue specific deregulation of GR levels. [ABSTRACT FROM AUTHOR]

Published
2011
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42. Functional Analysis of a Potassium-Chloride Co-Transporter 3 (SLC12A6) Promoter Polymorphism Leading to an Additional DNA Methylation Site.

Author

Moser, Dirk, Ekawardhani, Savira, Kumsta, Robert, Palmason, Haukur, Bock, Christoph, Athanassiadou, Zoi, Lesch, Klaus-Peter, and Meyer, Jobst

Subjects
POTASSIUM chloride, GENETIC polymorphisms, CELL proliferation, BIPOLAR disorder, SCHIZOPHRENIA, METHYLATION, EPILEPSY, PSYCHOSES
Abstract

The human potassium-chloride co-transporter 3 (KCC3, SLC12A6) is involved in cell proliferation and in electro-neutral movement of ions across the cell membrane. The gene (SLC12A6) is located on chromosome 15q14, a region that has previously shown linkage with bipolar disorder, schizophrenia, rolandic epilepsy, idiopathic generalized epilepsy, autism and attention deficit/hyperactivity disorder. Furthermore, recessively inherited mutations of SLC12A6 cause Andermann syndrome, characterized by agenesis of the corpus callosum, which is associated with peripheral neuropathy and psychoses. Recently, we have demonstrated the association of two G/A promoter polymorphisms of SLC12A6 with bipolar disorder in a case–control study, and familial segregation of the rare variants as well as a trend toward association with schizophrenia. To investigate functional consequences of these polymorphisms, lymphocyte DNA was extracted, bisulfite modified, and subsequently sequenced. To investigate SLC12A6 promoter activity, various promoter constructs were generated and analyzed by luciferase reporter gene assays. We provide evidence that the G- allele showed a significant reduction of reporter gene expression. In human lymphocytes, the allele harboring the rare upstream G nucleotide was found to be methylated at the adjacent C position, possibly accountable for tissue-specific reduction in gene expression in vivo. Here we demonstrate functionality of an SNP associated with psychiatric disease and our results may represent a functional link between genetic variation and an epigenetic modification.Neuropsychopharmacology (2009) 34, 458–467; doi:10.1038/npp.2008.77; published online 4 June 2008 [ABSTRACT FROM AUTHOR]

Published
2009
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43. High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression

Author

Hamshere, Marian L., Langley, Kate, Martin, Joanna, Agha, Sharifah Shameem, Stergiakouli, Evangelia, Anney, Richard J.L., Buitelaar, Jan, Faraone, Stephen V., Lesch, Klaus-Peter, Neale, Benjamin M., Franke, Barbara, Sonuga-Barke, Edmund, Asherson, Philip, Merwood, Andrew, Kuntsi, Jonna, Medland, Sarah E., Ripke, Stephan, Steinhausen, Hans-Christoph, Freitag, Christine, Reif, Andreas, Renner, Tobias J., Romanos, Marcel, Romanos, Jasmin, Warnke, Andreas, Meyer, Jobst, Palmason, Haukur, Vasquez, Alejandro Arias, Lambregts-Rommelse, Nanda, Roeyers, Herbert, Biederman, Joseph, Doyle, Alysa E., Hakonarson, Hakon, Rothenberger, Aribert, Banaschewski, Tobias, Oades, Robert D., McGough, James J., Kent, Lindsey, Williams, Nigel, Owen, Michael J., Holmans, Peter, O’Donovan, Michael C., and Thapar, Anita

Subjects
Articles
Abstract

Objective: Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. Method Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. Results: Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. Conclusions: Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

Published
2014
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44. A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder

Author

Martin, Joanna, Walters, Raymond K., Demontis, Ditte, Mattheisen, Manuel, Lee, S. Hong, Robinson, Elise, Brikell, Isabell, Ghirardi, Laura, Larsson, Henrik, Lichtenstein, Paul, Eriksson, Nicholas, Werge, Thomas, Mortensen, Preben Bo, Pedersen, Marianne Giørtz, Mors, Ole, Nordentoft, Merete, Hougaard, David M., Bybjerg-Grauholm, Jonas, Wray, Naomi R., Franke, Barbara, Faraone, Stephen V., O’Donovan, Michael C., Thapar, Anita, Børglum, Anders D., Neale, Benjamin M., Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Hinds, David A., Hromatka, Bethann S., Huber, Karen E., Kleinman, Aaron, Litterman, Nadia K., McIntyre, Matthew H., Mountain, Joanna L., Northover, Carrie A.M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Vacic, Vladimir, Wilson, Catherine H., Albayrak, Özgür, Anney, Richard J.L., Vasquez, Alejandro Arias, Arranz, Maria Jesús, Asherson, Philip, Banaschewski, Tobias, Banaschewski, Tobias J., Bau, Claiton, Biederman, Joseph, Børglum, Anders, Buitelaar, Jan K., Casas, Miguel, Charach, Alice, Cormand, Bru, Crosbie, Jennifer, Dalsgaard, Soeren, Daly, Mark J., Dempfle, Astrid, Doyle, Alysa E., Ebstein, Richard P., Elia, Josephine, Föcker, Manuel, Freitag, Christine, Gelernter, Joel, Gill, Michael, Grevet, Eugenio, Haavik, Jan, Hakonarson, Hakon, Hawi, Ziarih, Hebebrand, Johannes, Herpertz-Dahlmann, Beate, Hervas, Amaia, Hinney, Anke, Hohmann, Sarah, Holmans, Peter, Hutz, Mara, Ickowitz, Abel, Johansson, Stefan, Kent, Lindsey, Kittel-Schneider, Sarah, Kranzler, Henry, Kuntsi, Jonna, Lambregts-Rommelse, Nanda, Langley, Kate, Lehmkuhl, Gerd, Lesch, Klaus-Peter, Loo, Sandra K., McGough, James J., Medland, Sarah E., Meyer, Jobst, Mick, Eric, Middletion, Frank, Miranda, Ana, Mulas, Fernando, Mulligan, Aisling, Nelson, Stan F., Nguyen, T. Trang, Oades, Robert D., Owen, Michael J., Palmason, Haukur, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Renner, Tobias J., Rhode, Luis, Ribasés, Marta, Rietschel, Marcella, Ripke, Stephan, Rivero, Olga, Roeyers, Herbert, Romanos, Marcel, Romanos, Jasmin, Mota, Nina Roth, Rothenberger, Aribert, Sánchez-Mora, Cristina, Schachar, Russell, Schäfer, Helmut, Scherag, André, Schimmelmann, Benno G., Sergeant, Joseph, Sinzig, Judith, Smalley, Susan L., Sonuga-Barke, Edmund J.S., Steinhausen, Hans-Christoph, Sullivan, Patrick F., Thompsom, Margaret, Todorov, Alexandre, Waldman, Irwin, Walitza, Susanne, Walters, Raymond, Wang, Yufeng, Warnke, Andreas, Williams, Nigel, Witt, Stephanie H., Yang, Li, Zayats, Tetyana, Zhang-James, Yanli, Agerbo, Esben, Als, Thomas Damm, Bækved-Hansen, Marie, Belliveau, Rich, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dalsgaard, Søren, Dumont, Ashley, Goldstein, Jacqueline, Grove, Jakob, Hansen, Christine S., Hauberg, Mads Engel, Hollegaard, Mads V., Howrigan, Daniel P., Huang, Hailiang, Maller, Julian, Martin, Alicia R., Moran, Jennifer, Pallesen, Jonatan, Palmer, Duncan S., Pedersen, Carsten Bøcker, Poterba, Timothy, Poulsen, Jesper Buchhave, Robinson, Elise B., Satterstrom, F. Kyle, Stevens, Christine, and Turley, Patrick

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45. Genome-Wide Analysis of Copy Number Variants in Attention Deficit Hyperactivity Disorder: The Role of Rare Variants and Duplications at 15q13.3

Author

Williams, Nigel M., Franke, Barbara, Mick, Eric, Anney, Richard J.L., Freitag, Christine M., Gill, Michael, Thapar, Anita, O'Donovan, Michael C., Owen, Michael J., Holmans, Peter, Kent, Lindsey, Middleton, Frank, Zhang-James, Yanli, Liu, Lu, Meyer, Jobst, Nguyen, Thuy Trang, Romanos, Jasmin, Romanos, Marcel, Seitz, Christiane, Renner, Tobias J., Walitza, Susanne, Warnke, Andreas, Palmason, Haukur, Buitelaar, Jan, Rommelse, Nanda, Vasquez, Alejandro Arias, Hawi, Ziarih, Langley, Kate, Sergeant, Joseph, Steinhausen, Hans-Christoph, Roeyers, Herbert, Biederman, Joseph, Zaharieva, Irina, Hakonarson, Hakon, Elia, Josephine, Lionel, Anath C., Crosbie, Jennifer, Marshall, Christian R., Schachar, Russell, Scherer, Stephen W., Todorov, Alexandre, Smalley, Susan L., Loo, Sandra, Nelson, Stanley, Shtir, Corina, Asherson, Philip, Reif, Andreas, Lesch, Klaus-Peter, and Faraone, Stephen V.

Abstract

Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. Method: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. Results: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. Conclusions: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

Published
2013
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46. Mutational Analysis of the SOX9 Gene in Campomelic Dysplasia and Autosomal Sex Reversal: Lack of Genotype/Phenotype Correlations

Author

Meyer, Jobst, Südbeck, Peter, Held, Marika, Wagner, Thomas, Schmitz, M. Lienhard, Dagna Bricarelli, Franca, Eggermont, Ephrem, Friedrich, Ursula, Haas, Oskar A., Kobelt, Albrecht, Leroy, Jules G., Van Maldergem, Lionel, Michel, Erik, Mitulla, Beate, Pfeiffer, Rudolf A., Schinzel, Albert, Schmidt, Heinrich, Scherer, Gerd, Meyer, Jobst, Südbeck, Peter, Held, Marika, Wagner, Thomas, Schmitz, M. Lienhard, Dagna Bricarelli, Franca, Eggermont, Ephrem, Friedrich, Ursula, Haas, Oskar A., Kobelt, Albrecht, Leroy, Jules G., Van Maldergem, Lionel, Michel, Erik, Mitulla, Beate, Pfeiffer, Rudolf A., Schinzel, Albert, Schmidt, Heinrich, and Scherer, Gerd

Abstract

It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations

47. DIRAS2 is Associated with Adult ADHD, Related Traits, and Co-Morbid Disorders.

Author

Reif, Andreas, Nguyen, T Trang, Weißflog, Lena, Jacob, Christian P, Romanos, Marcel, Renner, Tobias J, Buttenschon, Henriette N, Kittel-Schneider, Sarah, Gessner, Alexandra, Weber, Heike, Neuner, Maria, Gross-Lesch, Silke, Zamzow, Karin, Kreiker, Susanne, Walitza, Susanne, Meyer, Jobst, Freitag, Christine M, Bosch, Rosa, Casas, Miquel, and Gómez, Nuria

Subjects
ATTENTION-deficit hyperactivity disorder
Abstract

A correction to the article "DIRAS2 is Associated with Adult ADHD, Related Traits, and Co-Morbid Disorders," published online in the July 13, 2011 issue of the journal.

Published
2012
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48. Haplotype Co-Segregation With Attention Deficit-Hyperactivity Disorder in Unrelated German Multi-Generation Families

Author

Christian Jacob, Tobias J. Renner, Andrea B. Schote, Michelle K. Lin, Haukur Palmason, Christine M. Freitag, Christiane Seitz, Andreas Reif, Jobst Meyer, Marcel Romanos, Rita M. Cantor, Susanne Walitza, Klaus-Peter Lesch, Andreas Warnke, University of Zurich, Meyer, Jobst, Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, and RS: MHeNs School for Mental Health and Neuroscience

Subjects
2716 Genetics (clinical), haplotypes, 2804 Cellular and Molecular Neuroscience, 610 Medicine & health, Pedigree chart, Biology, Mendelian, German, Loss of heterozygosity, 2738 Psychiatry and Mental Health, Cellular and Molecular Neuroscience, symbols.namesake, Chromosome Segregation, Germany, co-segregation, medicine, Chromosomes, Human, Humans, Attention deficit hyperactivity disorder, ADHD, Genetic Predisposition to Disease, Genetics(clinical), Gene, Genetics (clinical), Genes, Dominant, Genetics, Family Characteristics, Models, Genetic, Haplotype, 10058 Department of Child and Adolescent Psychiatry, medicine.disease, language.human_language, Psychiatry and Mental health, Attention Deficit Disorder with Hyperactivity, Mendelian inheritance, symbols, language, Microsatellite, Lod Score
Abstract

Complex disorders have proved to be elusive in the search for underlying genetic causes. In the presence of large multi-generation pedigrees with multiple affected individuals, heritable familial forms of the disorders can be postulated. Observations of particular chromosomal haplotypes shared among all affected individuals within pedigrees may reveal chromosomal regions, in which the disease-related genes may be located. Hence, the biochemical pathways involved in pathogenesis can be exposed. We have recruited eight large Attention Deficit-Hyperactivity Disorder (ADHD, OMIM: #143465) families of German descent. Densely spaced informative microsatellite markers with high heterozygosity rates were used to fine-map and haplotype chromosomal regions of interest in these families. In three subsets and one full family of the eight ADHD families, haplotypes co-segregating with ADHD-affected individuals were identified at chromosomes 1q25, 5q11–5q13, 9q31–9q32, and 18q11–18q21. Positive LOD scores supported these co-segregations. The existence of haplotypes co-segregating among affected individuals in large ADHD pedigrees suggests the existence of Mendelian forms of the disorder and that ADHD-related genes are located within these haplotypes. In depth sequencing of these haplotype regions can identify causative genetic mechanisms and will allow further insights into the clinico-genetics of this complex disorder. © 2013 Wiley Periodicals, Inc.

Published
2013

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