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1. Genome-wide association study of Tourettes syndrome.

Author

Neale, B, Stewart, S, Fagerness, J, Evans, P, Gamazon, E, Edlund, C, Service, S, Tikhomirov, A, Osiecki, L, Illmann, C, Pluzhnikov, A, Konkashbaev, A, Davis, L, Han, B, Crane, J, Scharf, J, Yu, D, Rangel-Lugo, M, Chouinard, S, Dion, Y, Girard, S, Cath, D, Smit, J, King, R, Fernandez, T, Leckman, J, Kidd, K, Kidd, J, Pakstis, A, Herrera, L, Romero, R, Fournier, E, Sandor, P, Barr, C, Phan, N, Gross-Tsur, V, Benarroch, F, Pollak, Y, Budman, C, Bruun, R, Erenberg, G, Naarden, A, Lee, P, Weiss, N, Kremeyer, B, Berrío, G, Campbell, D, Cardona Silgado, J, Ochoa, W, Mesa Restrepo, S, Muller, H, Valencia Duarte, A, Lyon, G, Leppert, M, Morgan, J, Weiss, R, Grados, M, Anderson, K, Davarya, S, Singer, H, Walkup, J, Jankovic, J, Tischfield, J, Heiman, G, Gilbert, D, Hoekstra, P, Robertson, M, Kurlan, R, Liu, C, Gibbs, J, Singleton, A, Hardy, J, Strengman, E, Crenshaw, A, Parkin, M, Wagner, M, Moessner, R, Mirel, D, Posthuma, D, Sabatti, C, Conti, D, Knowles, J, Ruiz-Linares, A, Rouleau, G, Purcell, S, Heutink, P, Oostra, B, McMahon, W, Cox, N, Pauls, D, Reus, Victor, State, Matthew, Eskin, Eleazar, Mathews, Carol, Lowe, Thomas, Freimer, Nelson, Ophoff, Roel, and Moorjani, Priya

Subjects
Adolescent, Adult, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Chromosomes, Human, Pair 9, Female, Fibrillar Collagens, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, International Cooperation, Male, Meta-Analysis as Topic, Obsessive-Compulsive Disorder, Polymorphism, Single Nucleotide, Tourette Syndrome, White People, Young Adult
Abstract

Tourettes syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P

Published
2013

2. Genome-wide association study of Tourette's syndrome.

Author

Scharf, JM, Yu, D, Mathews, CA, Neale, BM, Stewart, SE, Fagerness, JA, Evans, P, Gamazon, E, Edlund, CK, Service, SK, Tikhomirov, A, Osiecki, L, Illmann, C, Pluzhnikov, A, Konkashbaev, A, Davis, LK, Han, B, Crane, J, Moorjani, P, Crenshaw, AT, Parkin, MA, Reus, VI, Lowe, TL, Rangel-Lugo, M, Chouinard, S, Dion, Y, Girard, S, Cath, DC, Smit, JH, King, RA, Fernandez, TV, Leckman, JF, Kidd, KK, Kidd, JR, Pakstis, AJ, State, MW, Herrera, LD, Romero, R, Fournier, E, Sandor, P, Barr, CL, Phan, N, Gross-Tsur, V, Benarroch, F, Pollak, Y, Budman, CL, Bruun, RD, Erenberg, G, Naarden, AL, Lee, PC, Weiss, N, Kremeyer, B, Berrío, GB, Campbell, DD, Cardona Silgado, JC, Ochoa, WC, Mesa Restrepo, SC, Muller, H, Valencia Duarte, AV, Lyon, GJ, Leppert, M, Morgan, J, Weiss, R, Grados, MA, Anderson, K, Davarya, S, Singer, H, Walkup, J, Jankovic, J, Tischfield, JA, Heiman, GA, Gilbert, DL, Hoekstra, PJ, Robertson, MM, Kurlan, R, Liu, C, Gibbs, JR, Singleton, A, North American Brain Expression Consortium, Hardy, J, UK Human Brain Expression Database, Strengman, E, Ophoff, RA, Wagner, M, Moessner, R, Mirel, DB, Posthuma, D, Sabatti, C, Eskin, E, Conti, DV, Knowles, JA, Ruiz-Linares, A, Rouleau, GA, Purcell, S, Heutink, P, Oostra, BA, McMahon, WM, Freimer, NB, Cox, NJ, and Pauls, DL

Subjects
North American Brain Expression Consortium, UK Human Brain Expression Database, Chromosomes, Human, Pair 9, Humans, Tourette Syndrome, Genetic Predisposition to Disease, Fibrillar Collagens, Case-Control Studies, Obsessive-Compulsive Disorder, Attention Deficit Disorder with Hyperactivity, Genotype, Polymorphism, Single Nucleotide, International Cooperation, Adolescent, Adult, Female, Male, Meta-Analysis as Topic, Genome-Wide Association Study, Young Adult, White People, Genetics, Human Genome, Mental Health, Brain Disorders, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, genetics, GWAS, neurodevelopmental disorder, tics, Tourette's syndrome, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P

Published
2013

5. Neuropsychological Aspects of Developmental Dyscalculia.

Author

Shalev, R. S., Manor, O., and Gross-Tsur, V.

Abstract

Classification of arithmetic disorders is predicated on neuropsychological features and associated learning disabilities. Assesses the compatibility of these classifications on a nonreferred, population-based cohort of children (N=139) with developmental dyscalculia. Concludes that children with dyscalculia and disabilities in reading and/or writing are more profoundly impaired in arithmetic than children with dyscalculia alone or attention deficit hyperactivity disorder. Contains 36 references. (Author/ASK)

Published
1997

15. Developmental dyscalculia behavioral and attentional aspects: a research note

Author

Shalev, R.S., Auerbach, J., and Gross-Tsur, V.

Subjects
Developmental disabilities -- Psychological aspects, Behavioral assessment of children -- Analysis, Attention-deficit hyperactivity disorder -- Psychological aspects, Psychology and mental health
Abstract

Behavior problems of the children with developmental dyscalculia (DC) were compared to those of other children using the Child Behavior Checklist. DC children whose scores reflected dyslexia and low verbal IQ showed poor attention control. Overall, DC children were not found to be more likely to suffer from anxiety or depression.

Published
1995

18. Copy number variations in cryptogenic cerebral palsy

Author

Segel, R., primary, Ben-Pazi, H., additional, Zeligson, S., additional, Fatal-Valevski, A., additional, Aran, A., additional, Gross-Tsur, V., additional, Schneebaum-Sender, N., additional, Shmueli, D., additional, Lev, D., additional, Perlberg, S., additional, Blumkin, L., additional, Deutsch, L., additional, and Levy-Lahad, E., additional

Published
2015
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19. Copy number variation in obsessive-compulsive disorder and tourette syndrome: A cross-disorder study

Author

McGrath, L.M., Yu, D. (D.), Marshall, C.R. (Christian), Davis, L.K. (Lea), Thiruvahindrapuram, B. (Bhooma), Li, B. (Bingbin), Cappi, C. (Carolina), Gerber, G. (Gloria), Wolf, A. (Anneke) de, Schroeder, F.A. (Frederick), Osiecki, L. (Lisa), O'Dushlaine, C. (Colm), Kirby, A. (Andrew), Illmann, C. (Cornelia), Haddad, S. (Stephen), Gallagher, P. (Patience), Fagerness, J. (Jesen), Barr, C.L. (Cathy), Bellodi, L. (Laura), Benarroch, F. (Fortu), Bienvenu, O.J. (Oscar), Black, D.W. (Donald), Bloch, J. (Jocelyne), Bruun, R.D. (Ruth), Budman, C.L. (Cathy), Camarena, B. (Beatriz), Cath, D. (Daniëlle), Cavallini, M.C. (Maria), Chouinard, S., Coric, V. (Vladimir), Cullen, C., Delorme, R. (Richard), Denys, D.A.J.P. (Damiaan), Derks, E.M. (Eske), Dion, Y. (Yves), Rosário, M.C. (Maria), Eapen, C.E. (Chundamannil Eapen), Evans, P., Falkai, P. (Peter), Fernandez, T.V. (Thomas), Garrido, H. (Helena), Geller, D. (Daniel), Grabe, H.J. (Hans Jörgen), Grados, M. (Marco), Greenberg, B.D. (Benjamin), Gross-Tsur, V. (Varda), Grünblatt, E. (Edna), Heiman, M.L. (Mark), Hemmings, S.M.J. (Sian), Herrera, L.D. (Luis), Hounie, A.G. (Ana), Jankovic, J. (Joseph), Kennedy, J.L., King, R.A., Kurlan, R., Lanzagorta, N. (Nuria), Leboyer, M. (Marion), Leckman, J.F., Lennertz, L. (Leonhard), Lochner, C. (Christine), Lowe, T.L. (Thomas), Lyon, H.N. (Helen), MacCiardi, F. (Fabio), Maier, W. (Wolfgang), McCracken, J.T. (James), McMahon, W.M. (William), Murphy, D.L. (Dennis), Naarden, A.L. (Allan), Nurmi, E. (Erika), Pakstis, A.J., Pato, C. (Carlos), Piacentini, J. (John), Pittenger, C. (Christopher), Pollak, M.N. (Michael), Reus, V.I. (Victor), Richter, M.A. (Margaret), Riddle, M. (Mark), Robertson, M.M., Rosenberg, D. (David), Rouleau, G.A., Ruhrmann, S. (Stephan), Sampaio, A.S. (Aline), Samuels, J. (Jonathan), Sandor, P. (Paul), Sheppard, B. (Brooke), Singer, H.S. (Harvey), Smit, J.H. (Jan), Stein, D.J. (Dan), Tischfield, J.A. (Jay), Vallada, H. (Homero), Veenstra-Vanderweele, J. (Jeremy), Walitza, S. (Susanne), Wang, Y. (Ying), Wendland, A. (Annika), Shugart, Y.Y., Miguel, E.C. (Euripedes), Nicolini, H. (Humberto), Oostra, B.A. (Ben), Moessner, R. (Rainald), Wagner, M. (Michael), Ruiz-Linares, A. (Andres), Heutink, P. (Peter), Nestadt, G. (Gerald), Freimer, N.B. (Nelson), Petryshen, T.L. (Tracey), Posthuma, D. (Danielle), Jenike, M.A. (Michael), Cox, N.J. (Nancy), Hanna, G.L. (Gregory), Brentani, H. (Helena), Scherer, S.W. (Stephen), Arnold, P.D. (Paul), Stewart, S.E., Mathews, C., Knowles, J.A. (James A), Cook, E.H. (Edwin), Pauls, D.L. (David), Wang, K. (Kai), Scharf, J.M., Neale, B.M. (Benjamin), McGrath, L.M., Yu, D. (D.), Marshall, C.R. (Christian), Davis, L.K. (Lea), Thiruvahindrapuram, B. (Bhooma), Li, B. (Bingbin), Cappi, C. (Carolina), Gerber, G. (Gloria), Wolf, A. (Anneke) de, Schroeder, F.A. (Frederick), Osiecki, L. (Lisa), O'Dushlaine, C. (Colm), Kirby, A. (Andrew), Illmann, C. (Cornelia), Haddad, S. (Stephen), Gallagher, P. (Patience), Fagerness, J. (Jesen), Barr, C.L. (Cathy), Bellodi, L. (Laura), Benarroch, F. (Fortu), Bienvenu, O.J. (Oscar), Black, D.W. (Donald), Bloch, J. (Jocelyne), Bruun, R.D. (Ruth), Budman, C.L. (Cathy), Camarena, B. (Beatriz), Cath, D. (Daniëlle), Cavallini, M.C. (Maria), Chouinard, S., Coric, V. (Vladimir), Cullen, C., Delorme, R. (Richard), Denys, D.A.J.P. (Damiaan), Derks, E.M. (Eske), Dion, Y. (Yves), Rosário, M.C. (Maria), Eapen, C.E. (Chundamannil Eapen), Evans, P., Falkai, P. (Peter), Fernandez, T.V. (Thomas), Garrido, H. (Helena), Geller, D. (Daniel), Grabe, H.J. (Hans Jörgen), Grados, M. (Marco), Greenberg, B.D. (Benjamin), Gross-Tsur, V. (Varda), Grünblatt, E. (Edna), Heiman, M.L. (Mark), Hemmings, S.M.J. (Sian), Herrera, L.D. (Luis), Hounie, A.G. (Ana), Jankovic, J. (Joseph), Kennedy, J.L., King, R.A., Kurlan, R., Lanzagorta, N. (Nuria), Leboyer, M. (Marion), Leckman, J.F., Lennertz, L. (Leonhard), Lochner, C. (Christine), Lowe, T.L. (Thomas), Lyon, H.N. (Helen), MacCiardi, F. (Fabio), Maier, W. (Wolfgang), McCracken, J.T. (James), McMahon, W.M. (William), Murphy, D.L. (Dennis), Naarden, A.L. (Allan), Nurmi, E. (Erika), Pakstis, A.J., Pato, C. (Carlos), Piacentini, J. (John), Pittenger, C. (Christopher), Pollak, M.N. (Michael), Reus, V.I. (Victor), Richter, M.A. (Margaret), Riddle, M. (Mark), Robertson, M.M., Rosenberg, D. (David), Rouleau, G.A., Ruhrmann, S. (Stephan), Sampaio, A.S. (Aline), Samuels, J. (Jonathan), Sandor, P. (Paul), Sheppard, B. (Brooke), Singer, H.S. (Harvey), Smit, J.H. (Jan), Stein, D.J. (Dan), Tischfield, J.A. (Jay), Vallada, H. (Homero), Veenstra-Vanderweele, J. (Jeremy), Walitza, S. (Susanne), Wang, Y. (Ying), Wendland, A. (Annika), Shugart, Y.Y., Miguel, E.C. (Euripedes), Nicolini, H. (Humberto), Oostra, B.A. (Ben), Moessner, R. (Rainald), Wagner, M. (Michael), Ruiz-Linares, A. (Andres), Heutink, P. (Peter), Nestadt, G. (Gerald), Freimer, N.B. (Nelson), Petryshen, T.L. (Tracey), Posthuma, D. (Danielle), Jenike, M.A. (Michael), Cox, N.J. (Nancy), Hanna, G.L. (Gregory), Brentani, H. (Helena), Scherer, S.W. (Stephen), Arnold, P.D. (Paul), Stewart, S.E., Mathews, C., Knowles, J.A. (James A), Cook, E.H. (Edwin), Pauls, D.L. (David), Wang, K. (Kai), Scharf, J.M., and Neale, B.M. (Benjamin)

Abstract

Objective Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date. Method The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios. Results Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p =.09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p =.08 in the current study, p =.025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%). Conclusion Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.

Published
2014
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20. Interhemispheric and intrahemispheric connectivity and manual skills in children with unilateral cerebral palsy

Author

Weinstein, M., Green, Dido, Geva, R., Schertz, M., Fattal-Valevski, A., Artzi, M., Myers, V., Shiran, S., Gordon, A. M., Gross-Tsur, V., Bashat, D. B., Weinstein, M., Green, Dido, Geva, R., Schertz, M., Fattal-Valevski, A., Artzi, M., Myers, V., Shiran, S., Gordon, A. M., Gross-Tsur, V., and Bashat, D. B.

Abstract

This study investigated patterns of motor brain activation, white matter (WM) integrity of inter- and intrahemispheric connectivity and their associations with hand function in children with unilateral cerebral palsy (CP-U). Fourteen CP-U (mean age 10.6 ± 2.7 years) and 14 typically developing children (TDC) underwent magnetic resonance imaging. CP-U underwent extensive motor evaluation. Pattern of brain activation during a motor task was studied in 12 CP-U and six TDC, by calculating laterality index (LI) and percent activation in the sensorimotor areas (around the central sulcus), and quantifying the activation in the supplementary motor area (SMA). Diffusivity parameters were measured in CP-U and eight other TDC for the corpus callosum (CC), affected and less affected cortico-spinal tracts (CST), and posterior limb of the internal capsule (PLIC). Abnormal patterns of brain activation were detected in areas around the central sulcus in 9/12 CP-U, with bilateral activation and/or reduced percent activation. More activation in areas around the central sulcus of the affected hemisphere was associated with better hand function. CP-U demonstrated more activation in the SMA when moving the affected hand compared to the less affected hand. CP-U displayed reduced WM integrity compared to TDC, in the midbody and splenium of the CC, affected CST and affected PLIC. WM integrity in these tracts was correlated with hand function. While abnormal pattern of brain activation was detected mainly when moving the affected hand, the integrity of the CC was correlated with function of both hands and bimanual skills. This study highlights the importance of interhemispheric connectivity for hand function in CP-U, which may have clinical implications regarding prognosis and management.

Published
2014
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23. Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

Author

Davis, L.K. (Lea), Yu, D. (D.), Keenan, C.L. (Clare), Gamazon, E. (Eric), Konkashbaev, A.I. (Anuar), Derks, E.M. (Eske), Neale, B.M. (Benjamin), Yang, J. (Joanna), Lee, S.H. (Sang Hong), Evans, P., Barr, C.L. (Cathy), Bellodi, L. (Laura), Benarroch, F. (Fortu), Berrio, G.B. (Gabriel Bedoya), Bienvenu, O.J. (Oscar), Bloch, J. (Jocelyne), Blom, R.M. (Rianne), Bruun, R.D. (Ruth), Budman, C.L. (Cathy), Camarena, B. (Beatriz), Campbell, D. (Desmond), Cappi, C. (Carolina), Cardona Silgado, J.C. (Julio), Cath, D. (Daniëlle), Cavallini, M.C. (Maria), Chavira, D.A. (Denise), Chouinard, S., Conti, G. (Giario), Cook, E.H. (Edwin), Coric, V. (Vladimir), Cullen, C., Deforce, D. (Dieter), Delorme, R. (Richard), Dion, Y. (Yves), Edlund, C.K. (Christopher), Egberts, K. (Karin), Falkai, P. (Peter), Fernandez, T.V. (Thomas), Gallagher, P. (Patience), Garrido, H. (Helena), Geller, D. (Daniel), Girard, S.L. (Simon), Grabe, H.J. (Hans Jörgen), Grados, M. (Marco), Greenberg, B.D. (Benjamin), Gross-Tsur, V. (Varda), Haddad, S. (Stephen), Heiman, M.L. (Mark), Hemmings, S.M.J. (Sian), Hounie, A.G. (Ana), Illmann, C. (Cornelia), Jankovic, J. (Joseph), Jenike, M.A. (Michael), Kennedy, J.L., King, R.A., Kremeyer, B. (Barbara), Kurlan, R. (Roger), Lanzagorta, N. (Nuria), Leboyer, M. (Marion), Leckman, J.F., Lennertz, L. (Leonhard), Liu, C. (Chunyu), Lochner, C. (Christine), Lowe, T.L. (Thomas), MacCiardi, F. (Fabio), McCracken, J.T. (James), McGrath, L.M., Mesa Restrepo, S.C. (Sandra), Moessner, R. (Rainald), Morgan, J. (John), Muller, H., Murphy, D.L. (Dennis), Naarden, A.L. (Allan), Ochoa, W.C. (William Cornejo), Ophoff, R.A. (Roel), Osiecki, L. (Lisa), Pakstis, A.J., Pato, C. (Carlos), Piacentini, J. (John), Pittenger, C. (Christopher), Pollak, M.N. (Michael), Rauch, S.L. (Scott), Renner, T.J. (Tobias), Reus, V.I. (Victor), Richter, M.A. (Margaret), Riddle, M.A. (Mark), Robertson, M.M., Romero, R. (Roxana), Rosário, M.C. (Maria), Rosenberg, D. (David), Rouleau, G. (Guy), Ruhrmann, S. (Stephan), Ruiz-Linares, A. (Andres), Sampaio, A.S. (Aline), Samuels, J. (Jonathan), Sandor, P., Sheppard, B. (Brooke), Singer, H.S., Smit, J.H. (Jan), Stein, D.J. (Dan), Strengman, E. (Eric), Tischfield, J.A. (Jay), Valencia Duarte, A.V. (Ana), Vallada, H. (Homero), Nieuwerburgh, F. (Filip) van, Veenstra-Vanderweele, J. (Jeremy), Walitza, S. (Susanne), Wang, Y. (Ying), Wendland, A. (Annika), Westenberg, H.G.M. (Herman G.), Shugart, Y.Y., Miguel, E.C. (Euripedes), McMahon, W.M. (William), Wagner, M. (Michael), Nicolini, H. (Humberto), Posthuma, D. (Danielle), Hanna, G.L. (Gregory), Heutink, P. (Peter), Denys, D.A.J.P. (Damiaan), Arnold, P.D. (Paul), Oostra, B.A. (Ben), Nestadt, G. (Gerald), Freimer, N.B. (Nelson), Pauls, D.L. (David), Wray, N.R. (Naomi), Stewart, S.E., Mathews, C.A., Knowles, J.A. (James), Cox, N.J. (Nancy), Scharf, J.M., Davis, L.K. (Lea), Yu, D. (D.), Keenan, C.L. (Clare), Gamazon, E. (Eric), Konkashbaev, A.I. (Anuar), Derks, E.M. (Eske), Neale, B.M. (Benjamin), Yang, J. (Joanna), Lee, S.H. (Sang Hong), Evans, P., Barr, C.L. (Cathy), Bellodi, L. (Laura), Benarroch, F. (Fortu), Berrio, G.B. (Gabriel Bedoya), Bienvenu, O.J. (Oscar), Bloch, J. (Jocelyne), Blom, R.M. (Rianne), Bruun, R.D. (Ruth), Budman, C.L. (Cathy), Camarena, B. (Beatriz), Campbell, D. (Desmond), Cappi, C. (Carolina), Cardona Silgado, J.C. (Julio), Cath, D. (Daniëlle), Cavallini, M.C. (Maria), Chavira, D.A. (Denise), Chouinard, S., Conti, G. (Giario), Cook, E.H. (Edwin), Coric, V. (Vladimir), Cullen, C., Deforce, D. (Dieter), Delorme, R. (Richard), Dion, Y. (Yves), Edlund, C.K. (Christopher), Egberts, K. (Karin), Falkai, P. (Peter), Fernandez, T.V. (Thomas), Gallagher, P. (Patience), Garrido, H. (Helena), Geller, D. (Daniel), Girard, S.L. (Simon), Grabe, H.J. (Hans Jörgen), Grados, M. (Marco), Greenberg, B.D. (Benjamin), Gross-Tsur, V. (Varda), Haddad, S. (Stephen), Heiman, M.L. (Mark), Hemmings, S.M.J. (Sian), Hounie, A.G. (Ana), Illmann, C. (Cornelia), Jankovic, J. (Joseph), Jenike, M.A. (Michael), Kennedy, J.L., King, R.A., Kremeyer, B. (Barbara), Kurlan, R. (Roger), Lanzagorta, N. (Nuria), Leboyer, M. (Marion), Leckman, J.F., Lennertz, L. (Leonhard), Liu, C. (Chunyu), Lochner, C. (Christine), Lowe, T.L. (Thomas), MacCiardi, F. (Fabio), McCracken, J.T. (James), McGrath, L.M., Mesa Restrepo, S.C. (Sandra), Moessner, R. (Rainald), Morgan, J. (John), Muller, H., Murphy, D.L. (Dennis), Naarden, A.L. (Allan), Ochoa, W.C. (William Cornejo), Ophoff, R.A. (Roel), Osiecki, L. (Lisa), Pakstis, A.J., Pato, C. (Carlos), Piacentini, J. (John), Pittenger, C. (Christopher), Pollak, M.N. (Michael), Rauch, S.L. (Scott), Renner, T.J. (Tobias), Reus, V.I. (Victor), Richter, M.A. (Margaret), Riddle, M.A. (Mark), Robertson, M.M., Romero, R. (Roxana), Rosário, M.C. (Maria), Rosenberg, D. (David), Rouleau, G. (Guy), Ruhrmann, S. (Stephan), Ruiz-Linares, A. (Andres), Sampaio, A.S. (Aline), Samuels, J. (Jonathan), Sandor, P., Sheppard, B. (Brooke), Singer, H.S., Smit, J.H. (Jan), Stein, D.J. (Dan), Strengman, E. (Eric), Tischfield, J.A. (Jay), Valencia Duarte, A.V. (Ana), Vallada, H. (Homero), Nieuwerburgh, F. (Filip) van, Veenstra-Vanderweele, J. (Jeremy), Walitza, S. (Susanne), Wang, Y. (Ying), Wendland, A. (Annika), Westenberg, H.G.M. (Herman G.), Shugart, Y.Y., Miguel, E.C. (Euripedes), McMahon, W.M. (William), Wagner, M. (Michael), Nicolini, H. (Humberto), Posthuma, D. (Danielle), Hanna, G.L. (Gregory), Heutink, P. (Peter), Denys, D.A.J.P. (Damiaan), Arnold, P.D. (Paul), Oostra, B.A. (Ben), Nestadt, G. (Gerald), Freimer, N.B. (Nelson), Pauls, D.L. (David), Wray, N.R. (Naomi), Stewart, S.E., Mathews, C.A., Knowles, J.A. (James), Cox, N.J. (Nancy), and Scharf, J.M.

Abstract

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained b

Published
2013
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24. Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

Author

Davis, LK, Yu, DM, Keenan, CL, Gamazon, ER, Konkashbaev, AI, Derks, EM, Neale, BM, Yang, Jiaqi, Lee, SH, Evans, P, Barr, CL, Bellodi, L, Benarroch, F, Berrio, GB, Bienvenu, OJ, Bloch, MH, Blom, RM, Bruun, RD, Budman, CL, Camarena, B, Campbell, D, Cappi, C, Silgado, JCC, Cath, DC, Cavallini, MC, Chavira, DA, Chouinard, S, Conti, DV, Cook, EH, Coric, V, Cullen, BA, Deforce, D, Delorme, R, Dion, Y, Edlund, CK, Egberts, K, Falkai, P, Fernandez, TV, Gallagher, PJ, Garrido, H, Geller, D, Girard, SL, Grabe, HJ, Grados, MA, Greenberg, BD, Gross-Tsur, V, Haddad, S, Heiman, GA, Hemmings, SMJ, Hounie, AG, Illmann, C, Jankovic, J, Jenike, MA, Kennedy, JL, King, RA, Kremeyer, B, Kurlan, R, Lanzagorta, N, Leboyer, M, Leckman, JF, Lennertz, L, Liu, C, Lochner, C, Lowe, TL, Macciardi, F, McCracken, JT, McGrath, LM, Restrepo, SCM, Moessner, R, Morgan, J, Muller, Heike, Murphy, DL, Naarden, AL, Ochoa, WC, Ophoff, RA, Osiecki, L, Pakstis, AJ, Pato, MT, Pato, CN, Piacentini, J, Pittenger, C, Pollak, Y, Rauch, SL, Renner, TJ, Reus, VI, Richter, MA, Riddle, MA, Robertson, MM, Romero, R, Rosario, MC, Rosenberg, D, Rouleau, GA, Ruhrmann, S, Ruiz-Linares, A, Sampaio, AS, Samuels, J, Sandor, P, Sheppard, B, Singer, HS, Smit, JH, Stein, DJ, Strengman, E, Tischfield, JA, Duarte, AVV, Vallada, H, Van Nieuwerburgh, F, Veenstra-VanderWeele, J, Walitza, S, Wang, Y, Wendland, JR, Westenberg, HGM, Shugart, YY, Miguel, EC, McMahon, W, Wagner, M, Nicolini, H, Posthuma, Daniëlle, Hanna, GL, Heutink, P, Denys, D, Arnold, PD, Oostra, Ben, Nestadt, G, Freimer, NB, Pauls, DL, Wray, NR, Stewart, SE, Mathews, CA, Knowles, JA, Cox, NJ, Scharf, JM, Davis, LK, Yu, DM, Keenan, CL, Gamazon, ER, Konkashbaev, AI, Derks, EM, Neale, BM, Yang, Jiaqi, Lee, SH, Evans, P, Barr, CL, Bellodi, L, Benarroch, F, Berrio, GB, Bienvenu, OJ, Bloch, MH, Blom, RM, Bruun, RD, Budman, CL, Camarena, B, Campbell, D, Cappi, C, Silgado, JCC, Cath, DC, Cavallini, MC, Chavira, DA, Chouinard, S, Conti, DV, Cook, EH, Coric, V, Cullen, BA, Deforce, D, Delorme, R, Dion, Y, Edlund, CK, Egberts, K, Falkai, P, Fernandez, TV, Gallagher, PJ, Garrido, H, Geller, D, Girard, SL, Grabe, HJ, Grados, MA, Greenberg, BD, Gross-Tsur, V, Haddad, S, Heiman, GA, Hemmings, SMJ, Hounie, AG, Illmann, C, Jankovic, J, Jenike, MA, Kennedy, JL, King, RA, Kremeyer, B, Kurlan, R, Lanzagorta, N, Leboyer, M, Leckman, JF, Lennertz, L, Liu, C, Lochner, C, Lowe, TL, Macciardi, F, McCracken, JT, McGrath, LM, Restrepo, SCM, Moessner, R, Morgan, J, Muller, Heike, Murphy, DL, Naarden, AL, Ochoa, WC, Ophoff, RA, Osiecki, L, Pakstis, AJ, Pato, MT, Pato, CN, Piacentini, J, Pittenger, C, Pollak, Y, Rauch, SL, Renner, TJ, Reus, VI, Richter, MA, Riddle, MA, Robertson, MM, Romero, R, Rosario, MC, Rosenberg, D, Rouleau, GA, Ruhrmann, S, Ruiz-Linares, A, Sampaio, AS, Samuels, J, Sandor, P, Sheppard, B, Singer, HS, Smit, JH, Stein, DJ, Strengman, E, Tischfield, JA, Duarte, AVV, Vallada, H, Van Nieuwerburgh, F, Veenstra-VanderWeele, J, Walitza, S, Wang, Y, Wendland, JR, Westenberg, HGM, Shugart, YY, Miguel, EC, McMahon, W, Wagner, M, Nicolini, H, Posthuma, Daniëlle, Hanna, GL, Heutink, P, Denys, D, Arnold, PD, Oostra, Ben, Nestadt, G, Freimer, NB, Pauls, DL, Wray, NR, Stewart, SE, Mathews, CA, Knowles, JA, Cox, NJ, and Scharf, JM

Abstract

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.

Published
2013

25. Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture

Author

Davis, L. K., Yu, D., Keenan, C. L., Gamazon, E. R., Konkashbaev, A. I., Derks, E. M., Neale, B. M., Yang, J., Lee, S. H., Evans, P., Barr, C. L., Bellodi, L., Benarroch, F., Berrio, G. B., Bienvenu, O. J., Bloch, M. H., Blom, R. M., Bruun, R. D., Budman, C. L., Camarena, B., Campbell, D., Cappi, C., Cardona Silgado, J. C., Cath, D. C., Cavallini, M. C., Chavira, D. A., Chouinard, S., Conti, D. V., Cook, E. H., Coric, V., Cullen, B. A., Deforce, D., Delorme, R., Dion, Y., Edlund, C. K., Egberts, K., Falkai, P., Fernandez, T. V., Gallagher, P. J., Garrido, H., Geller, D., Girard, Simon, Grabe, H. J., Grados, M. A., Greenberg, B. D., Gross-Tsur, V., Haddad, S., Heiman, G. A., Hemmings, S. M.J., Hounie, A. G., Illmann, C., Jankovic, J., Jenike, M. A., Kennedy, J. L., King, R. A., Kremeyer, B., Kurlan, R., Lanzagorta, N., Leboyer, M., Leckman, J. F., Lennertz, L., Liu, C., Lochner, C., Lowe, T. L., Macciardi, F., McCracken, J. T., McGrath, L. M., Mesa Restrepo, S. C., Moessner, R., Morgan, J., Muller, H., Murphy, D. L., Naarden, A. L., Ochoa, W. C., Ophoff, R. A., Osiecki, L., Pakstis, A. J., Pato, M. T., Pato, C. N., Piacentini, J., Pittenger, C., Pollak, Y., Rauch, S. L., Renner, T. J., Reus, V. I., Richter, M. A., Riddle, M. A., Robertson, M. M., Romero, R., Rosario, M. C., Rosenberg, D., Rouleau, G. A., Ruhrmann, S., Ruiz-Linares, A., Sampaio, A. S., Samuels, J., Sandor, P., Sheppard, B., Singer, H. S., Smit, J. H., Stein, D. J., Strengman, E., Tischfield, J. A., Valencia Duarte, A. V., Vallada, H., Van Nieuwerburgh, F., Veenstra-Vanderweele, J., Walitza, S., Wang, Y., Wendland, J. R., Westenberg, H. G.M., Shugart, Y. Y., Miguel, E. C., McMahon, W., Wagner, M., Nicolini, H., Posthuma, D., Hanna, G. L., Heutink, P., Denys, D., Arnold, P. D., Oostra, B. A., Nestadt, G., Freimer, N. B., Pauls, D. L., Wray, N. R., Stewart, S. E., Mathews, C. A., Knowles, J. A., Cox, N. J., Scharf, J. M., Davis, L. K., Yu, D., Keenan, C. L., Gamazon, E. R., Konkashbaev, A. I., Derks, E. M., Neale, B. M., Yang, J., Lee, S. H., Evans, P., Barr, C. L., Bellodi, L., Benarroch, F., Berrio, G. B., Bienvenu, O. J., Bloch, M. H., Blom, R. M., Bruun, R. D., Budman, C. L., Camarena, B., Campbell, D., Cappi, C., Cardona Silgado, J. C., Cath, D. C., Cavallini, M. C., Chavira, D. A., Chouinard, S., Conti, D. V., Cook, E. H., Coric, V., Cullen, B. A., Deforce, D., Delorme, R., Dion, Y., Edlund, C. K., Egberts, K., Falkai, P., Fernandez, T. V., Gallagher, P. J., Garrido, H., Geller, D., Girard, Simon, Grabe, H. J., Grados, M. A., Greenberg, B. D., Gross-Tsur, V., Haddad, S., Heiman, G. A., Hemmings, S. M.J., Hounie, A. G., Illmann, C., Jankovic, J., Jenike, M. A., Kennedy, J. L., King, R. A., Kremeyer, B., Kurlan, R., Lanzagorta, N., Leboyer, M., Leckman, J. F., Lennertz, L., Liu, C., Lochner, C., Lowe, T. L., Macciardi, F., McCracken, J. T., McGrath, L. M., Mesa Restrepo, S. C., Moessner, R., Morgan, J., Muller, H., Murphy, D. L., Naarden, A. L., Ochoa, W. C., Ophoff, R. A., Osiecki, L., Pakstis, A. J., Pato, M. T., Pato, C. N., Piacentini, J., Pittenger, C., Pollak, Y., Rauch, S. L., Renner, T. J., Reus, V. I., Richter, M. A., Riddle, M. A., Robertson, M. M., Romero, R., Rosario, M. C., Rosenberg, D., Rouleau, G. A., Ruhrmann, S., Ruiz-Linares, A., Sampaio, A. S., Samuels, J., Sandor, P., Sheppard, B., Singer, H. S., Smit, J. H., Stein, D. J., Strengman, E., Tischfield, J. A., Valencia Duarte, A. V., Vallada, H., Van Nieuwerburgh, F., Veenstra-Vanderweele, J., Walitza, S., Wang, Y., Wendland, J. R., Westenberg, H. G.M., Shugart, Y. Y., Miguel, E. C., McMahon, W., Wagner, M., Nicolini, H., Posthuma, D., Hanna, G. L., Heutink, P., Denys, D., Arnold, P. D., Oostra, B. A., Nestadt, G., Freimer, N. B., Pauls, D. L., Wray, N. R., Stewart, S. E., Mathews, C. A., Knowles, J. A., Cox, N. J., and Scharf, J. M.

Abstract

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.

Published
2013

27. Posterior quadrantic dysplasia or hemi-hemimegalencephaly: a characteristic brain malformation

Author

UCL - MD/FARM - Ecole de pharmacie, D'Agostino, M. D., Bastos, A., Piras, C., Bernasconi, A., Grisar, T., Gross Tsur, V., Snipes, J., Juhasz, C., Chugani, H., Guerrini, R., Cross, H., Andermann, E., Dubeau, F., Montes, J., Olivier, Aurélie, Andermann, F., UCL - MD/FARM - Ecole de pharmacie, D'Agostino, M. D., Bastos, A., Piras, C., Bernasconi, A., Grisar, T., Gross Tsur, V., Snipes, J., Juhasz, C., Chugani, H., Guerrini, R., Cross, H., Andermann, E., Dubeau, F., Montes, J., Olivier, Aurélie, and Andermann, F.

Abstract

Introduction: Posterior quadrantic dysplasia (PQD), a developmental malformation involving the temporal, parietal, and occipital lobes of one cerebral hemisphere, leads to intractable epilepsy. Objective: To characterize the clinical features of 19 patients with PQD and analyze the postsurgical outcome of those who underwent resection of dysplastic tissue. Methods: The extent and nature of the malformation were primarily assessed with high-resolution brain imaging. Fourteen patients underwent complete or partial temporoparieto-occipital resection or temporal resection associated with parieto-occipital disconnection. Postoperative follow-up period ranged from 8 months to 7 years. The authors used the Engel classification for postoperative outcome. Results: All patients were sporadic. Clinical features included infantile spasms, partial seizures, mental retardation, mild hemiparesis, and visual field defects. Neuroimaging localized the malformation within the posterior cerebral quadrant contralateral to the neurologic deficit and demonstrated hemihemimegalencephaly in 14 of 19 patients and multilobar cortical dysplasia in 5 of 19 patients. The authors observed class I outcome in six patients. Two patients had class II and four patients had class III outcome. Class IV outcome was seen in two patients. After surgery, two patients developed mild hemiparesis, and two developed a visual field defect. Conclusions: Widespread cortical dysplasia is more frequent in the posterior quadrant. In our series, posterior quadrantic dysplasia represents either hemi-hemimegalencephaly or multilobar cortical dysplasia. Individuals with posterior quadrantic dysplasia share a spectrum of clinical features. The intractable epilepsy in these patients may be alleviated by a large quadrantic temporoparieto-occipital resection.

Published
2004

43. Locus of control, perceived parenting style, and symptoms of anxiety and depression in children with Tourette's syndrome.

Author

Cohen E, Sade M, Benarroch F, Pollak Y, and Gross-Tsur V

Abstract

Aim: This study explored the contribution of two psychosocial factors, locus of control (LOC) and perceived parenting style, to symptoms of internalizing disorders in children with Tourette syndrome (TS). This contribution was further evaluated in relation to TS severity. Methods: Sixty-five children (53 boys, 12 girls) ages 9.0-16.9 years, of normal intelligence, completed questionnaires evaluating their depression and anxiety symptoms, LOC, and maternal parenting style. Their mothers rated TS severity, determined by tic severity, symptoms of attention-deficit hypreactivity disorder (ADHD) and obsessive compulsive symptoms (OCS). Results: Higher rates of symptoms of anxiety and depression were associated with a more external LOC and a more rejecting and controlling parenting style. Additionally, depression correlated significantly with tic severity, ADHD and OCS, whereas anxiety correlated only with ADHD symptoms and OCS, but not with tics. Regression analyses showed that LOC, OCS and ADHD symptoms each significantly contributed to predicting anxiety level, whereas LOC and ADHD symptoms significantly contributed to predicting depression symptoms. Conclusions: Rates of symptoms of anxiety and depression in children with TS are markedly influenced by psychosocial factors, extending beyond the influence of ADHD and OCD, both common comorbid disorders in TS. An internal LOC, which is associated with an accepting and autonomy-granting parenting style, appears to be a protective factor against anxiety and depression. [ABSTRACT FROM AUTHOR]

Published
2008
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48. Persistence of developmental dyscalculia: What counts?

Author

Shalev, R.S., Manor, O., Auerbach, J., and Gross-Tsur, V.

Abstract

Objective: To study the natural history of developmental dyscalculia (DC), a specific learning disability affecting approximately 5% of the normal school age population and to identify factors that contribute to persistence. Study design: Of a cohort of 3029 fourth-grade students, 185 children were classified as having DC; 140 participated in phase 1 in which they underwent IQ testing; arithmetic, reading, and writing evaluations; and an assessment for attention-deficit/hyperactivity disorder over a 3-year period. Three years later (phase 2), 88% of the children (123 of 140) were retested. Results: The arithmetic scores of 95% of the 123 children with DC fell within the lowest quartile for their class. At phase 2, 47% (57 of 123) of the children were reclassified as having persistent DC, scoring in the lowest 5% for their age group (13 to 14 years old). Factors significantly associated with persistence of DC in a multivariate model were severity of the arithmetic disorder and arithmetic problems in siblings of the probands. Factors that were not associated with persistence included socioeconomic status, gender, the presence of another learning disability, and educational interventions. Conclusions: The outcome of DC is similar to that of other learning disabilities, with a persisting course in almost half of affected children; the remainder continue to perform poorly in arithmetic. The ultimate outcome of children with dyscalculia and the effect on education, employment, and psychologic well-being have yet to be determined. (J Pediatr 1998;133:358-62)

Published
1998
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50. Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette's Syndrome and OCD

Author

Mary M. Robertson, Peter Heutink, Leonhard Lennertz, Victor I. Reus, John Hardy, Mark A. Riddle, Beatriz Camarena, Helena Garrido, Robert A. King, Simon Girard, Christine Lochner, Michael H. Bloch, Patrick Evans, Anuar Konkashbaev, Jack Samuels, Priya Moorjani, Chiara Sabatti, Andrew J. Pakstis, Ying Wang, O. Joseph Bienvenu, Richard Delorme, David L. Pauls, Rainald Moessner, Gary A. Heiman, Daniel A. Geller, Marco A. Grados, Eric R. Gamazon, John Piacentini, Dan J. Stein, William Cornejo Ochoa, Maria Conceição do Rosário, Karin Egberts, Thomas L. Lowe, Christopher K. Edlund, Jan Smit, Christopher Pittenger, Denise A. Chavira, Marion Leboyer, Homero Vallada, Sandra Catalina Mesa Restrepo, Jacquelyn Crane, Donald W. Black, David V. Conti, Paul Sandor, Humberto Nicolini, Lisa Osiecki, Jeremy Veenstra-VanderWeele, Catherine Mayerfeld, Danielle Posthuma, Edna Grünblatt, Carolina Cappi, Robert B. Weiss, Cristina Barlassina, Sara Lupoli, Chunyu Liu, Sian M. J. Hemmings, Ben A. Oostra, D. Denys, Susanne Walitza, Lea K. Davis, Stephen A. Haddad, Luis Diego Herrera, Jubel Morgan, Hans Joergen Grabe, Benjamin M. Neale, Thomas V. Fernandez, Yehuda Pollak, Roel A. Ophoff, Gerald Nestadt, Harvey S. Singer, Stephan Ruhrmann, Bernadette Cullen, Michael Wagner, Nuria Lanzagorta, Jeremiah M. Scharf, Cathy L. Budman, Ruth D. Bruun, R. Kurlan, Valsama Eapen, Jesen Fagerness, Desmond Campbell, James L. Kennedy, Carlos N. Pato, Nancy J. Cox, Pieter J. Hoekstra, Joseph Jankovic, Cathy L. Barr, Peter Falkai, Donald L. Gilbert, Fortu Benarroch, Dianne M. Hezel, Maria Cristina Cavallini, Brooke Sheppard, Fabio Macciardi, William M. McMahon, Laura Bellodi, Maurizio Turiel, Wolfgang Maier, Varda Gross-Tsur, Helena Brentani, Dongmei Yu, Danielle C. Cath, Ana V. Valencia Duarte, Eduardo Fournier, James A. Knowles, Tobias J. Renner, Erika L. Nurmi, Guy A. Rouleau, Benjamin D. Greenberg, Nelson B. Freimer, Shaun Purcell, Patience J. Gallagher, Roxana Romero, Gregory L. Hanna, Paolo Manunta, Edwin H. Cook, Michele T. Pato, Sylvain Chouinard, Scott L. Rauch, James T. McCracken, Gloria Gerber, Carol A. Mathews, Jens R. Wendland, Sampath Arepalli, Dennis L. Murphy, Daniele Cusi, Barbara Kremeyer, Vladimir Coric, Aline S. Sampaio, Erika Salvi, Julio C. Cardona Silgado, Cornelia Illmann, James F. Leckman, Euripedes Constantino Miguel, H. Müller, Yin Yao Shugart, Eric Strengman, Ana Gabriela Hounie, Michael E. Weale, Gabriel Bedoya Berrió, Margaret A. Richter, Maurizio Marconi, Allan L. Naarden, Michael A. Jenike, M.R. Cookson, David R. Rosenberg, Andres Ruiz-Linares, S. Evelyn Stewart, Paul D. Arnold, H.G.M. Westenberg, Yves Dion, Jay A. Tischfield, Eske M. Derks, Lauren M. McGrath, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Yu, D., Mathews, C. A., Scharf, J. M., Neale, B. M., Davis, L. K., Gamazon, E. R., Derks, E. M., Evans, P., Edlund, C. K., Crane, J., Fagerness, J. A., Osiecki, L., Gallagher, P., Gerber, G., Haddad, S., Illmann, C., Mcgrath, L. M., Mayerfeld, C., Arepalli, S., Barlassina, C., Barr, C. L., Bellodi, L., Benarroch, F., Berrio, G. B., Bienvenu, O. J., Black, D., Bloch, M. H., Brentani, H., Bruun, R. D., Budman, C. L., Camarena, B., Campbell, D. D., Cappi, C., Cardona Silgado, J. C., Cavallini, M. C., Chavira, D. A., Chouinard, S., Cook, E. H., Cookson, M. R., Coric, V., Cullen, B., Cusi, D., Delorme, R., Denys, D., Dion, Y., Eapen, V., Egberts, K., Falkai, P., Fernandez, T., Fournier, E., Garrido, H., Geller, D., Gilbert, D., Girard, S. L., Grabe, H. J., Grados, M. A., Greenberg, B. D., Gross-Tsur, V., Grunblatt, E., Hardy, J., Heiman, G. A., Hemmings, S. M. J., Herrera, L. D., Hezel, D. M., Hoekstra, P. J., Jankovic, J., Kennedy, J. L., King, R. A., Konkashbaev, A. I., Kremeyer, B., Kurlan, R., Lanzagorta, N., Leboyer, M., Leckman, J. F., Lennertz, L., Liu, C., Lochner, C., Lowe, T. L., Lupoli, S., Macciardi, F., Maier, W., Manunta, P., Marconi, M., Mccracken, J. T., Mesa Restrepo, S. C., Moessner, R., Moorjani, P., Morgan, J., Muller, H., Murphy, D. L., Naarden, A. L., Ochoa, W. C., Ophoff, R. A., Pakstis, A. J., Pato, M. T., Pato, C. N., Piacentini, J., Pittenger, C., Pollak, Y., Rauch, S. L., Renner, T., Reus, V. I., Richter, M. A., Riddle, M. A., Robertson, M. M., Romero, R., Rosario, M. C., Rosenberg, D., Ruhrmann, S., Sabatti, C., Salvi, E., Sampaio, A. S., Samuels, J., Sandor, P., Service, S. K., Sheppard, B., Singer, H. S., Smit, J. H., Stein, D. J., Strengman, E., Tischfield, J. A., Turiel, M., Valencia Duarte, A. V., Vallada, H., Veenstra-VanderWeele, J., Walitza, S., Walkup, J., Wang, Y., Weale, M., Weiss, R., Wendland, J. R., Westenberg, H. G. M., Yao, Y., Hounie, A. G., Miguel, E. C., Nicolini, H., Wagner, M., Ruiz-Linares, A., Cath, D. C., Mcmahon, W., Posthuma, D., Oostra, B. A., Nestadt, G., Rouleau, G. A., Purcell, S., Jenike, M. A., Heutink, P., Hanna, G. L., Conti, D. V., Arnold, P. D., Freimer, N., Stewart, S. E., Knowles, J. A., Cox, N. J., Pauls, D. L., Netherlands Institute for Neuroscience (NIN), Sub String Theory Cosmology and ElemPart, Leerstoel Hout, Experimental psychopathology, Psychiatry, Human genetics, NCA - Neurobiology of mental health, EMGO - Mental health, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Other departments, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Adult Psychiatry, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, and EMGO+ - Mental Health

Subjects
Adult, Male, Obsessive-Compulsive Disorder, diagnosis [Tourette Syndrome], Tics, Single-nucleotide polymorphism, Genome-wide association study, Comorbidity, VARIANTS, Tourette syndrome, Polymorphism, Single Nucleotide, Severity of Illness Index, ASSOCIATION SCANS, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Polymorphism (computer science), Severity of illness, mental disorders, medicine, TICS, Humans, ddc:610, Polymorphism, 030304 developmental biology, Genetics, Psychiatric Status Rating Scales, genetics [Obsessive-Compulsive Disorder], 0303 health sciences, GENERALIST GENES, Single Nucleotide, OBSESSIVE-COMPULSIVE DISORDER, epidemiology [Tourette Syndrome], medicine.disease, Genetic architecture, Psychiatry and Mental health, genetics [Tourette Syndrome], Female, epidemiology [Obsessive-Compulsive Disorder], Psychology, 030217 neurology & neurosurgery, diagnosis [Obsessive-Compulsive Disorder], Genome-Wide Association Study, Tourette Syndrome
Abstract

Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.Method: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders Polygenic score analyses identified a significant polygenic component for OCD (p=2x10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).Conclusions: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring burette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Published
2015

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