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182 results on '"Vorstman J"'

1. P249: Gaps in the phenotype descriptions of ultra-rare genetic conditions: Review and multi-center consensus reporting guidelines

Author

AlMail, A, Jamjoom, A, Pan, A, Feng, A, Chau, V, D'Gama, A, Howell, K, Yan Liang, NS, McTague, A, Poduri, A, Wiltrout, K, Bassett, A, Christodoulou, J, Dupuis, L, Gill, P, Levy, T, Siper, P, Stark, Z, Vorstman, J, Diskin, C, Jewitt, N, Baribeau, D, Costain, G, AlMail, A, Jamjoom, A, Pan, A, Feng, A, Chau, V, D'Gama, A, Howell, K, Yan Liang, NS, McTague, A, Poduri, A, Wiltrout, K, Bassett, A, Christodoulou, J, Dupuis, L, Gill, P, Levy, T, Siper, P, Stark, Z, Vorstman, J, Diskin, C, Jewitt, N, Baribeau, D, and Costain, G

Published
2024

2. Copy-number variation of the glucose transporter gene SLC2A3 and congenital heart defects in the 22q11.2 deletion syndrome

Author

Mlynarski, EE, Sheridan, MB, Xie, M, Guo, T, Racedo, SE, McDonald-Mcginn, DM, Gai, X, Chow, EWC, Vorstman, J, Swillen, A, Devriendt, K, Breckpot, J, Digilio, MC, Marino, B, Dallapiccola, B, Philip, N, Simon, TJ, Roberts, AE, Piotrowicz, M, Bearden, CE, Eliez, S, Gothelf, D, Coleman, K, Kates, WR, Devoto, M, Zackai, E, Heine-Suñer, D, Shaikh, TH, Bassett, AS, Goldmuntz, E, Morrow, BE, and Emanuel, BS

Subjects
Genetics & Heredity, Biological Sciences, Medical and Health Sciences
Abstract

The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS) is the most common microdeletion syndrome and the phenotypic presentation is highly variable. Approximately 65% of individuals with 22q11DS have a congenital heart defect (CHD), mostly of the conotruncal type, and/or an aortic arch defect. The etiology of this phenotypic variability is not currently known. We hypothesized that copy-number variants (CNVs) outside the 22q11.2 deleted region might increase the risk of being born with a CHD in this sensitized population. Genotyping with Affymetrix SNP Array 6.0 was performed on two groups of subjects with 22q11DS separated by time of ascertainment and processing. CNV analysis was completed on a total of 949 subjects (cohort 1, n = 562; cohort 2, n = 387), 603 with CHDs (cohort 1, n = 363; cohort 2, n = 240) and 346 with normal cardiac anatomy (cohort 1, n = 199; cohort 2, n = 147). Our analysis revealed that a duplication of SLC2A3 was the most frequent CNV identified in the first cohort. It was present in 18 subjects with CHDs and 1 subject without (p = 3.12 × 10-3, two-tailed Fisher's exact test). In the second cohort, the SLC2A3 duplication was also significantly enriched in subjects with CHDs (p = 3.30 × 10-2, two-tailed Fisher's exact test). The SLC2A3 duplication was the most frequent CNV detected and the only significant finding in our combined analysis (p = 2.68 × 10-4, two-tailed Fisher's exact test), indicating that the SLC2A3 duplication might serve as a genetic modifier of CHDs and/or aortic arch anomalies in individuals with 22q11DS.

Published
2015

5. Barriers to genetic testing in clinical psychiatry and ways to overcome them: from clinicians' attitudes to sociocultural differences between patients across the globe

Author

Pinzón-Espinosa, J., Horst, M. van der, Zinkstok, J.R., Austin, J., Aalfs, C., Batalla, A., Sullivan, P., Vorstman, J., Luykx, J.J., Pinzón-Espinosa, J., Horst, M. van der, Zinkstok, J.R., Austin, J., Aalfs, C., Batalla, A., Sullivan, P., Vorstman, J., and Luykx, J.J.

Abstract

Item does not contain fulltext, Genetic testing has evolved rapidly over recent years and new developments have the potential to provide insights that could improve the ability to diagnose, treat, and prevent diseases. Information obtained through genetic testing has proven useful in other specialties, such as cardiology and oncology. Nonetheless, a range of barriers impedes techniques, such as whole-exome or whole-genome sequencing, pharmacogenomics, and polygenic risk scoring, from being implemented in psychiatric practice. These barriers may be procedural (e.g., limitations in extrapolating results to the individual level), economic (e.g., perceived relatively elevated costs precluding insurance coverage), or related to clinicians' knowledge, attitudes, and practices (e.g., perceived unfavorable cost-effectiveness, insufficient understanding of probability statistics, and concerns regarding genetic counseling). Additionally, several ethical concerns may arise (e.g., increased stigma and discrimination through exclusion from health insurance). Here, we provide an overview of potential barriers for the implementation of genetic testing in psychiatry, as well as an in-depth discussion of strategies to address these challenges.

Published
2022

6. A normative chart for cognitive development in a genetically selected population

Author

Fiksinski, A.M., Bearden, C.E., Bassett, A.S., Kahn, R.S., Zinkstok, J.R., Hooper, S.R., Tempelaar, W., McDonald-McGinn, D., Swillen, A., Emanuel, B., Morrow, B., Gur, R., Chow, E., Bree, M. van, Vermeesch, J., Warren, S., Owen, M., Amelsvoort, T. van, Eliez, S., Gothelf, D., Arango, C., Kates, W., Simon, T., Murphy, K., Repetto, G., Suner, D.H., Vicari, S., Cubells, J., Armando, M., Philip, N., Campbell, L., Garcia-Minaur, S., Schneider, M., Shashi, V., Vorstman, J., Breetvelt, E.J., Fiksinski, A.M., Bearden, C.E., Bassett, A.S., Kahn, R.S., Zinkstok, J.R., Hooper, S.R., Tempelaar, W., McDonald-McGinn, D., Swillen, A., Emanuel, B., Morrow, B., Gur, R., Chow, E., Bree, M. van, Vermeesch, J., Warren, S., Owen, M., Amelsvoort, T. van, Eliez, S., Gothelf, D., Arango, C., Kates, W., Simon, T., Murphy, K., Repetto, G., Suner, D.H., Vicari, S., Cubells, J., Armando, M., Philip, N., Campbell, L., Garcia-Minaur, S., Schneider, M., Shashi, V., Vorstman, J., and Breetvelt, E.J.

Abstract

Item does not contain fulltext, Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQ-scores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p < 0.01). Our findings suggest that using variant-specific normative IQ data significantly reduces required sample size in a research context, and may facilitate a more clinically informative interpretation of IQ data. This approach allows identification of individuals that deviate from their expected, variant-specific, trajectory. This group may be at increased risk for comorbid conditions, such as schizophrenia in the case of 22q11DS.

Published
2022

8. Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome

Author

Davies, R. W., Fiksinski, A. M., Breetvelt, E. J., Williams, N. M., Hooper, S. R., Monfeuga, T., Bassett, A. S., Owen, M. J., Gur, R. E., Morrow, B. E., McDonald-McGinn, D. M., Swillen, A., Chow, E. W. C., van den Bree, M., Emanuel, B. S., Vermeesch, J. R., van Amelsvoort, T., Arango, C., Armando, M., Campbell, L. E., Cubells, J. F., Eliez, S., Garcia-Minaur, S., Gothelf, D., Kates, W. R., Murphy, K. C., Murphy, C. M., Murphy, D. G., Philip, N., Repetto, G. M., Shashi, V., Simon, T. J., Suner, D. H., Vicari, Stefano, Scherer, S. W., Epstein, M. P., Warren, S. T., Morrison, S., Chawner, S., Vingerhoets, C., Breckpot, J., Vergaelen, E., Vogels, A., Monks, S., Prasad, S. E., Sandini, C., Schneider, M., Maeder, J., Fraguas, D., Evers, R., Tassone, F., Morey-Canyelles, J., Ousley, O. Y., Antshel, K. M., Fremont, W., Fritsch, R., Ornstein, C., Daly, E. M., Costain, G. A., Boot, E., Heung, T., Crowley, T. B., Zackai, E. H., Calkins, M. E., Gur, R. C., Mccabe, K. L., Busa, T., Schoch, K., Pontillo, M., Duijff, S. N., Kahn, R. S., Houben, Mariasofia, Kushan, L., Jalbrzikowski, M., Carmel, M., Mekori-Domachevsky, E., Michaelovsky, E., Weinberger, R., Bearden, C. E., Vorstman, J. A. S., Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, and MUMC+: MA Med Staf Spec Psychiatrie (9)

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, [SDV]Life Sciences [q-bio], INTELLIGENCE, Medical and Health Sciences, Cohort Studies, ddc:616.89, 0302 clinical medicine, Borderline intellectual functioning, Risk Factors, Intellectual disability, 2.1 Biological and endogenous factors, PREMORBID IQ, Cognitive decline, Aetiology, Child, ComputingMilieux_MISCELLANEOUS, Intelligence quotient, ABNORMALITIES, General Medicine, Middle Aged, Serious Mental Illness, Mental Health, Phenotype, Schizophrenia, 030220 oncology & carcinogenesis, Child, Preschool, Cohort, Female, Clinical psychology, Adult, Psychosis, Adolescent, Immunology, behavioral disciplines and activities, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Young Adult, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, PSYCHOSIS, Clinical Research, Intellectual Disability, Genetic variation, Behavioral and Social Science, mental disorders, medicine, Genetics, DiGeorge Syndrome, Humans, Cognitive Dysfunction, Preschool, METAANALYSIS, International 22q11.2 Brain and Behavior Consortium, Aged, DECLINE, reliability, business.industry, Prevention, cognitive-development, Genetic Variation, PERFORMANCE, medicine.disease, Brain Disorders, schizophrenia, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, business
Abstract

The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.Polygenic risk scores are nearing a level of differentiation required for their clinical utility in risk prediction in populations with high-risk rare pathogenic genetic variants.

Published
2020
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11. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Author

Cleynen, I., Engchuan, W., Hestand, M. S., Heung, T., Holleman, A. M., Johnston, H. R., Monfeuga, T., McDonald-McGinn, D. M., Gur, R. E., Morrow, B. E., Swillen, A., Vorstman, J. A. S., Bearden, C. E., Chow, E. W. C., van den Bree, M., Emanuel, B. S., Vermeesch, J. R., Warren, S. T., Owen, M. J., Chopra, P., Cutler, D. J., Duncan, R., Kotlar, A. V., Mulle, J. G., Voss, A. J., Zwick, M. E., Diacou, A., Golden, A., Guo, T., Lin, J. -R., Wang, T., Zhang, Z., Zhao, Yu Yang, Marshall, C., Merico, D., Jin, A., Lilley, B., Salmons, H. I., Tran, O., Holmans, P., Pardinas, A., Walters, J. T. R., Demaerel, W., Boot, E., Butcher, N. J., Costain, G. A., Lowther, C., Evers, R., van Amelsvoort, T. A. M. J., van Duin, E., Vingerhoets, C., Breckpot, J., Devriendt, K., Vergaelen, E., Vogels, A., Crowley, T. B., Mcginn, D. E., Moss, E. M., Sharkus, R. J., Unolt, M., Zackai, E. H., Calkins, M. E., Gallagher, R. S., Gur, R. C., Tang, S. X., Fritsch, R., Ornstein, C., Repetto, G. M., Breetvelt, E., Duijff, S. N., Fiksinski, A., Moss, H., Niarchou, M., Murphy, K. C., Prasad, S. E., Daly, E. M., Gudbrandsen, M., Murphy, C. M., Murphy, D. G., Buzzanca, A., Fabio, F. D., Digilio, M. C., Pontillo, M., Marino, B., Vicari, Stefano, Coleman, K., Cubells, J. F., Ousley, O. Y., Carmel, M., Gothelf, D., Mekori-Domachevsky, E., Michaelovsky, E., Weinberger, R., Weizman, A., Kushan, L., Jalbrzikowski, M., Armando, M., Eliez, S., Sandini, C., Schneider, M., Bena, F. S., Antshel, K. M., Fremont, W., Kates, W. R., Belzeaux, R., Busa, T., Philip, N., Campbell, L. E., Mccabe, K. L., Hooper, S. R., Schoch, K., Shashi, V., Simon, T. J., Tassone, F., Arango, C., Fraguas, D., Garcia-Minaur, S., Morey-Canyelles, J., Rosell, J., Suner, D. H., Raventos-Simic, J., Epstein, M. P., Williams, N. M., Bassett, A. S., Zhao Y., Vicari S. (ORCID:0000-0002-5395-2262), Cleynen, I., Engchuan, W., Hestand, M. S., Heung, T., Holleman, A. M., Johnston, H. R., Monfeuga, T., McDonald-McGinn, D. M., Gur, R. E., Morrow, B. E., Swillen, A., Vorstman, J. A. S., Bearden, C. E., Chow, E. W. C., van den Bree, M., Emanuel, B. S., Vermeesch, J. R., Warren, S. T., Owen, M. J., Chopra, P., Cutler, D. J., Duncan, R., Kotlar, A. V., Mulle, J. G., Voss, A. J., Zwick, M. E., Diacou, A., Golden, A., Guo, T., Lin, J. -R., Wang, T., Zhang, Z., Zhao, Yu Yang, Marshall, C., Merico, D., Jin, A., Lilley, B., Salmons, H. I., Tran, O., Holmans, P., Pardinas, A., Walters, J. T. R., Demaerel, W., Boot, E., Butcher, N. J., Costain, G. A., Lowther, C., Evers, R., van Amelsvoort, T. A. M. J., van Duin, E., Vingerhoets, C., Breckpot, J., Devriendt, K., Vergaelen, E., Vogels, A., Crowley, T. B., Mcginn, D. E., Moss, E. M., Sharkus, R. J., Unolt, M., Zackai, E. H., Calkins, M. E., Gallagher, R. S., Gur, R. C., Tang, S. X., Fritsch, R., Ornstein, C., Repetto, G. M., Breetvelt, E., Duijff, S. N., Fiksinski, A., Moss, H., Niarchou, M., Murphy, K. C., Prasad, S. E., Daly, E. M., Gudbrandsen, M., Murphy, C. M., Murphy, D. G., Buzzanca, A., Fabio, F. D., Digilio, M. C., Pontillo, M., Marino, B., Vicari, Stefano, Coleman, K., Cubells, J. F., Ousley, O. Y., Carmel, M., Gothelf, D., Mekori-Domachevsky, E., Michaelovsky, E., Weinberger, R., Weizman, A., Kushan, L., Jalbrzikowski, M., Armando, M., Eliez, S., Sandini, C., Schneider, M., Bena, F. S., Antshel, K. M., Fremont, W., Kates, W. R., Belzeaux, R., Busa, T., Philip, N., Campbell, L. E., Mccabe, K. L., Hooper, S. R., Schoch, K., Shashi, V., Simon, T. J., Tassone, F., Arango, C., Fraguas, D., Garcia-Minaur, S., Morey-Canyelles, J., Rosell, J., Suner, D. H., Raventos-Simic, J., Epstein, M. P., Williams, N. M., Bassett, A. S., Zhao Y., and Vicari S. (ORCID:0000-0002-5395-2262)

Abstract

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

Published
2020

18. Social brain, social dysfunction and social withdrawal

Author

Porcelli, S., Wee, N.J.A. van der, Werff, S. van der, Aghajani, M., Glennon, J.C., Heukelum, S. van, Mogavero, F., Lobo, A., Olivera, F.J., Lobo, E., Posadas, M., Dukart, J., Kozak, R., Arce, E., Ikram, A., Vorstman, J., Bilderbeck, A., Saris, I., Kas, M.J., Serretti, A., Porcelli, S., Wee, N.J.A. van der, Werff, S. van der, Aghajani, M., Glennon, J.C., Heukelum, S. van, Mogavero, F., Lobo, A., Olivera, F.J., Lobo, E., Posadas, M., Dukart, J., Kozak, R., Arce, E., Ikram, A., Vorstman, J., Bilderbeck, A., Saris, I., Kas, M.J., and Serretti, A.

Abstract

Contains fulltext : 204838.pdf (publisher's version ) (Open Access), The human social brain is complex. Current knowledge fails to define the neurobiological processes underlying social behaviour involving the (patho-) physiological mechanisms that link system-level phenomena to the multiple hierarchies of brain function. Unfortunately, such a high complexity may also be associated with a high susceptibility to several pathogenic interventions. Consistently, social deficits sometimes represent the first signs of a number of neuropsychiatric disorders including schizophrenia (SCZ), Alzheimer's disease (AD) and major depressive disorder (MDD) which leads to a progressive social dysfunction. In the present review we summarize present knowledge linking neurobiological substrates sustaining social functioning, social dysfunction and social withdrawal in major psychiatric disorders. Interestingly, AD, SCZ, and MDD affect the social brain in similar ways. Thus, social dysfunction and its most evident clinical expression (i.e., social withdrawal) may represent an innovative transdiagnostic domain, with the potential of being an independent entity in terms of biological roots, with the perspective of targeted interventions.

Published
2019

20. Neurocognition and adaptive functioning in a genetic high risk model of schizophrenia

Author

Onderzoek, Onderzoeksgroep 11, Brain, Fiksinski, A. M., Breetvelt, E. J., Lee, Y. J., Boot, E., Butcher, N., Palmer, L., Chow, E. W.C., Kahn, R. S., Vorstman, J. A.S., Bassett, A. S., Onderzoek, Onderzoeksgroep 11, Brain, Fiksinski, A. M., Breetvelt, E. J., Lee, Y. J., Boot, E., Butcher, N., Palmer, L., Chow, E. W.C., Kahn, R. S., Vorstman, J. A.S., and Bassett, A. S.

Published
2019

21. Analysis of shared heritability in common disorders of the brain

Author

Anttila, V. Bulik-Sullivan, B. Finucane, H.K. Walters, R.K. Bras, J. Duncan, L. Escott-Price, V. Falcone, G.J. Gormley, P. Malik, R. Patsopoulos, N.A. Ripke, S. Wei, Z. Yu, D. Lee, P.H. Turley, P. Grenier-Boley, B. Chouraki, V. Kamatani, Y. Berr, C. Letenneur, L. Hannequin, D. Amouyel, P. Boland, A. Deleuze, J.-F. Duron, E. Vardarajan, B.N. Reitz, C. Goate, A.M. Huentelman, M.J. Ilyas Kamboh, M. Larson, E.B. Rogaeva, E. George-Hyslop, P.S. Hakonarson, H. Kukull, W.A. Farrer, L.A. Barnes, L.L. Beach, T.G. Yesim Demirci, F. Head, E. Hulette, C.M. Jicha, G.A. Kauwe, J.S.K. Kaye, J.A. Leverenz, J.B. Levey, A.I. Lieberman, A.P. Pankratz, V.S. Poon, W.W. Quinn, J.F. Saykin, A.J. Schneider, L.S. Smith, A.G. Sonnen, J.A. Stern, R.A. Van Deerlin, V.M. Van Eldik, L.J. Harold, D. Russo, G. Rubinsztein, D.C. Bayer, A. Tsolaki, M. Proitsi, P. Fox, N.C. Hampel, H. Owen, M.J. Mead, S. Passmore, P. Morgan, K. Nöthen, M.M. Rossor, M. Lupton, M.K. Hoffmann, P. Kornhuber, J. Lawlor, B. McQuillin, A. Al-Chalabi, A. Bis, J.C. Ruiz, A. Boada, M. Seshadri, S. Beiser, A. Rice, K. Van Der Lee, S.J. De Jager, P.L. Geschwind, D.H. Riemenschneider, M. Riedel-Heller, S. Rotter, J.I. Ransmayr, G. Hyman, B.T. Cruchaga, C. Alegret, M. Winsvold, B. Palta, P. Farh, K.-H. Cuenca-Leon, E. Furlotte, N. Kurth, T. Ligthart, L. Terwindt, G.M. Freilinger, T. Ran, C. Gordon, S.D. Borck, G. Adams, H.H.H. Lehtimäki, T. Wedenoja, J. Buring, J.E. Schürks, M. Hrafnsdottir, M. Hottenga, J.-J. Penninx, B. Artto, V. Kaunisto, M. Vepsäläinen, S. Martin, N.G. Montgomery, G.W. Kurki, M.I. Hämäläinen, E. Huang, H. Huang, J. Sandor, C. Webber, C. Muller-Myhsok, B. Schreiber, S. Salomaa, V. Loehrer, E. Göbel, H. Macaya, A. Pozo-Rosich, P. Hansen, T. Werge, T. Kaprio, J. Metspalu, A. Kubisch, C. Ferrari, M.D. Belin, A.C. Van Den Maagdenberg, A.M.J.M. Zwart, J.-A. Boomsma, D. Eriksson, N. Olesen, J. Chasman, D.I. Nyholt, D.R. Avbersek, A. Baum, L. Berkovic, S. Bradfield, J. Buono, R. Catarino, C.B. Cossette, P. De Jonghe, P. Depondt, C. Dlugos, D. Ferraro, T.N. French, J. Hjalgrim, H. Jamnadas-Khoda, J. Kälviäinen, R. Kunz, W.S. Lerche, H. Leu, C. Lindhout, D. Lo, W. Lowenstein, D. McCormack, M. Møller, R.S. Molloy, A. Ng, P.-W. Oliver, K. Privitera, M. Radtke, R. Ruppert, A.-K. Sander, T. Schachter, S. Schankin, C. Scheffer, I. Schoch, S. Sisodiya, S.M. Smith, P. Sperling, M. Striano, P. Surges, R. Neil Thomas, G. Visscher, F. Whelan, C.D. Zara, F. Heinzen, E.L. Marson, A. Becker, F. Stroink, H. Zimprich, F. Gasser, T. Gibbs, R. Heutink, P. Martinez, M. Morris, H.R. Sharma, M. Ryten, M. Mok, K.Y. Pulit, S. Bevan, S. Holliday, E. Attia, J. Battey, T. Boncoraglio, G. Thijs, V. Chen, W.-M. Mitchell, B. Rothwell, P. Sharma, P. Sudlow, C. Vicente, A. Markus, H. Kourkoulis, C. Pera, J. Raffeld, M. Silliman, S. Perica, V.B. Thornton, L.M. Huckins, L.M. William Rayner, N. Lewis, C.M. Gratacos, M. Rybakowski, F. Keski-Rahkonen, A. Raevuori, A. Hudson, J.I. Reichborn-Kjennerud, T. Monteleone, P. 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Ramos, E.M. Reus, V. Richter, M.A. Riddle, M.A. Robertson, M.M. Roessner, V. Rosário, M. Samuels, J.F. Sandor, P. Stein, D.J. Tsetsos, F. Van Nieuwerburgh, F. Weatherall, S. Wendland, J.R. Wolanczyk, T. Worbe, Y. Zai, G. Goes, F.S. McLaughlin, N. Nestadt, P.S. Grabe, H.-J. Depienne, C. Konkashbaev, A. Lanzagorta, N. Valencia-Duarte, A. Bramon, E. Buccola, N. Cahn, W. Cairns, M. Chong, S.A. Cohen, D. Crespo-Facorro, B. Crowley, J. Davidson, M. DeLisi, L. Dinan, T. Donohoe, G. Drapeau, E. Duan, J. Haan, L. Hougaard, D. Karachanak-Yankova, S. Khrunin, A. Klovins, J. Kučinskas, V. Keong, J.L.C. Limborska, S. Loughland, C. Lönnqvist, J. Maher, B. Mattheisen, M. McDonald, C. Murphy, K.C. Nenadic, I. Van Os, J. Pantelis, C. Pato, M. Petryshen, T. Quested, D. Roussos, P. Sanders, A.R. Schall, U. Schwab, S.G. Sim, K. So, H.-C. Stögmann, E. Subramaniam, M. Toncheva, D. Waddington, J. Walters, J. Weiser, M. Cheng, W. Cloninger, R. Curtis, D. Gejman, P.V. Henskens, F. Mattingsdal, M. Oh, S.-Y. Scott, R. Webb, B. Breen, G. Churchhouse, C. Bulik, C.M. Daly, M. Dichgans, M. Faraone, S.V. Guerreiro, R. Holmans, P. Kendler, K.S. Koeleman, B. Mathews, C.A. Price, A. Scharf, J. Sklar, P. Williams, J. Wood, N.W. Cotsapas, C. Palotie, A. Smoller, J.W. Sullivan, P. Rosand, J. Corvin, A. Neale, B.M. The Brainstorm Consortium

Abstract

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology. © 2018 American Association for the Advancement of Science. All rights reserved.

Published
2018

22. Analysis of shared heritability in common disorders of the brain

Author

Anttila, V, Bulik-Sullivan, B, Finucane, H, Walters, R, Bras, J, Duncan, L, Escott-Price, V, Falcone, G, Gormley, P, Malik, R, Patsopoulos, N, Ripke, S, Wei, Z, Yu, D, Lee, P, Turley, P, Grenier-Boley, B, Chouraki, V, Kamatani, Y, Berr, C, Letenneur, L, Hannequin, D, Amouyel, P, Boland, A, Deleuze, J, Duron, E, Vardarajan, B, Reitz, C, Goate, A, Huentelman, M, Ilyas Kamboh, M, Larson, E, Rogaeva, E, George-Hyslop, P, Hakonarson, H, Kukull, W, Farrer, L, Barnes, L, Beach, T, Yesim Demirci, F, Head, E, Hulette, C, Jicha, G, Kauwe, J, Kaye, J, Leverenz, J, Levey, A, Lieberman, A, Pankratz, V, Poon, W, Quinn, J, Saykin, A, Schneider, L, Smith, A, Sonnen, J, Stern, R, Van Deerlin, V, Van Eldik, L, Harold, D, Russo, G, Rubinsztein, D, Bayer, A, Tsolaki, M, Proitsi, P, Fox, N, Hampel, H, Owen, M, Mead, S, Passmore, P, Morgan, K, Nöthen, M, Rossor, M, Lupton, M, Hoffmann, P, Kornhuber, J, Lawlor, B, Mcquillin, A, Al-Chalabi, A, Bis, J, Ruiz, A, Boada, M, Seshadri, S, Beiser, A, Rice, K, Van Der Lee, S, De Jager, P, Geschwind, D, Riemenschneider, M, Riedel-Heller, S, Rotter, J, Ransmayr, G, Hyman, B, Cruchaga, C, Alegret, M, Winsvold, B, Palta, P, Farh, K, Cuenca-Leon, E, Furlotte, N, Kurth, T, Ligthart, L, Terwindt, G, Freilinger, T, Ran, C, Gordon, S, Borck, G, Adams, H, Lehtimäki, T, Wedenoja, J, Buring, J, Schürks, M, Hrafnsdottir, M, Hottenga, J, Penninx, B, Artto, V, Kaunisto, M, Vepsäläinen, S, Martin, N, Montgomery, G, Kurki, M, Hämäläinen, E, Huang, H, Huang, J, Sandor, C, Webber, C, Muller-Myhsok, B, Schreiber, S, Salomaa, V, Loehrer, E, Göbel, H, Macaya, A, Pozo-Rosich, P, Hansen, T, Werge, T, Kaprio, J, Metspalu, A, Kubisch, C, Ferrari, M, Belin, A, Van Den Maagdenberg, A, Zwart, J, Boomsma, D, Eriksson, N, Olesen, J, Chasman, D, Nyholt, D, Avbersek, A, Baum, L, Berkovic, S, Bradfield, J, Buono, R, Catarino, C, Cossette, P, De Jonghe, P, Depondt, C, Dlugos, D, Ferraro, T, French, J, Hjalgrim, H, Jamnadas-Khoda, J, Kälviäinen, R, Kunz, W, Lerche, H, Leu, C, 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K., Kaye, Jeffrey A., Leverenz, James B., Levey, Allan I., Lieberman, Andrew P., Pankratz, Vernon S., Poon, Wayne W., Quinn, Joseph F., Saykin, Andrew J., Schneider, Lon S., Smith, Amanda G., Sonnen, Joshua A., Stern, Robert A., Van Deerlin, Vivianna M., Van Eldik, Linda J., Harold, Denise, Russo, Giancarlo, Rubinsztein, David C., Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C., Hampel, Harald, Owen, Michael J., Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M., Rossor, Martin, Lupton, Michelle K., Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C., Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J., De Jager, Philip L., Geschwind, Daniel H., Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I., Ransmayr, Gerhard, Hyman, Bradley T., Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nicholas, Kurth, Tobias, Ligthart, Lannie, Terwindt, Gisela M., Freilinger, Tobias, Ran, Caroline, Gordon, Scott D., Borck, Guntram, Adams, Hieab H. H., Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E., Schürks, Markus, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G., Montgomery, Grant W., Kurki, Mitja I., Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfons, Pozo-Rosich, Patricia, Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Metspalu, Andres, Kubisch, Christian, Ferrari, Michel D., Belin, Andrea C., Van Den Maagdenberg, Arn M. J. M., Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nicholas, Olesen, Jes, Chasman, Daniel I., Nyholt, Dale R., Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell, Catarino, Claudia B., Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Dennis, Ferraro, Thomas N., French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S., Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S., Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thomas, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M., Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Neil Thomas, G., Visscher, Frank, Whelan, Christopher D., Zara, Federico, Heinzen, Erin L., Marson, Anthony, Becker, Felicitas, Stroink, Hans, Zimprich, Fritz, Gasser, Thomas, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R., Sharma, Manu, Ryten, Mina, Mok, Kin Y., Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thomas, BONCORAGLIO, GIORGIO BATTISTA, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Perica, Vesna Boraska, Thornton, Laura M., Huckins, Laura M., William Rayner, N., Lewis, Cathryn M., Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I., Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andreas, Mannik, Katrin, Baker, Jessica H., O'Toole, Julie K., Trace, Sara E., Davis, Oliver S. 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D., Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K., McGough, James J., Grevet, Eugenio H., Medland, Sarah E., Robinson, Elise, Weiss, Lauren A., Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M., Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, Moreno-De-Luca, Daniel, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thomas, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Roge, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G., Thompson, Robert C., Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Douglas, McIntosh, Andrew, Bergen, Sarah E., Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B., Reinbold, Céline S., Fullerton, Janice M., Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R., Cichon, Sven, Mühleisen, Thomas W., Degenhardt, Franziska, Schumacher, Johannes, Bauer, Michael, Mitchell, Philip B., Gershon, Elliot S., Rice, John, Potash, James B., Zandi, Peter P., Craddock, Nick, Nicol Ferrier, I., Alda, Martin, Rouleau, Guy A., Turecki, Gustavo, Ophoff, Roel, Pato, Carlos, Anjorin, Adebayo, Stahl, Eli, Leber, Markus, Czerski, Piotr M., Cruceanu, Cristiana, Jones, Ian R., Posthuma, Danielle, Andlauer, Till F. M., Forstner, Andreas J., Streit, Fabian, Baune, Bernhard T., Air, Tracy, Sinnamon, Grant, Wray, Naomi R., MacIntyre, Donald J., Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M., Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H., Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S., Nauck, Matthias, Schoevers, Robert A., Beekman, Aartjan TF, Knowles, James A., Viktorin, Alexander, Arnold, Paul, Barr, Cathy L., Bedoya-Berrio, Gabriel, Joseph Bienvenu, O., Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M., Dietrich, Andrea, Fernandez, Thomas, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L., Hartmann, Andreas, Hirschtritt, Matthew E., Hoekstra, Pieter J., Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J., Macciardi, Fabio, Madruga-Garrido, Marcos, Malaty, Irene A., Maras, Athanasios, McGrath, Lauren, Miguel, Eurípedes C., Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S., Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M., Reus, Victor, Richter, Margaret A., Riddle, Mark A., Robertson, Mary M., Roessner, Veit, Rosário, Maria, Samuels, Jack F., Sandor, Paul, Stein, Dan J., Tsetsos, Fotis, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R., Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S., McLaughlin, Nicole, Nestadt, Paul S., Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A., Cohen, David, Crespo-Facorro, Benedicto, Crowley, James, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Janis, Kučinskas, Vaidutis, Keong, Jimmy Lee Chee, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C., Nenadic, Igor, Van Os, Jim, Pantelis, Christos, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Panos, Sanders, Alan R., Schall, Ulrich, Schwab, Sibylle G., Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, James, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V., Henskens, Frans, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M., Daly, Mark, Dichgans, Martin, Faraone, Stephen V., Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S., Koeleman, Bobby, Mathews, Carol A., Price, Alkes, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W., Cotsapas, Chris, Palotie, Aarno, Smoller, Jordan W., Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M., Anttila, V, Bulik-Sullivan, B, Finucane, H, Walters, R, Bras, J, Duncan, L, Escott-Price, V, Falcone, G, Gormley, P, Malik, R, Patsopoulos, N, Ripke, S, Wei, Z, Yu, D, Lee, P, Turley, P, Grenier-Boley, B, Chouraki, V, Kamatani, Y, Berr, C, Letenneur, L, Hannequin, D, Amouyel, P, Boland, A, Deleuze, J, Duron, E, Vardarajan, B, Reitz, C, Goate, A, Huentelman, M, Ilyas Kamboh, M, Larson, E, Rogaeva, E, George-Hyslop, P, Hakonarson, H, Kukull, W, Farrer, L, Barnes, L, Beach, T, Yesim Demirci, F, Head, E, Hulette, C, Jicha, G, Kauwe, J, Kaye, J, Leverenz, J, Levey, A, Lieberman, A, Pankratz, V, Poon, W, Quinn, J, Saykin, A, Schneider, L, Smith, A, Sonnen, J, Stern, R, Van Deerlin, V, Van Eldik, L, Harold, D, Russo, G, Rubinsztein, D, Bayer, A, Tsolaki, M, Proitsi, P, Fox, N, Hampel, H, Owen, M, Mead, S, Passmore, P, Morgan, K, Nöthen, M, Rossor, M, Lupton, M, 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Jonghe, P, Depondt, C, Dlugos, D, Ferraro, T, French, J, Hjalgrim, H, Jamnadas-Khoda, J, Kälviäinen, R, Kunz, W, Lerche, H, Leu, C, Lindhout, D, Lo, W, Lowenstein, D, Mccormack, M, Møller, R, Molloy, A, Ng, P, Oliver, K, Privitera, M, Radtke, R, Ruppert, A, Sander, T, Schachter, S, Schankin, C, Scheffer, I, Schoch, S, Sisodiya, S, Smith, P, Sperling, M, Striano, P, Surges, R, Neil Thomas, G, Visscher, F, Whelan, C, Zara, F, Heinzen, E, Marson, A, Becker, F, Stroink, H, Zimprich, F, Gasser, T, Gibbs, R, Heutink, P, Martinez, M, Morris, H, Sharma, M, Ryten, M, Mok, K, Pulit, S, Bevan, S, Holliday, E, Attia, J, Battey, T, Boncoraglio, G, Thijs, V, Chen, W, Mitchell, B, Rothwell, P, Sharma, P, Sudlow, C, Vicente, A, Markus, H, Kourkoulis, C, Pera, J, Raffeld, M, Silliman, S, Perica, V, Thornton, L, Huckins, L, William Rayner, N, Lewis, C, Gratacos, M, Rybakowski, F, Keski-Rahkonen, A, Raevuori, A, Hudson, J, Reichborn-Kjennerud, T, Monteleone, P, Karwautz, A, Mannik, K, Baker, J, O'Toole, J, Trace, S, Davis, O, Helder, S, Ehrlich, S, Herpertz-Dahlmann, B, Danner, U, Van Elburg, A, Clementi, M, Forzan, M, Docampo, E, Lissowska, J, Hauser, J, Tortorella, A, Maj, M, Gonidakis, F, Tziouvas, K, Papezova, H, Yilmaz, Z, Wagner, G, Cohen-Woods, S, Herms, S, Julia, A, Rabionet, R, Dick, D, Ripatti, S, Andreassen, O, Espeseth, T, Lundervold, A, Steen, V, Pinto, D, Scherer, S, Aschauer, H, Schosser, A, Alfredsson, L, Padyukov, L, Halmi, K, Mitchell, J, Strober, M, Bergen, A, Kaye, W, Szatkiewicz, J, Cormand, B, Ramos-Quiroga, J, Sánchez-Mora, C, Ribasés, M, Casas, M, Hervas, A, Arranz, M, Haavik, J, Zayats, T, Johansson, S, Williams, N, Dempfle, A, Rothenberger, A, Kuntsi, J, Oades, R, Banaschewski, T, Franke, B, Buitelaar, J, Vasquez, A, Doyle, A, Reif, A, Lesch, K, Freitag, C, Rivero, O, Palmason, H, Romanos, M, Langley, K, Rietschel, M, Witt, S, Dalsgaard, S, Børglum, A, Waldman, I, Wilmot, B, Molly, N, Bau, C, Crosbie, J, Schachar, R, Loo, S, Mcgough, J, Grevet, E, Medland, S, Robinson, E, Weiss, L, Bacchelli, E, Bailey, A, Bal, V, Battaglia, A, Betancur, C, Bolton, P, Cantor, R, Celestino-Soper, P, Dawson, G, De Rubeis, S, Duque, F, Green, A, Klauck, S, Leboyer, M, Levitt, P, Maestrini, E, Mane, S, Moreno-De-Luca, D, Parr, J, Regan, R, Reichenberg, A, Sandin, S, Vorstman, J, Wassink, T, Wijsman, E, Cook, E, Santangelo, S, Delorme, R, Roge, B, Magalhaes, T, Arking, D, Schulze, T, Thompson, R, Strohmaier, J, Matthews, K, Melle, I, Morris, D, Blackwood, D, Mcintosh, A, Bergen, S, Schalling, M, Jamain, S, Maaser, A, Fischer, S, Reinbold, C, Fullerton, J, Guzman-Parra, J, Mayoral, F, Schofield, P, Cichon, S, Mühleisen, T, Degenhardt, F, Schumacher, J, Bauer, M, Mitchell, P, Gershon, E, Rice, J, Potash, J, Zandi, P, Craddock, N, Nicol Ferrier, I, Alda, M, Rouleau, G, Turecki, G, Ophoff, R, Pato, C, Anjorin, A, Stahl, E, Leber, M, Czerski, P, Cruceanu, C, Jones, I, Posthuma, D, Andlauer, T, Forstner, A, Streit, F, Baune, B, Air, T, Sinnamon, G, Wray, N, Macintyre, D, Porteous, D, Homuth, G, Rivera, M, Grove, J, Middeldorp, C, Hickie, I, Pergadia, M, Mehta, D, Smit, J, Jansen, R, De Geus, E, Dunn, E, Li, Q, Nauck, M, Schoevers, R, Beekman, A, Knowles, J, Viktorin, A, Arnold, P, Barr, C, Bedoya-Berrio, G, Joseph Bienvenu, O, Brentani, H, Burton, C, Camarena, B, Cappi, C, Cath, D, Cavallini, M, Cusi, D, Darrow, S, Denys, D, Derks, E, Dietrich, A, Fernandez, T, Figee, M, Freimer, N, Gerber, G, Grados, M, Greenberg, E, Hanna, G, Hartmann, A, Hirschtritt, M, Hoekstra, P, Huang, A, Huyser, C, Illmann, C, Jenike, M, Kuperman, S, Leventhal, B, Lochner, C, Lyon, G, Macciardi, F, Madruga-Garrido, M, Malaty, I, Maras, A, Mcgrath, L, Miguel, E, Mir, P, Nestadt, G, Nicolini, H, Okun, M, Pakstis, A, Paschou, P, Piacentini, J, Pittenger, C, Plessen, K, Ramensky, V, Ramos, E, Reus, V, Richter, M, Riddle, M, Robertson, M, Roessner, V, Rosário, M, Samuels, J, Sandor, P, Stein, D, Tsetsos, F, Van Nieuwerburgh, F, Weatherall, S, Wendland, J, Wolanczyk, T, Worbe, Y, Zai, G, Goes, F, Mclaughlin, N, Nestadt, P, Grabe, H, Depienne, C, Konkashbaev, A, Lanzagorta, N, Valencia-Duarte, A, Bramon, E, Buccola, N, Cahn, W, Cairns, M, Chong, S, Cohen, D, Crespo-Facorro, B, Crowley, J, Davidson, M, Delisi, L, Dinan, T, Donohoe, G, Drapeau, E, Duan, J, Haan, L, Hougaard, D, Karachanak-Yankova, S, Khrunin, A, Klovins, J, Kučinskas, V, Keong, J, Limborska, S, Loughland, C, Lönnqvist, J, Maher, B, Mattheisen, M, Mcdonald, C, Murphy, K, Nenadic, I, Van Os, J, Pantelis, C, Pato, M, Petryshen, T, Quested, D, Roussos, P, Sanders, A, Schall, U, Schwab, S, Sim, K, So, H, Stögmann, E, Subramaniam, M, Toncheva, D, Waddington, J, Walters, J, Weiser, M, Cheng, W, Cloninger, R, Curtis, D, Gejman, P, Henskens, F, Mattingsdal, M, Oh, S, Scott, R, Webb, B, Breen, G, Churchhouse, C, Bulik, C, Daly, M, Dichgans, M, Faraone, S, Guerreiro, R, Holmans, P, Kendler, K, Koeleman, B, Mathews, C, Price, A, Scharf, J, Sklar, P, Williams, J, Wood, N, Cotsapas, C, Palotie, A, Smoller, J, Sullivan, P, Rosand, J, Corvin, A, Neale, B, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K., Walters, Raymond K., Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J., Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A., Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H., Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N., Reitz, Christiane, Goate, Alison M., Huentelman, Matthew J., Ilyas Kamboh, M., Larson, Eric B., Rogaeva, Ekaterina, George-Hyslop, Peter St, Hakonarson, Hakon, Kukull, Walter A., Farrer, Lindsay A., Barnes, Lisa L., Beach, Thomas G., Yesim Demirci, F., Head, Elizabeth, Hulette, Christine M., Jicha, Gregory A., Kauwe, John S. K., Kaye, Jeffrey A., Leverenz, James B., Levey, Allan I., Lieberman, Andrew P., Pankratz, Vernon S., Poon, Wayne W., Quinn, Joseph F., Saykin, Andrew J., Schneider, Lon S., Smith, Amanda G., Sonnen, Joshua A., Stern, Robert A., Van Deerlin, Vivianna M., Van Eldik, Linda J., Harold, Denise, Russo, Giancarlo, Rubinsztein, David C., Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C., Hampel, Harald, Owen, Michael J., Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M., Rossor, Martin, Lupton, Michelle K., Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C., Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J., De Jager, Philip L., Geschwind, Daniel H., Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I., Ransmayr, Gerhard, Hyman, Bradley T., Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nicholas, Kurth, Tobias, Ligthart, Lannie, Terwindt, Gisela M., Freilinger, Tobias, Ran, Caroline, Gordon, Scott D., Borck, Guntram, Adams, Hieab H. H., Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E., Schürks, Markus, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G., Montgomery, Grant W., Kurki, Mitja I., Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfons, Pozo-Rosich, Patricia, Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Metspalu, Andres, Kubisch, Christian, Ferrari, Michel D., Belin, Andrea C., Van Den Maagdenberg, Arn M. J. M., Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nicholas, Olesen, Jes, Chasman, Daniel I., Nyholt, Dale R., Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell, Catarino, Claudia B., Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Dennis, Ferraro, Thomas N., French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S., Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S., Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thomas, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M., Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Neil Thomas, G., Visscher, Frank, Whelan, Christopher D., Zara, Federico, Heinzen, Erin L., Marson, Anthony, Becker, Felicitas, Stroink, Hans, Zimprich, Fritz, Gasser, Thomas, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R., Sharma, Manu, Ryten, Mina, Mok, Kin Y., Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thomas, BONCORAGLIO, GIORGIO BATTISTA, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Perica, Vesna Boraska, Thornton, Laura M., Huckins, Laura M., William Rayner, N., Lewis, Cathryn M., Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I., Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andreas, Mannik, Katrin, Baker, Jessica H., O'Toole, Julie K., Trace, Sara E., Davis, Oliver S. P., Helder, Sietske G., Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N., Van Elburg, Annemarie A., Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragiskos, Tziouvas, Konstantinos, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julia, Antonio, Rabionet, Raquel, Dick, Danielle M., Ripatti, Samuli, Andreassen, Ole A., Espeseth, Thomas, Lundervold, Astri J., Steen, Vidar M., Pinto, Dalila, Scherer, Stephen W., Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lars, Padyukov, Leonid, Halmi, Katherine A., Mitchell, James, Strober, Michael, Bergen, Andrew W., Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesús, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D., Banaschewski, Tobias, Franke, Barbara, Buitelaar, Jan K., Vasquez, Alejandro Arias, Doyle, Alysa E., Reif, Andreas, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H., Dalsgaard, Soeren, Børglum, Anders D., Waldman, Irwin, Wilmot, Beth, Molly, Nikolas, Bau, Claiton H. D., Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K., McGough, James J., Grevet, Eugenio H., Medland, Sarah E., Robinson, Elise, Weiss, Lauren A., Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M., Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, Moreno-De-Luca, Daniel, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thomas, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Roge, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G., Thompson, Robert C., Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Douglas, McIntosh, Andrew, Bergen, Sarah E., Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B., Reinbold, Céline S., Fullerton, Janice M., Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R., Cichon, Sven, Mühleisen, Thomas W., Degenhardt, Franziska, Schumacher, Johannes, Bauer, Michael, Mitchell, Philip B., Gershon, Elliot S., Rice, John, Potash, James B., Zandi, Peter P., Craddock, Nick, Nicol Ferrier, I., Alda, Martin, Rouleau, Guy A., Turecki, Gustavo, Ophoff, Roel, Pato, Carlos, Anjorin, Adebayo, Stahl, Eli, Leber, Markus, Czerski, Piotr M., Cruceanu, Cristiana, Jones, Ian R., Posthuma, Danielle, Andlauer, Till F. M., Forstner, Andreas J., Streit, Fabian, Baune, Bernhard T., Air, Tracy, Sinnamon, Grant, Wray, Naomi R., MacIntyre, Donald J., Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M., Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H., Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S., Nauck, Matthias, Schoevers, Robert A., Beekman, Aartjan TF, Knowles, James A., Viktorin, Alexander, Arnold, Paul, Barr, Cathy L., Bedoya-Berrio, Gabriel, Joseph Bienvenu, O., Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M., Dietrich, Andrea, Fernandez, Thomas, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L., Hartmann, Andreas, Hirschtritt, Matthew E., Hoekstra, Pieter J., Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J., Macciardi, Fabio, Madruga-Garrido, Marcos, Malaty, Irene A., Maras, Athanasios, McGrath, Lauren, Miguel, Eurípedes C., Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S., Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M., Reus, Victor, Richter, Margaret A., Riddle, Mark A., Robertson, Mary M., Roessner, Veit, Rosário, Maria, Samuels, Jack F., Sandor, Paul, Stein, Dan J., Tsetsos, Fotis, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R., Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S., McLaughlin, Nicole, Nestadt, Paul S., Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A., Cohen, David, Crespo-Facorro, Benedicto, Crowley, James, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Janis, Kučinskas, Vaidutis, Keong, Jimmy Lee Chee, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C., Nenadic, Igor, Van Os, Jim, Pantelis, Christos, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Panos, Sanders, Alan R., Schall, Ulrich, Schwab, Sibylle G., Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, James, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V., Henskens, Frans, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M., Daly, Mark, Dichgans, Martin, Faraone, Stephen V., Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S., Koeleman, Bobby, Mathews, Carol A., Price, Alkes, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W., Cotsapas, Chris, Palotie, Aarno, Smoller, Jordan W., Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, and Neale, Benjamin M.

Abstract

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Published
2018

25. The role of COMT and plasma proline in the variable penetrance of autistic spectrum symptoms in 22q11.2 deletion syndrome

Author

Hidding, E., Swaab, H., de Sonneville, L. M J, van Engeland, H., and Vorstman, J. A S

Subjects
22q11.2 deletion, catechol-O-methyltransferase, Genetics, Journal Article, 2 deletion, Genetics(clinical), autism symptomatology, social cognition, plasma proline, 22q11
Abstract

This paper examines how COMT158 genotypes and plasma proline levels are associated with variable penetrance of social behavioural and social cognitive problems in 22q11.2 deletion syndrome (22q11DS). Severity of autistic spectrum symptoms of 45 participants with 22q11DS was assessed using the Autism Diagnostic Interview Revised. Face and facial emotion recognition was evaluated using standardized computer-based test-paradigms. Associations with COMT158 genotypes and proline levels were examined. High proline levels and poor face recognition in individuals with the COMTMET allele, and poor facial emotion recognition, explained almost 50% of the variance in severity of autism symptomatology in individuals with 22q11DS. High proline levels and a decreased capacity to break down dopamine as a result of the COMTMET variant are both relevant in the expression of the social phenotype in patients. This epistatic interaction effect between the COMT158 genotype and proline on the expression of social deficits in 22q11DS shows how factors other than the direct effects of the deletion itself can modulate the penetrance of associated cognitive and behavioural outcomes. These findings are not only relevant to our insight into 22q11DS, but also provide a model to better understand the phenomenon of variable penetrance in other pathogenic genetic variants.

Published
2016

26. Psychose : Symptomen en stoornissen onderscheiden bij kinderen en adolescenten

Author

Vorstman, J. A., Breetvelt, E. J., Hillegers, M. H., and Scheepers, F. E.

Subjects
Psychiatry and Mental health, Children and adolescents, Psychotic disorder, Symptoms
Abstract

BACKGROUND: Psychotic symptoms can occur during normal development, but they can also indicate the presence of or an increased risk of a psychotic disorder. By studying children who are at risk of developing a psychotic disorder we can obtain information that will help to distinguish more accurately between developmental phenomena and psychopathology AIM: To present the current state of our knowledge about the development of psychotic symptoms and psychotic disorders and to discuss the importance of continuing research into subpopulations of children who are at risk of developing a psychotic disorder. METHOD: We give an epidemiological and clinical description of psychosis in childhood and we report on recent Dutch and international studies about children with an increased risk of developing psychotic disorders. RESULTS: Results so far indicate that these children tend to have an increased risk of developing not only psychotic disorders but also a wide range of psychopathological conditions in later life. The degree of risk depends on the nature and number of risk factors involved. CONCLUSION: More research is needed to follow the development of children with an increased risk of psychotic disorders.

Published
2015

27. Genome-wide association study of NMDA receptor coagonists in human cerebrospinal fluid and plasma

Author

Luykx, J. J., Bakker, S. C., Visser, W. F., Verhoeven-Duif, N., Buizer-Voskamp, J. E., den Heijer, J. M., Boks, M. P M, Sul, J. H., Eskin, E., Ori, A. P., Cantor, R. M., Vorstman, J., Strengman, E., DeYoung, J., Kappen, T. H., Pariama, E., van Dongen, E. P A, Borgdorff, P., Bruins, P., de Koning, T. J., Kahn, R. S., and Ophoff, R. A.

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Molecular Biology
Abstract

The N-methyl-d-aspartate receptor (NMDAR) coagonists glycine, d-serine and l-proline play crucial roles in NMDAR-dependent neurotransmission and are associated with a range of neuropsychiatric disorders. We conducted the first genome-wide association study of concentrations of these coagonists and their enantiomers in plasma and cerebrospinal fluid (CSF) of human subjects from the general population (N=414). Genetic variants at chromosome 22q11.2, located in and near PRODH (proline dehydrogenase), were associated with l-proline in plasma (β=0.29; P=6.38 × 10-10). The missense variant rs17279437 in the proline transporter SLC6A20 was associated with l-proline in CSF (β=0.28; P=9.68 × 10-9). Suggestive evidence of association was found for the d-serine plasma-CSF ratio at the d-amino-acid oxidase (DAO) gene (β=−0.28; P=9.08 × 10-8), whereas a variant in SRR (that encodes serine racemase and is associated with schizophrenia) constituted the most strongly associated locus for the l-serine to d-serine ratio in CSF. All these genes are highly expressed in rodent meninges and choroid plexus, anatomical regions relevant to CSF physiology. The enzymes and transporters they encode may be targeted to further construe the nature of NMDAR coagonist involvement in NMDAR gating. Furthermore, the highlighted genetic variants may be followed up in clinical populations, for example, schizophrenia and 22q11 deletion syndrome. Overall, this targeted metabolomics approach furthers the understanding of NMDAR coagonist concentration variability and sets the stage for non-targeted CSF metabolomics projects.Molecular Psychiatry advance online publication, 10 February 2015; doi:10.1038/mp.2014.190.

Published
2015

28. The Sociability Score: App-based social profiling from a healthcare perspective

Author

Eskes, P., Spruit, M., Brinkkemper, S., Vorstman, J., Kas, M., Eskes, P., Spruit, M., Brinkkemper, S., Vorstman, J., and Kas, M.

Abstract

As the smartphone becomes an integral part of our lives, its value as a rich data source reaches an increasing potential. Several previous studies have used smartphone-derived data to discover relationships between user characteristics and different types of smartphone use. However, none tried to use smartphone data to capture an individual's social behavior into one profile, aimed at providing additional information for the diagnostic evaluation of social deficits. This study presents a novel way of combining different modalities of smartphone data for the creation of sociability profiles using a scoring mechanism that allows for easy addition and removal of data sources. Following installation of the smartphone application, data is being sampled in the background to allow for the assessment of spontaneous smartphone use. Sociability scores were based on the integration of social communication and social exploration scores derived from smartphone use and environmental data sampling (e.g., GPS and external Bluetooth signals). Finally, we have applied our Sociability model to create social profiles of ten test subjects as a baseline for future studies. This pilot study provided insight in the usability of the individual sociability scores for future smartphone application to provide longitudinal objective measures of normal and atypical human social behavioral profiles in their natural environment.

Published
2016

31. Unmet needs in paediatric psychopharmacology: Present scenario and future perspectives

Author

Persico, A.M., Arango, C., Buitelaar, J.K., Correll, C.U., Glennon, J.C., Hoekstra, P.J., Moreno, C., Vitiello, B., Vorstman, J., Zuddas, A., Persico, A.M., Arango, C., Buitelaar, J.K., Correll, C.U., Glennon, J.C., Hoekstra, P.J., Moreno, C., Vitiello, B., Vorstman, J., and Zuddas, A.

Abstract

Item does not contain fulltext, Paediatric psychopharmacology holds great promise in two equally important areas of enormous biomedical and social impact, namely the treatment of behavioural abnormalities in children and adolescents, and the prevention of psychiatric disorders with adolescent- or adult-onset. Yet, in striking contrast, pharmacological treatment options presently available in child and adolescent psychiatry are dramatically limited. The most important currently unmet needs in paediatric psychopharmacology are: the frequent off-label prescription of medications to children and adolescents based exclusively on data from randomized controlled studies involving adult patients; the frequent lack of age-specific dose, long-term efficacy and tolerability/safety data; the lack of effective medications for many paediatric psychiatric disorders, most critically autism spectrum disorder; the scarcity and limitations of randomized placebo-controlled trials in paediatric psychopharmacology; the unexplored potential for the prevention of psychiatric disorders with adolescent- and adult-onset; the current lack of biomarkers to predict treatment response and severe adverse effects; the need for better preclinical data to foster the successful development of novel drug therapies; and the effective dissemination of evidence-based treatments to the general public, to better inform patients and families of the benefits and risks of pharmacological interventions during development. Priorities and strategies are proposed to overcome some of these limitations, including the European Child and Adolescent Clinical Psychopharmacology Network, as an overarching Pan-European infrastructure aimed at reliably carrying out much needed psychopharmacological trials in children and adolescents, in order to fill the identified gaps and improve overall outcomes.

Published
2015

32. Psychose: Symptomen en stoornissen onderscheiden bij kinderen en adolescenten

Author

UMC Utrecht, Ontwikkelingsstoornissen Med., Brain, Onderzoeksgroep 3, Psychiatrie_Medisch, Other research (not in main researchprogram), Vorstman, J. A., Breetvelt, E. J., Hillegers, M. H., Scheepers, F. E., UMC Utrecht, Ontwikkelingsstoornissen Med., Brain, Onderzoeksgroep 3, Psychiatrie_Medisch, Other research (not in main researchprogram), Vorstman, J. A., Breetvelt, E. J., Hillegers, M. H., and Scheepers, F. E.

Published
2015

33. Intellectual functioning in relation to autism and ADHD symptomatology in children and adolescents with 22q11.2 deletion syndrome

Author

Ontwikkelingsstoornissen Med., Brain, Onderzoek, Psychosociale zorg patientenzorg, Child Health, Cluster Ontwikkelingsgerichte zorg, Hidding, E., Swaab, H., de Sonneville, L. M. J., van Engeland, H., Sijmens-Morcus, M. E. J., Klaassen, P. W. J., Duijff, S. N., Vorstman, J. A. S., Ontwikkelingsstoornissen Med., Brain, Onderzoek, Psychosociale zorg patientenzorg, Child Health, Cluster Ontwikkelingsgerichte zorg, Hidding, E., Swaab, H., de Sonneville, L. M. J., van Engeland, H., Sijmens-Morcus, M. E. J., Klaassen, P. W. J., Duijff, S. N., and Vorstman, J. A. S.

Published
2015

34. Genome-wide association study of NMDA receptor coagonists in human cerebrospinal fluid and plasma

Author

Ontwikkelingsstoornissen Med., Brain, Neurogenetica, Affectieve & Psychotische Med., Genetica Sectie Metabole Diagnostiek, Other research (not in main researchprogram), Child Health, Onderzoeksgroep 2, Pathologie, Circulatory Health, Onderzoek, Hersenen-Bedrijfsvoering, Luykx, J. J., Bakker, S. C., Visser, W. F., Verhoeven-Duif, N., Buizer-Voskamp, J. E., den Heijer, J. M., Boks, M. P M, Sul, J. H., Eskin, E., Ori, A. P., Cantor, R. M., Vorstman, J., Strengman, E., DeYoung, J., Kappen, T. H., Pariama, E., van Dongen, E. P A, Borgdorff, P., Bruins, P., de Koning, T. J., Kahn, R. S., Ophoff, R. A., Ontwikkelingsstoornissen Med., Brain, Neurogenetica, Affectieve & Psychotische Med., Genetica Sectie Metabole Diagnostiek, Other research (not in main researchprogram), Child Health, Onderzoeksgroep 2, Pathologie, Circulatory Health, Onderzoek, Hersenen-Bedrijfsvoering, Luykx, J. J., Bakker, S. C., Visser, W. F., Verhoeven-Duif, N., Buizer-Voskamp, J. E., den Heijer, J. M., Boks, M. P M, Sul, J. H., Eskin, E., Ori, A. P., Cantor, R. M., Vorstman, J., Strengman, E., DeYoung, J., Kappen, T. H., Pariama, E., van Dongen, E. P A, Borgdorff, P., Bruins, P., de Koning, T. J., Kahn, R. S., and Ophoff, R. A.

Published
2015

35. Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome

Author

Vorstman, J. A. S., Breetvelt, E. J., Duijff, S. N., Eliez, S., Schneider, M., Jalbrzikowski, M., Armando, M., Vicari, S., Shashi, V., Hooper, S. R., Chow, E. W. C., Fung, W. L. A., Butcher, N. J., Young, D. A., McDonald-McGinn, D. M., Vogels, A., Van Amelsvoort, T., Gothelf, D., Weinberger, R., Weizman, A., Klaassen, P. W. J., Koops, S., Kates, W. R., Antshel, K. M., Simon, T. J., Ousley, O. Y., Swillen, A., Gur, R. E., Bearden, C. E., Kahn, R. S., Bassett, A. S., Emanuel, B. S., Zackai, E. H., Kushan, L., Fremont, W., Schoch, K., Stoddard, J., Cubells, J., Fu, F., Campbell, L. E., Fritsch, R., Vergaelen, E., Neeleman, M., Boot, E., Debbane, M., Philip, N., Green, T., Van DenBree, M. B. M., Murphy, D., Canyelles, J. M., Arango, C., Murphy, K. C., Pontillo, M., Vicari S. (ORCID:0000-0002-5395-2262), Vorstman, J. A. S., Breetvelt, E. J., Duijff, S. N., Eliez, S., Schneider, M., Jalbrzikowski, M., Armando, M., Vicari, S., Shashi, V., Hooper, S. R., Chow, E. W. C., Fung, W. L. A., Butcher, N. J., Young, D. A., McDonald-McGinn, D. M., Vogels, A., Van Amelsvoort, T., Gothelf, D., Weinberger, R., Weizman, A., Klaassen, P. W. J., Koops, S., Kates, W. R., Antshel, K. M., Simon, T. J., Ousley, O. Y., Swillen, A., Gur, R. E., Bearden, C. E., Kahn, R. S., Bassett, A. S., Emanuel, B. S., Zackai, E. H., Kushan, L., Fremont, W., Schoch, K., Stoddard, J., Cubells, J., Fu, F., Campbell, L. E., Fritsch, R., Vergaelen, E., Neeleman, M., Boot, E., Debbane, M., Philip, N., Green, T., Van DenBree, M. B. M., Murphy, D., Canyelles, J. M., Arango, C., Murphy, K. C., Pontillo, M., and Vicari S. (ORCID:0000-0002-5395-2262)

Abstract

Importance: Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age.Objective: To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS.Design, Setting, And Participants: Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with≥1 assessment at age 8-24 years).Main Outcomes And Measures: Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test.Results: Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds r

Published
2015

37. Individual common variants exert weak effects on the risk for autism spectrum disorderspi

Author

Anney, Richard Klei, Lambertus Pinto, Dalila Almeida, Joana and Bacchelli, Elena Baird, Gillian Bolshakova, Nadia and Boelte, Sven Bolton, Patrick F. Bourgeron, Thomas Brennan, Sean Brian, Jessica Casey, Jillian Conroy, Judith and Correia, Catarina Corsello, Christina Crawford, Emily L. de Jonge, Maretha Delorme, Richard Duketis, Eftichia Duque, Frederico Estes, Annette Farrar, Penny Fernandez, Bridget A. and Folstein, Susan E. Fombonne, Eric Gilbert, John and Gillberg, Christopher Glessner, Joseph T. Green, Andrew and Green, Jonathan Guter, Stephen J. Heron, Elizabeth A. Holt, Richard Howe, Jennifer L. Hughes, Gillian Hus, Vanessa and Igliozzi, Roberta Jacob, Suma Kenny, Graham P. Kim, Cecilia and Kolevzon, Alexander Kustanovich, Vlad Lajonchere, Clara M. and Lamb, Janine A. Law-Smith, Miriam Leboyer, Marion Le Couteur, Ann Leventhal, Bennett L. Liu, Xiao-Qing Lombard, Frances Lord, Catherine Lotspeich, Linda Lund, Sabata C. and Magalhaes, Tiago R. Mantoulan, Carine McDougle, Christopher J. and Melhem, Nadine M. Merikangas, Alison Minshew, Nancy J. and Mirza, Ghazala K. Munson, Jeff Noakes, Carolyn Nygren, Gudrun Papanikolaou, Katerina Pagnamenta, Alistair T. and Parrini, Barbara Paton, Tara Pickles, Andrew Posey, David J. and Poustka, Fritz Ragoussis, Jiannis Regan, Regina Roberts, Wendy Roeder, Kathryn Roge, Bernadette Rutter, Michael L. and Schlitt, Sabine Shah, Naisha Sheffield, Val C. Soorya, Latha Sousa, Ines Stoppioni, Vera Sykes, Nuala Tancredi, Raffaella Thompson, Ann P. Thomson, Susanne Tryfon, Ana and Tsiantis, John Van Engeland, Herman Vincent, John B. and Volkmar, Fred Vorstman, J. A. S. Wallace, Simon Wing, Kirsty and Wittemeyer, Kerstin Wood, Shawn Zurawiecki, Danielle and Zwaigenbaum, Lonnie Bailey, Anthony J. Battaglia, Agatino and Cantor, Rita M. Coon, Hilary Cuccaro, Michael L. Dawson, Geraldine Ennis, Sean Freitag, Christine M. Geschwind, Daniel H. Haines, Jonathan L. Klauck, Sabine M. McMahon, William M. Maestrini, Elena Miller, Judith Monaco, Anthony P. Nelson, Stanley F. Nurnberger, Jr., John I. Oliveira, Guiomar Parr, Jeremy R. Pericak-Vance, Margaret A. Piven, Joseph Schellenberg, Gerard D. Scherer, StephenW. Vicente, Astrid M. Wassink, Thomas H. Wijsman, Ellen M. Betancur, Catalina Buxbaum, Joseph D. Cook, Edwin H. Gallagher, Louise and Gill, Michael Hallmayer, Joachim Paterson, Andrew D. and Sutcliffe, James S. Szatmari, Peter Vieland, Veronica J. and Hakonarson, Hakon Devlin, Bernie

Subjects
mental disorders
Abstract

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm 1). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Published
2012

38. Practical Guidelines for Managing Patients with 22q11.2 Deletion Syndrome

Author

Bassett, A, McDonald McGinn, D, Devriendt, K, Digilio, M, Goldenberg, P, Habel, A, Marino, B, Oskarsdottir, S, Philip, N, Sullivan, K, Swillen, A, Vorstman, J, Abadie, V, Allgrove, J, Amati, F, Baker, K, Baylis, A, Beaujard, M, Beemer, F, Boers, M, Bolton, P, Boot, E, Brigstocke, S, Burtey, S, Campbell, L, Chabloz, M, Chow, E, Clayton Smith, J, Cubells, J, Debbané, M, Delrue, M, De Smedt, B, Duijff, S, Eicher, P, Emanuel, B, Evers, L, Flahault, A, Forsythe, A, Frebourg, T, Gennery, A, Goldmuntz, E, Gosling, A, Handler, S, Heine Suñer, D, Hilmarsson, A, Hogan, A, Hordijk, R, Howley, S, Illingworth, E, Jackson, O, Joyce, H, Kawame, H, Kelly, R, Kemp, A, Kempf, L, Kimpen, J, Kirschner, R, Klaassen, P, Kumararatne, D, Lambert, M, Lima, K, Lindsay, E, Macerola, S, Malki, M, Marlin, S, Mascarenhas, M, Monks, S, Moran, V, Morrow, B, Moss, E, Murphy, C, Naqvi, N, Nielsen, B, Niklasson, L, Nordgarden, H, Oenema Mostert, C, Ottet, M, Pasca, C, Pasquariello, P, Persson, C, Portnoi, M, Prasad, S, Rockers, K, Saitta, S, Scambler, P, Schaer, M, Schneider, M, Sell, D, Solot, C, Sommerlad, B, Unanue, N, Sundram, F, Van Aken, K, van Amelsvoort, T, van der Molen, A, Widdershoven, J, Zackai, E, Schneider, Maud, Debbané, Martin, Schaer, Marie, and Schneider, Michel

Subjects
Male, medicine.medical_specialty, Pediatrics, Genetic Techniques/standards, Chromosomes, Human, Pair 22, Physical examination, Genetic Counseling, Scoliosis, Short stature, Article, 03 medical and health sciences, 0302 clinical medicine, ddc:150, DiGeorge syndrome, medicine, DiGeorge Syndrome, Humans, Pediatrics, Perinatology, and Child Health, Child, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, business.industry, medicine.disease, 3. Good health, Surgery, Settore MED/03 - Genetica Medica, Hypoparathyroidism, Genetic Techniques, Pediatrics, Perinatology and Child Health, Practice Guidelines as Topic, Etiology, Genetic Counseling/standards, Sacral dimple, Asymmetric crying facies, medicine.symptom, Chromosome Deletion, business, DiGeorge Syndrome/diagnosis/genetics/therapy, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 22/genetics
Abstract

A 12-year-old boy currently is followed by multiple sub-specialists for problems caused by the chromosome 22q11.2 deletion syndrome (22q11DS) (Figure). He was born via spontaneous vaginal delivery, weighing 3033 g, to a 31-year-old G3P3 mother after a full-term pregnancy complicated only by mild polyhydramnios. Family history was non-contributory. Apgar scores were 8 at 1 minute and 9 at 5 minutes. With the exception of a weak cry, the results of the infant’s initial examination were unremarkable, and he was moved to the well-baby nursery. Shortly thereafter, a cardiac murmur was noted, the cardiology department was consulted, and the child was transferred to a local tertiary care facility with a diagnosis of tetralogy of Fallot. Stable, he was discharged home at 3 days of life. Figure Mild dysmorphic facial features of a boy aged 11 years with 22q11.2DS, including a short forehead, hooded eyelids with upslanting palpebral fissures, malar flatness, bulbous nasal tip with hypoplastic alae nasi, and protuberant ears. At 5 days of life, he had jerky movements. On presentation to the local emergency department, his total calcium level was 4.7 mg/dL, and later partial hypoparathyroidism was diagnosed. At that time, a consulting geneticist suggested the diagnosis of chromosome 22q11DS. Weeks later, the family received a telephone call confirming the diagnosis with fluorescence in situ hybridization (FISH). No additional information about the diagnosis, prognosis, etiology, or recurrence risk was provided until the child was 5 months of age, when he underwent cardiac repair at a third hospital, where a comprehensive 22q11DS program was in operation. In the interim, the child had feeding difficulties requiring supplemental nasogastric tube feeds, nasal regurgitation, and gastroesophageal reflux, while the parents searched the internet for reliable information about their son’s diagnosis. Subsequent notable abnormalities and interventions included: recurrent otitis media with bilateral myringotomy tube placement at 6 months; angioplasty with left pulmonary artery stent placement after the identification of pulmonary artery stenosis with bilateral pleural effusions at age 6 years; chronic upper respiratory infections with significant T cell dysfunction requiring live viral vaccines to be held until age 7 years; velopharyngeal incompetence necessitating posterior pharyngeal flap surgery at 7 years; enamel hypoplasia and numerous caries resulting in 3 separate dental procedures under general cardiac anesthesia beginning at age 7 years; multiple cervical and thoracic vertebral anomalies with thoracic levoconvex scoliosis and upper lumbar dextroscoliosis requiring growing rod placement at age 11 years with subsequent rod extension at ages 11.5 and 12 years; postoperative hypocalcemia; short stature; constipation; and persistent idiopathic thrombocytopenia. Pertinent negative test results included normal renal ultrasound scanning and parental 22q11.2 deletion studies. On physical examination, the boy’s height and weight have consistently tracked just below the fifth percentile, with no evidence of growth hormone deficiency. His head circumference is within reference range at the 25th percentile. Dysmorphic features include: a low anterior hairline; hooded eyelids; malar flatness; normally formed but protuberant ears with attached lobes; a mildly deviated nose with a bulbous nasal tip and hypoplastic alae nasi; asymmetric crying facies with a thin upper lip; mild micrognathia; a sacral dimple; and soft tissue syndactyly of the second and third toes. Developmentally, the boy had mild delays in achieving motor milestones, sitting at 11 months and walking at 18 months. However, he exhibited significant delays in the emergence of language: he never babbled, spoke his first words at age 3 years, and only achieved full conversational speech at 7 years. However, he had relative strengths in receptive language and communicated appropriately by the use of sign language. Now quite conversant, he is mainstreamed in the seventh grade with resource room supports. Moreover, he is affable, but exhibits anxiety and perseverations. Lastly, despite numerous medical, academic, and social challenges, he participates in assisted athletics, is an avid wrestling fan, and enjoys travel. However, his exceptionally supportive parents, siblings, and extended family continue to worry about his long-term outcome and transition of care as he approaches adulthood. As demonstrated by this boy’s complicated course, practical multi-system guidelines are needed to assist the general practitioner and specialists in caring for patients with 22q11DS. Although still under-recognized, detection, including in the prenatal setting, is increasing. Moreover, the phenotypic spectrum is highly variable, and patients may present at any age. Thus, initial guidelines developed by an international panel of experts present the best practice recommendations currently available across the lifespan, with a major focus on the changing issues through childhood development.

Published
2011

40. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: Results from the international consortium on brain and behavior in 22q11.2 deletion syndrome

Author

Schneider, M., Debbane, M., Bassett, A. S., Chow, E. W. C., Fung, W. L. A., Van Den Bree, M. B. M., Owen, M., Murphy, K. C., Niarchou, M., Kates, W. R., Antshel, K. M., Fremont, W., McDonald-McGinn, D. M., Gur, R. E., Zackai, E. H., Vorstman, J., Duijff, S. N., Klaassen, P. W. J., Swillen, A., Gothelf, D., Green, T., Weizman, A., Van Amelsvoort, T., Evers, L., Boot, E., Shashi, V., Hooper, S. R., Bearden, C. E., Jalbrzikowski, M., Armando, M., Vicari, Stefano, Murphy, D. G., Ousley, O., Campbell, L. E., Simon, T. J., Eliez, S., Vicari S. (ORCID:0000-0002-5395-2262), Schneider, M., Debbane, M., Bassett, A. S., Chow, E. W. C., Fung, W. L. A., Van Den Bree, M. B. M., Owen, M., Murphy, K. C., Niarchou, M., Kates, W. R., Antshel, K. M., Fremont, W., McDonald-McGinn, D. M., Gur, R. E., Zackai, E. H., Vorstman, J., Duijff, S. N., Klaassen, P. W. J., Swillen, A., Gothelf, D., Green, T., Weizman, A., Van Amelsvoort, T., Evers, L., Boot, E., Shashi, V., Hooper, S. R., Bearden, C. E., Jalbrzikowski, M., Armando, M., Vicari, Stefano, Murphy, D. G., Ousley, O., Campbell, L. E., Simon, T. J., Eliez, S., and Vicari S. (ORCID:0000-0002-5395-2262)

Abstract

Objective: Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants. Method: The 1,402 participants with 22q11.2 deletion syndrome, ages 6-68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years. Results: Attention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were over-represented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills. Conclusions: To the authors' knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome.

Published
2014

41. The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Author

Hadley, D., Wu, Z., Kao, C., Kini, A., Mohamed-Hadley, A., Thomas, K., Vazquez, L., Qiu, H., Mentch, F., Pellegrino, R., Kim, C., Connolly, J., Glessner, J., Hakonarson, H., Pinto, D., Merikangas, A., Klei, L., Vorstman, J., Thompson, A., Regan, R., Pagnamenta, A., Oliveira, B., Magalhaes, T., Gilbert, J., Duketis, E., De Jonge, M., Cuccaro, M., Correia, C., Conroy, J., Conceiça, I., Chiocchetti, A., Casey, J., Bolshakova, N., Bacchelli, E., Anney, R., Zwaigenbaum, L., Wittemeyer, K., Wallace, S., Van Engeland, H., Soorya, L., Rogé, B., Roberts, W., Poustka, F., Mouga, S., Minshew, N., McGrew, S., Lord, C., Leboyer, M., Le Couteur, A., Kolevzon, A., Jacob, S., Guter, S., Green, J., Green, A., Gillberg, C., Fernandez, B., Duque, F., Delorme, R., Dawson, G., Brennan, S., Bourgeron, T., Bolton, P., Bolte, Sven, Hadley, D., Wu, Z., Kao, C., Kini, A., Mohamed-Hadley, A., Thomas, K., Vazquez, L., Qiu, H., Mentch, F., Pellegrino, R., Kim, C., Connolly, J., Glessner, J., Hakonarson, H., Pinto, D., Merikangas, A., Klei, L., Vorstman, J., Thompson, A., Regan, R., Pagnamenta, A., Oliveira, B., Magalhaes, T., Gilbert, J., Duketis, E., De Jonge, M., Cuccaro, M., Correia, C., Conroy, J., Conceiça, I., Chiocchetti, A., Casey, J., Bolshakova, N., Bacchelli, E., Anney, R., Zwaigenbaum, L., Wittemeyer, K., Wallace, S., Van Engeland, H., Soorya, L., Rogé, B., Roberts, W., Poustka, F., Mouga, S., Minshew, N., McGrew, S., Lord, C., Leboyer, M., Le Couteur, A., Kolevzon, A., Jacob, S., Guter, S., Green, J., Green, A., Gillberg, C., Fernandez, B., Duque, F., Delorme, R., Dawson, G., Brennan, S., Bourgeron, T., Bolton, P., and Bolte, Sven

Abstract

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P 2.40E 09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P 3.83E 23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P 4.16 04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions. © 2014 Macmillan Publishers Limited. All rights reserved.

Published
2014

42. Effect of learning a new language on children’s willingness to communicate

Author

Le Pichon, E., de Swart, H., Vorstman, J., van den Bergh, H., and Instituut voor de Lerarenopleiding (tot 2012)

Abstract

The present study was set up to evaluate to what extent multilingual study groups can be considered homogeneous. A series of interviews were conducted to investigate the metacommunicative awareness of 101 children. We compared children who had learned an additional language in a formal context (abbreviated LLE, i.e. Language Learning Experience) to those who had not (abbreviated nLLE, i.e. without a Language Learning Experience). The primary outcome measure consisted of the reactions to an imaginary situation of communication. The results of the current study suggest that LLE children were more inclined to carry out the exchange than the nLLE children. Studying the same outcome measure, no such difference was identified when comparing monolingual to multilingual children. These findings indicate that with regard to the present tasks, the presence or absence of LLE may be a more relevant factor than mono- or multilingualism.

Published
2009

43. Individual common variants exert weak effects on the risk for autism spectrum disorders

Author

Anney, R., Klei, L., Pinto, D., Almeida, J., Bacchelli, E., Baird, G., Bolshakova, N., Bölte, Sven, Bolton, P., Bourgeron, T., Brennan, S., Brian, J., Casey, J., Conroy, J., Correia, C., Corsello, C., Crawford, E., De jonge, M., Delorme, R., Duketis, E., Duque, F., Estes, A., Farrar, P., Fernandez, B., Folstein, S., Fombonne, E., Gilbert, J., Gillberg, C., Glessner, J., Green, A., Green, J., Guter, S., Heron, E., Holt, R., Howe, J., Hughes, G., Hus, V., Igliozzi, R., Jacob, S., Kenny, G., Kim, C., Kolevzon, A., Kustanovich, V., Lajonchere, C., Lamb, J., Law-Smith, M., Leboyer, M., Le couteur, A., Leventhal, B., Liu, X., Lombard, F., Lord, C., Lotspeich, L., Lund, S., Magalhaes, T., Mantoulan, C., McDougle, C., Melhem, N., Merikangas, A., Minshew, N., Mirza, G., Munson, J., Noakes, C., Nygren, G., Papanikolaou, K., Pagnamenta, A., Parrini, B., Paton, T., Pickles, A., Posey, D., Poustka, F., Ragoussis, J., Regan, R., Roberts, W., Roeder, K., Roge, B., Rutter, M., Schlitt, S., Shah, N., Sheffield, V., Soorya, L., Sousa, I., Stoppioni, V., Sykes, N., Tancredi, R., Thompson, A., Thomson, S., Tryfon, A., Tsiantis, J., Van Engeland, H., Vincent, J., Volkmar, F., Vorstman, J., Anney, R., Klei, L., Pinto, D., Almeida, J., Bacchelli, E., Baird, G., Bolshakova, N., Bölte, Sven, Bolton, P., Bourgeron, T., Brennan, S., Brian, J., Casey, J., Conroy, J., Correia, C., Corsello, C., Crawford, E., De jonge, M., Delorme, R., Duketis, E., Duque, F., Estes, A., Farrar, P., Fernandez, B., Folstein, S., Fombonne, E., Gilbert, J., Gillberg, C., Glessner, J., Green, A., Green, J., Guter, S., Heron, E., Holt, R., Howe, J., Hughes, G., Hus, V., Igliozzi, R., Jacob, S., Kenny, G., Kim, C., Kolevzon, A., Kustanovich, V., Lajonchere, C., Lamb, J., Law-Smith, M., Leboyer, M., Le couteur, A., Leventhal, B., Liu, X., Lombard, F., Lord, C., Lotspeich, L., Lund, S., Magalhaes, T., Mantoulan, C., McDougle, C., Melhem, N., Merikangas, A., Minshew, N., Mirza, G., Munson, J., Noakes, C., Nygren, G., Papanikolaou, K., Pagnamenta, A., Parrini, B., Paton, T., Pickles, A., Posey, D., Poustka, F., Ragoussis, J., Regan, R., Roberts, W., Roeder, K., Roge, B., Rutter, M., Schlitt, S., Shah, N., Sheffield, V., Soorya, L., Sousa, I., Stoppioni, V., Sykes, N., Tancredi, R., Thompson, A., Thomson, S., Tryfon, A., Tsiantis, J., Van Engeland, H., Vincent, J., Volkmar, F., and Vorstman, J.

Abstract

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm < 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Published
2012

44. A double hit implicates DIAPH3 as an autism risk gene

Author

Vorstman, J A S, primary, van Daalen, E, additional, Jalali, G R, additional, Schmidt, E R E, additional, Pasterkamp, R J, additional, de Jonge, M, additional, Hennekam, E A M, additional, Janson, E, additional, Staal, W G, additional, van der Zwaag, B, additional, Burbach, J P H, additional, Kahn, R S, additional, Emanuel, B S, additional, van Engeland, H, additional, and Ophoff, R A, additional

Published
2010
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48. land van de wolf, beer en draculie

Author

Vorstman, J. and Vorstman, J.

Abstract

Een kijkje in de Roemeense Karpaten, het land waar de wolven nog huilen

Published
1996

49. A comprehensive overview of neuropsychiatric symptoms in adolescents with 22q11.2 deletion syndrome.

Author

Selten, I., Blok, J., Boerma, T., Djelantik, A. A. A. M. J., Houben, M., Wijnen, F., Zinkstok, J., Vorstman, J. A. S., and Fiksinski, A. M.

Subjects
*DIGEORGE syndrome, *GENETIC variation, *INTELLIGENCE tests, *CLINICAL medicine, *STATISTICAL correlation
Abstract

Background Methods Results Conclusions The 22q11.2 deletion syndrome (22q11DS) is associated with a variety of neuropsychiatric outcomes that vary across deletion carriers. We adopted a dimensional approach to provide a comprehensive overview of neuropsychiatric symptom expression in adolescents with 22q11DS and further our understanding of the observed phenotypical heterogeneity.Participants were 208 adolescents with 22q11DS between 10 and 19 years old. Semi‐structured clinical interviews and IQ tests were used to quantify symptom expression on multiple symptom dimensions, some reflecting DSM‐IV diagnostic domains. We investigated symptom expression in those with and without a formal DSM‐IV classification and examined between and within symptom dimensions. We used correlation analyses to explore associations between different symptom dimensions.We demonstrated inter‐individual differences in symptom expression, both between and within neuropsychiatric symptom dimensions. On most symptom dimensions, more than 50% of adolescents expressed at least one clinically relevant symptom. In addition, a significant proportion of youth without a formal DSM‐IV diagnosis reported clinically relevant symptoms (e.g. >85% of those without an ADHD diagnosis reported ADHD symptoms). The exploratory correlation analysis indicated mostly positive correlations between symptom dimensions.The finding that most adolescents with 22q11DS express neuropsychiatric symptoms, even in the absence of a DSM‐IV classification, has substantial ramifications for guiding adequate support. Findings may spur further research into the dimensional structure of neuropsychiatric symptoms in 22q11DS and aid in uncovering mechanisms that contribute to symptom expression. Ultimately, this provides leads to improve clinical care for 22q11DS and to understand phenotypical variation in other high‐risk genetic variants. [ABSTRACT FROM AUTHOR]

Published
2024
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50. The role of rare compound heterozygous events in autism spectrum disorder

Author

Thomas Bourgeron, Alistair T. Pagnamenta, Jeremy R. Parr, Louise Gallagher, Christine M. Freitag, Jacob A. S. Vorstman, Sean Ennis, Isaac J. Nijman, Fabrice Colas, Kristel R. van Eijk, Bochao Danae Lin, Jurjen J. Luykx, Jelena Medic, Sabine M. Klauck, Elena Maestrini, Astrid M. Vicente, Richard Anney, Guiomar Oliveira, Elena Bacchelli, Hilary Coon, Andreas G. Chiocchetti, William J. Brands, Utrecht University [Utrecht], Henan University, Kaifeng, Newcastle University [Newcastle], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Goethe-Universität Frankfurt am Main, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University of Utah School of Medicine [Salt Lake City], Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), Centro Hospitalar e Universitário [Coimbra], University of Oxford [Oxford], Trinity College Dublin, University College Dublin [Dublin] (UCD), Cardiff University, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), GGNet Mental Health [Apeldoorn, The Netherlands], The Hospital for sick children [Toronto] (SickKids), University of Toronto, This study has been funded by the Dutch Brain Foundation (Hersenstichting Nederland) to JV., Lin B.D., Colas F., Nijman I.J., Medic J., Brands W., Parr J.R., van Eijk K.R., Klauck S.M., Chiocchetti A.G., Freitag C.M., Maestrini E., Bacchelli E., Coon H., Vicente A., Oliveira G., Pagnamenta A.T., Gallagher L., Ennis S., Anney R., Bourgeron T., Luykx J.J., Vorstman J., Henan University, University of Oxford, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, Proband, DNA Copy Number Variations, Autism Spectrum Disorder, Autism, Biology, Compound heterozygosity, ASD, Article, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, Genetic Predisposition to Disease, Allele, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Gene, Biological Psychiatry, Alleles, MESH: Autism Spectrum Disorder, Genetics, Comparative genomics, MESH: Humans, MESH: Alleles, [SCCO.NEUR]Cognitive science/Neuroscience, MESH: Genetic Predisposition to Disease, Autism spectrum disorders, medicine.disease, Penetrance, Autism Spectrum Disorders, Autism, CNVs, Deletions, SNVs, Compound Heterozygosity, Targeted Sequencing, Psychiatry and Mental health, 030104 developmental biology, Autism spectrum disorder, Perturbações do Desenvolvimento Infantil e Saúde Mental, MESH: DNA Copy Number Variations, 030217 neurology & neurosurgery
Abstract

The identification of genetic variants underlying autism spectrum disorders (ASDs) may contribute to a better understanding of their underlying biology. To examine the possible role of a specific type of compound heterozygosity in ASD, namely, the occurrence of a deletion together with a functional nucleotide variant on the remaining allele, we sequenced 550 genes in 149 individuals with ASD and their deletion-transmitting parents. This approach allowed us to identify additional sequence variants occurring in the remaining allele of the deletion. Our main goal was to compare the rate of sequence variants in remaining alleles of deleted regions between probands and the deletion-transmitting parents. We also examined the predicted functional effect of the identified variants using Combined Annotation-Dependent Depletion (CADD) scores. The single nucleotide variant-deletion co-occurrence was observed in 13.4% of probands, compared with 8.1% of parents. The cumulative burden of sequence variants (n = 68) in pooled proband sequences was higher than the burden in pooled sequences from the deletion-transmitting parents (n = 41, X2 = 6.69, p = 0.0097). After filtering for those variants predicted to be most deleterious, we observed 21 of such variants in probands versus 8 in their deletion-transmitting parents (X2 = 5.82, p = 0.016). Finally, cumulative CADD scores conferred by these variants were significantly higher in probands than in deletion-transmitting parents (burden test, β = 0.13; p = 1.0 × 10−5). Our findings suggest that the compound heterozygosity described in the current study may be one of several mechanisms explaining variable penetrance of CNVs with known pathogenicity for ASD.

Published
2020
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