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1. Variants of the CNTNAP2 5′ promoter as risk factors for autism spectrum disorders: a genetic and functional approach

Author: Chiocchetti, A G, Kopp, M, Waltes, R, Haslinger, D, Duketis, E, Jarczok, T A, Poustka, F, Voran, A, Graab, U, Meyer, J, Klauck, S M, Fulda, S, and Freitag, C M
Published: 2015
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2. Mutation and expression analyses of the ribosomal protein gene RPL10 in an extended German sample of patients with autism spectrum disorder

Author: Chiocchetti, A., Pakalapati, G., Duketis, E., Wiemann, S., Poustka, A., Poustka, F., and Klauck, S. M.
Published: 2011
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3. Lack of replication of previous autism spectrum disorder GWAS hits in European populations

Author: Torrico, B., Chiocchetti, A.G., Bacchelli, E., Trabetti, E., Hervas, A., Franke, B., Buitelaar, J.K., Rommelse, N.N.J., Yousaf, A., Duketis, E., Freitag, C.M., Caballero-Andaluz, R., Martinez-Mir, A., Scholl, F.G., Ribases, M., Battaglia, A., Malerba, G., Delorme, R., Benabou, M., Maestrini, E., Bourgeron, T., Cormand, B., Toma, C., Torrico, B., Chiocchetti, A.G., Bacchelli, E., Trabetti, E., Hervas, A., Franke, B., Buitelaar, J.K., Rommelse, N.N.J., Yousaf, A., Duketis, E., Freitag, C.M., Caballero-Andaluz, R., Martinez-Mir, A., Scholl, F.G., Ribases, M., Battaglia, A., Malerba, G., Delorme, R., Benabou, M., Maestrini, E., Bourgeron, T., Cormand, B., and Toma, C.
Abstract: Contains fulltext : 169730.pdf (publisher's version ) (Closed access), Common variants contribute significantly to the genetics of autism spectrum disorder (ASD), although the identification of individual risk polymorphisms remains still elusive due to their small effect sizes and limited sample sizes available for association studies. During the last decade several genome-wide association studies (GWAS) have enabled the detection of a few plausible risk variants. The three main studies are family-based and pointed at SEMA5A (rs10513025), MACROD2 (rs4141463) and MSNP1 (rs4307059). In our study we attempted to replicate these GWAS hits using a case-control association study in five European populations of ASD patients and gender-matched controls, all Caucasians. Results showed no association of individual variants with ASD in any of the population groups considered or in the combined European sample. We performed a meta-analysis study across five European populations for rs10513025 (1,904 ASD cases and 2,674 controls), seven European populations for rs4141463 (2,855 ASD cases and 36,177 controls) and five European populations for rs4307059 (2,347 ASD cases and 2,764 controls). The results showed an odds ratio (OR) of 1.05 (95% CI = 0.84-1.32) for rs10513025, 1.0002 (95% CI = 0.93-1.08) for rs4141463 and 1.01 (95% CI = 0.92-1.1) for rs4307059, with no significant P-values (rs10513025, P = 0.73; rs4141463, P = 0.95; rs4307059, P = 0.9). No association was found when we considered either only high functioning autism (HFA), genders separately or only multiplex families. Ongoing GWAS projects with larger ASD cohorts will contribute to clarify the role of common variation in the disorder and will likely identify risk variants of modest effect not detected previously. Autism Res 2017, 10: 202-211. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
Published: 2017

4. Lack of replication of previous autism spectrum disorder GWAS hits in European populations

Author: Torrico, B, Chiocchetti, AG, Bacchelli, E, Trabetti, E, Hervás, A, Franke, B, Buitelaar, JK, Rommelse, N, Yousaf, A, Duketis, E, Freitag, CM, Caballero-Andaluz, R, Martinez-Mir, A, Scholl, FG, Ribasés, M, Battaglia, A, Malerba, G, Delorme, R, Benabou, M, Maestrini, E, Bourgeron, T, Cormand, B, Toma, C ; https://orcid.org/0000-0003-3901-7507, Torrico, B, Chiocchetti, AG, Bacchelli, E, Trabetti, E, Hervás, A, Franke, B, Buitelaar, JK, Rommelse, N, Yousaf, A, Duketis, E, Freitag, CM, Caballero-Andaluz, R, Martinez-Mir, A, Scholl, FG, Ribasés, M, Battaglia, A, Malerba, G, Delorme, R, Benabou, M, Maestrini, E, Bourgeron, T, Cormand, B, and Toma, C ; https://orcid.org/0000-0003-3901-7507
Abstract: Common variants contribute significantly to the genetics of autism spectrum disorder (ASD), although the identification of individual risk polymorphisms remains still elusive due to their small effect sizes and limited sample sizes available for association studies. During the last decade several genome-wide association studies (GWAS) have enabled the detection of a few plausible risk variants. The three main studies are family-based and pointed at SEMA5A (rs10513025), MACROD2 (rs4141463) and MSNP1 (rs4307059). In our study we attempted to replicate these GWAS hits using a case-control association study in five European populations of ASD patients and gender-matched controls, all Caucasians. Results showed no association of individual variants with ASD in any of the population groups considered or in the combined European sample. We performed a meta-analysis study across five European populations for rs10513025 (1,904 ASD cases and 2,674 controls), seven European populations for rs4141463 (2,855 ASD cases and 36,177 controls) and five European populations for rs4307059 (2,347 ASD cases and 2,764 controls). The results showed an odds ratio (OR) of 1.05 (95% CI = 0.84–1.32) for rs10513025, 1.0002 (95% CI = 0.93–1.08) for rs4141463 and 1.01 (95% CI = 0.92–1.1) for rs4307059, with no significant P-values (rs10513025, P = 0.73; rs4141463, P = 0.95; rs4307059, P = 0.9). No association was found when we considered either only high functioning autism (HFA), genders separately or only multiplex families. Ongoing GWAS projects with larger ASD cohorts will contribute to clarify the role of common variation in the disorder and will likely identify risk variants of modest effect not detected previously. Autism Res 2017, 10: 202–211. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
Published: 2017

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

Author: Hadley, D., Wu, Z.L., 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.A., Thompson, A., Regan, R., Pagnamenta, A.T., Oliveira, B., Magalhaes, T.R., Gilbert, J., Duketis, E., De Jonge, M.V., Cuccaro, M., Correia, C.T., Conroy, J., Conceição, I.C., Chiocchetti, A.G., Casey, J.P., Bolshakova, N., Bacchelli, E., Anney, R., Zwaigenbaum, L., Wittemeyer, K., Wallace, S., Engeland, Hv, Soorya, L., Rogé, B., Roberts, W., Poustka, F., Mouga, S., Minshew, N., McGrew, S.G., Lord, C., Leboyer, M., Le Couteur, A.S., Kolevzon, A., Jacob, S., Guter, S., Green, J., Green, A., Gillberg, C., Fernandez, B.A., Duque, F., Delorme, R., Dawson, G., Café, C., Brennan, S., Bourgeron, T., Bolton, P.F., Bölte, S., Bernier, R., Baird, G., Bailey, A.J., Anagnostou, E., Almeida, J., Wijsman, E.M., Vieland, V.J., Vicente, A.M., Schellenberg, G.D., Pericak-Vance, M., Paterson, A.D., Parr, J.R., Oliveira, G., Correia, C., Nurnberger, J.I., Monaco, A.P., Maestrini, E., Klauck, S.M., Haines, J.L., Geschwind, D.H., Freitag, C.M., Folstein, S.E., Ennis, S., Coon, H., Battaglia, A., Szatmari, P., Sutcliffe, J.S., Hallmayer, J., Gill, M., Cook, E.H., Buxbaum, J.D., Devlin, B., Gallagher, L., Betancur, C., and Scherer, S.W.
Subjects: Autism, Perturbações do Desenvolvimento Infantil e Saúde Mental
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≤4.16E-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.
Published: 2014

6. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders

Author: Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L, Thiruvahindrapuram, B., Xu, X., Ziman, R., Wang, Z., Vorstman, J.A., Thompson, A., Regan, R., Pilorge, M., Pellecchia, G., Pagnamenta, A.T., Oliveira, B., Marshall, C.R., Magalhães, T.R., Lowe, J.K., Howe, J.L., Griswold, A.J., Gilbert, J., Duketis, E., Dombroski, B.A., De Jonge, M.V., Cuccaro, M., Crawford, E.L., Correia, C.T., Conroy, J., Conceição, I.C, Chiocchetti, A.G., Casey, J.P., Cai, G., Cabrol, C., Bolshakova, N., Bacchelli, E., Anney, R., Gallinger, S., Cotterchio, M., Casey, G., Zwaigenbaum, L., Wittemeyer, K., Wing, K., Wallace, S., van Engeland, H., Tryfon, A., Thomson, S., Soorya, L., Rogé, B., Roberts, W., Poustka, F., Mouga, S., Minshew, N., McInnes, L.A., McGrew, S.G., Lord, C., Leboyer, M., Le Couteur, A.S., Kolevzon, A., Jiménez González, P., Jacob, S., Holt, R., Guter, S., Green, J., Green, A., Gillberg, C., Fernandez, B.A., Duque, F., Delorme, R., Dawson, G., Chaste, P., Café, C., Brennan, S., Bourgeron, T., Bolton, P.F., Bölte, S., Bernier, R., Baird, G., Bailey, A.J., Anagnostou, E., Almeida, J., Wijsman, E.M., Vieland, V.J., Vicente, A.M., Schellenberg, G.D., Pericak-Vance, M., Paterson, A.D., Parr, J.R., Oliveira, G., Nurnberger, J.I., Monaco, A.P., Maestrini, E., Klauck, S.M., Hakonarson, H., Haines, J.L., Geschwind, D.H., Freitag, C.M., Folstein, S.E., Ennis, S., Coon, H., Battaglia, A., Szatmari, P., Sutcliffe, J.S., Hallmayer, J., Gill, M., Cook, E.H., Buxbaum, J.D., Devlin, B., Gallagher, L., and Betancur, C.
Subjects: Autism Spectrum Disorders, Rare copy-number variation, Autism, mental disorders, Perturbações do Desenvolvimento Infantil e Saúde Mental
Abstract: Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
Published: 2014

7. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders

Author: State, M., Leblond, C.S., Heinrich, J., Delorme, R., Proepper, C., Betancur, C., Huguet, G., Konyukh, M., Chaste, P., Ey, E., Rastam, M., Anckarsäter, H., Nygren, G., Gillberg, I.C., Melke, J., Toro, R., Regnault, B., Fauchereau, F., Mercati, O., Lemière, N., Skuse, D., Poot, M., Holt, R., Monaco, A.P., Järvelä, I., Kantojärvi, K., Vanhala, R., Curran, S., Collier, D.A., Bolton, P., Chiocchetti, A., Klauck, S.M., Poustka, F., Freitag, C.M., Waltes, R., Kopp, M., Duketis, E., Bacchelli, E., Minopoli, F., Ruta, L., Battaglia, A., Mazzone, L., Maestrini, E., Sequeira, A.F., Oliveira, B., Vicente, A., Oliveira, G., Pinto, D., Scherer, S.W., Zelenika, D., Delepine, M., Lathrop, M., Bonneau, D., Guinchat, V., Devillard, F., Assouline, B., Mouren, M., Leboyer, M., Gillberg, C., Boeckers, T.M., and Bourgeron, T.
Subjects: mental disorders
Abstract: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
Published: 2012

8. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Author: Casey, J.P. Magalhaes, T. Conroy, J.M. Regan, R. Shah, N. Anney, R. Shields, D.C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bolton, P.F. Bourgeron, T. Brennan, S. Cali, P. Correia, C. Corsello, C. Coutanche, M. Dawson, G. De Jonge, M. Delorme, R. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Foley, S. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Green, J. Guter, S.J. Hakonarson, H. Holt, R. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Lamb, J.A. Leboyer, M. Couteur, A.L. Leventhal, B.L. Lord, C. Lund, S.C. Maestrini, E. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Miller, J. Minopoli, F. Mirza, G.K. Munson, J. Nelson, S.F. Nygren, G. Oliveira, G. Pagnamenta, A.T. Papanikolaou, K. Parr, J.R. Parrini, B. Pickles, A. Pinto, D. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Ragoussis, J. Roge, B. Rutter, M.L. Sequeira, A.F. Soorya, L. Sousa, I. Sykes, N. Stoppioni, V. Tancredi, R. Tauber, M. Thompson, A.P. Thomson, S. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Vorstman, J.A.S. Wallace, S. Wang, K. Wassink, T.H. White, K. Wing, K. Wittemeyer, K. Yaspan, B.L. Zwaigenbaum, L. Betancur, C. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Geschwind, D.H. Haines, J.L. Hallmayer, J. Monaco, A.P. Nurnberger Jr., J.I. Pericak-Vance, M.A. Schellenberg, G.D. Scherer, S.W. Sutcliffe, J.S. Szatmari, P. Vieland, V.J. Wijsman, E.M. Green, A. Gill, M. Gallagher, L. Vicente, A. Ennis, S.
Subjects: mental disorders
Abstract: Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data. © The Author(s) 2011.
Published: 2012

9. Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders

Author: Anney, R.J., Kenny, E.M., O'Dushlaine, C., Parkhomenka, E., Buxbaum, J.D., Sutcliffe, J., Gill, M., Gallagher, L., Bailey, A.J., Fernandez, B.A., Szatmari, P., Nurnberger Jr, J.I., McDougle, C.J., Posey, D.J., Lord, C., Corsello, C., Hus, V., Kolevzon, A., Soorya, L., Parkhomenko, E., Scherer, S.W., Leventhal, B.L., Dawson, G., Vieland, V.J., Hakonarson, H., Glessner, J.T., Kim, C., Wang, K., Schellenberg, G.D., Devlin, B., Klei, L., Patterson, A., Minshew, N., Sutcliffe, J.S., Haines, J.L., Lund, S.C., Thomson, S., Yaspan, B.L., Coon, H., Miller, J., McMahon, W.M., Munson, J., Marshall, C.R., Estes, A., Wijsman, EM., The Autism Genome Project, Pinto, D., Vincent, J.B., Fombonne, E., Betancur, C., Delorme, R., Leboyer, M., Bourgeron, T., Mantoulan, C., Roge, B., Tauber, M., Freitag, C.M., Poustka, F., Duketis, E., Klauck, S.M., Poustka, A., Papanikolaou, K., Tsiantis, J., Anney, R., Bolshakova, N., Brennan, S., Hughes, G., McGrath, J., Merikangas, A., Ennis, S., Green, A., Casey, J.P., Conroy, J.M., Regan, R., Shah, N., Maestrini, E., Bacchelli, E., Minopoli, F., Stoppioni, V., Battaglia, A., Igliozzi, R., Parrini, B., Tancredi, R., Oliveira, G., Almeida, J., Duque, F., Vicente, A.M., Correia, C., Magalhaes, T.R., Gillberg, C., Nygren, G., Jonge, M.D., Van Engeland, H., Vorstman, J.A., Wittemeyer, K., Baird, G., Bolton, P.F, Rutter, M.L., Green, J., Lamb, J.A., Pickles, A., Parr, J.R., Couteur, A.L., Berney, T., McConachie, H., Wallace, S., Coutanche, M., Foley, S., White, K., Monaco, A.P., Holt, R., Farrar, P., Pagnamenta, A.T., Mirza, G.K., Ragoussis, J., Sousa, I., Sykes, N., Wing, K., Hallmayer, J., Cantor, R.M., Nelson, S.F., Geschwind, D.H., Abrahams, B.S., Volkmar, F., Pericak-Vance, M.A., Cuccaro, M.L., Gilbert, J., Cook, E.H., Guter, S.J., and Jacob, S.
Subjects: Pathway analysis, Autism, Perturbações do Desenvolvimento Infantil e Saúde Mental, Gene ontology, Genome-wide association analysis, Family-based association test
Abstract: Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings.
Published: 2011

10. Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders

Author: Anney, R.J.L. Kenny, E.M. O'Dushlaine, C. Yaspan, B.L. Parkhomenka, E. Buxbaum, J.D. Sutcliffe, J. Gill, M. Gallagher, L. Bailey, A.J. Fernandez, B.A. Szatmari, P. Scherer, S.W. Patterson, A. Marshall, C.R. Pinto, D. Vincent, J.B. Fombonne, E. Betancur, C. Delorme, R. Leboyer, M. Bourgeron, T. Mantoulan, C. Roge, B. Tauber, M. Freitag, C.M. Poustka, F. Duketis, E. Klauck, S.M. Poustka, A. Papanikolaou, K. Tsiantis, J. Bolshakova, N. Brennan, S. Hughes, G. McGrath, J. Merikangas, A. Ennis, S. Green, A. Casey, J.P. Conroy, J.M. Regan, R. Shah, N. Maestrini, E. Bacchelli, E. Minopoli, F. Stoppioni, V. Battaglia, A. Igliozzi, R. Parrini, B. Tancredi, R. Oliveira, G. Almeida, J. Duque, F. Vicente, A. Correia, C. Magalhaes, T.R. Gillberg, C. Nygren, G. De Jonge, M. Van Engeland, H. Vorstman, J.A.S. Wittemeyer, K. Baird, G. Bolton, P.F. Rutter, M.L. Green, J. Lamb, J.A. Pickles, A. Parr, J.R. Le Couteur, A. Berney, T. McConachie, H. Wallace, S. Coutanche, M. Foley, S. White, K. Monaco, A.P. Holt, R. Farrar, P. Pagnamenta, A.T. Mirza, G.K. Ragoussis, J. Sousa, I. Sykes, N. Wing, K. Hallmayer, J. Cantor, R.M. Nelson, S.F. Geschwind, D.H. Abrahams, B.S. Volkmar, F. Pericak-Vance, M.A. Cuccaro, M.L. Gilbert, J. Cook, E.H. Guter, S.J. Jacob, S. Nurnberger, J.I., Jr. McDougle, C.J. Posey, D.J. Lord, C. Corsello, C. Hus, V. Kolevzon, A. Soorya, L. Parkhomenko, E. Leventhal, B.L. Dawson, G. Vieland, V.J. Hakonarson, H. Glessner, J.T. Kim, C. Wang, K. Schellenberg, G.D. Devlin, B. Klei, L. Minshew, N. Sutcliffe, J.S. Haines, J.L. Lund, S.C. Thomson, S. Coon, H. Miller, J. McMahon, W.M. Munson, J. Estes, A. Wijsman, E.M. Autism Genome Project
Abstract: Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings. © 2011 Macmillan Publishers Limited All rights reserved.
Published: 2011

11. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways.

Author: O'Dushlaine, C., Rossin, L., Lee, P.H., Duncan, L., Parikshak, N.N., Newhouse, S., Ripke, S., Neale, B.M., Purcell, S., Posthuma, D., Nurnberger, J.I., Lee, S.H., Faraone, S.V., Perlis, R.H., Mowry, B.J., Thapar, A., Goddard, M.E., Witte, J.S., Absher, D., Agartz, I., Akil, H., Amin, F., Andreassen, O.A., Anjorin, A., Anney, R., Anttila, V., Arking, D.E., Asherson, P., Azevedo, M.H., Backlund, L., Badner, J.A., Bailey, A.J., Banaschewski, T., Barchas, J.D., Barnes, M.R., Barrett, T.B., Bass, N., Battaglia, A., Bauer, M., Bayes, M., Bellivier, F., Bergen, S.E., Berrettini, W., Betancur, C., Bettecken, T., Biederman, J., Binder, E.B., Black, D.W., Blackwood, D.H., Bloss, C.S., Boehnke, M., Boomsma, D.I., Breuer, R., Bruggeman, R., Cormican, P., Buccola, N.G., Buitelaar, J.K., Bunney, W.E., Buxbaum, J.D., Byerley, W.F., Byrne, E.M., Caesar, S., Cahn, W., Cantor, R.M., Casas, M., Chakravarti, A., Chambert, K., Choudhury, K., Cichon, S., Mattheisen, M., Cloninger, C.R., Collier, D.A., Cook, E.H., Coon, H., Cormand, B., Corvin, A., Coryell, W.H., Craig, D.W., Craig, I., Crosbie, J., Cuccaro, M.L., Curtis, D., Czamara, D., Datta, S., Dawson, G., Day, R., Geus, E.J. de, Degenhardt, F., Djurovic, S., Donohoe, G., Doyle, A., Duan, J., Dudbridge, F., Duketis, E., Ebstein, R.P., Edenberg, H.J., Elia, J., Ennis, S., Etain, B., Fanous, A., Farmer, A., Ferrier, I.N., Flickinger, M., Foroud, T.M., Frank, J., Franke, B., Fraser, C., Freedman, R., Freimer, N.B., Freitag, C.M., Friedl, M., Frisen, L., Gallagher, L., Gejman, P.V., Georgieva, L., Gershon, E.S., Giegling, I., Gill, M., Gordon, S., Gordon-Smith, K., Green, E.K., Greenwood, T.A., Grice, D.E., Gross, M., Grozeva, D., Guan, W., Gurling, H., Haan, L. de, Haines, J.L., Hakonarson, H., Hallmayer, J., Hamilton, S.P., Hamshere, M., Hansen, T., Hartmann, A.M., Hauutzinger, M., Heath, A.C., Henders, A.K., Herms, S., Hickie, I., et al., O'Dushlaine, C., Rossin, L., Lee, P.H., Duncan, L., Parikshak, N.N., Newhouse, S., Ripke, S., Neale, B.M., Purcell, S., Posthuma, D., Nurnberger, J.I., Lee, S.H., Faraone, S.V., Perlis, R.H., Mowry, B.J., Thapar, A., Goddard, M.E., Witte, J.S., Absher, D., Agartz, I., Akil, H., Amin, F., Andreassen, O.A., Anjorin, A., Anney, R., Anttila, V., Arking, D.E., Asherson, P., Azevedo, M.H., Backlund, L., Badner, J.A., Bailey, A.J., Banaschewski, T., Barchas, J.D., Barnes, M.R., Barrett, T.B., Bass, N., Battaglia, A., Bauer, M., Bayes, M., Bellivier, F., Bergen, S.E., Berrettini, W., Betancur, C., Bettecken, T., Biederman, J., Binder, E.B., Black, D.W., Blackwood, D.H., Bloss, C.S., Boehnke, M., Boomsma, D.I., Breuer, R., Bruggeman, R., Cormican, P., Buccola, N.G., Buitelaar, J.K., Bunney, W.E., Buxbaum, J.D., Byerley, W.F., Byrne, E.M., Caesar, S., Cahn, W., Cantor, R.M., Casas, M., Chakravarti, A., Chambert, K., Choudhury, K., Cichon, S., Mattheisen, M., Cloninger, C.R., Collier, D.A., Cook, E.H., Coon, H., Cormand, B., Corvin, A., Coryell, W.H., Craig, D.W., Craig, I., Crosbie, J., Cuccaro, M.L., Curtis, D., Czamara, D., Datta, S., Dawson, G., Day, R., Geus, E.J. de, Degenhardt, F., Djurovic, S., Donohoe, G., Doyle, A., Duan, J., Dudbridge, F., Duketis, E., Ebstein, R.P., Edenberg, H.J., Elia, J., Ennis, S., Etain, B., Fanous, A., Farmer, A., Ferrier, I.N., Flickinger, M., Foroud, T.M., Frank, J., Franke, B., Fraser, C., Freedman, R., Freimer, N.B., Freitag, C.M., Friedl, M., Frisen, L., Gallagher, L., Gejman, P.V., Georgieva, L., Gershon, E.S., Giegling, I., Gill, M., Gordon, S., Gordon-Smith, K., Green, E.K., Greenwood, T.A., Grice, D.E., Gross, M., Grozeva, D., Guan, W., Gurling, H., Haan, L. de, Haines, J.L., Hakonarson, H., Hallmayer, J., Hamilton, S.P., Hamshere, M., Hansen, T., Hartmann, A.M., Hauutzinger, M., Heath, A.C., Henders, A.K., Herms, S., Hickie, I., and et al.
Abstract: Contains fulltext : 153763pre.pdf (preprint version ) (Open Access)
Published: 2015

12. Functional impact of global rare copy number variation in autism spectrum disorders

Author: Pinto, D. Pagnamenta, A.T. Klei, L. Anney, R. Merico, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bader, G.D. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Bryson, S.E. Carson, A.R. Casallo, G. Casey, J. Chung, B.H.Y. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Cytrynbaum, C. Dawson, G. De Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, A. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Pilorge, M. Piven, J. Ponting, C.P. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Sequeira, A.F. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stein, O. Sykes, N. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Webber, C. Weksberg, R. Wing, K. Wittemeyer, K. Wood, S. Wu, J. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Devlin, B. Ennis, S. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Hallmayer, J. Miller, J. Monaco, A.P. Nurnberger Jr, J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Scherer, S.W. Sutcliffe, J.S. Betancur, C.
Subjects: mental disorders
Abstract: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours 1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed the genome-wide characteristics of rare (
Published: 2010

13. A genome-wide scan for common alleles affecting risk for autism

Author: Anney, R. Klei, L. Pinto, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Sykes, N. Pagnamenta, A.T. Almeida, J. Bacchelli, E. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Carson, A.R. Casallo, G. Casey, J. Chu, S.H. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Dawson, G. de Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Melhem, N.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Wing, K. Wittemeyer, K. Wood, S. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Betancur, C. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Miller, J. Monaco, A.P. Nurnberger Jr., J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Scherer, S.W. Sutcliffe, J.S. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Devlin, B. Ennis, S. Hallmayer, J.
Abstract: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 3 10-28. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10-28 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C. © The Author 2010. Published by Oxford University Press. All rights reserved.
Published: 2010

14. A genome-wide linkage and association scan reveals novel loci for autism

Author: Weiss, L.A. Arking, D.E. Daly, M.J. Chakravarti, A. Brune, C.W. West, K. O'Connor, A. Hilton, G. Tomlinson, R.L. West, A.B. Cook Jr., E.H. Green, T. Chang, S.-C. Gabriel, S. Gates, C. Hanson, E.M. Kirby, A. Korn, J. Kuruvilla, F. McCarroll, S. Morrow, E.M. Neale, B. Purcell, S. Sasanfar, R. Sougnez, C. Stevens, C. Altshuler, D. Gusella, J. Santangelo, S.L. Sklar, P. Tanzi, R. Anney, R. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Betancur, C. Bölte, S. Bolton, P.F. Brian, J. Bryson, S.E. Buxbaum, J.D. Cabrito, I. Cai, G. Cantor, R.M. Coon, H. Conroy, J. Correia, C. Corsello, C. Crawford, E.L. Cuccaro, M.L. Dawson, G. De Jonge, M. Devlin, B. Duketis, E. Ennis, S. Estes, A. Farrar, P. Fombonne, E. Freitag, C.M. Gallagher, L. Geschwind, D.H. Gilbert, J. Gill, M. Gillberg, C. Goldberg, J. Green, A. Green, J. Guter, S.J. Haines, J.L. Hallmayer, J.F. Hus, V. Klauck, S.M. Korvatska, O. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventha, B.L. Liu, X.-Q. Lord, C. Lotspeich, L.J. Maestrini, E. Magalhaes, T. Mahoney, W. Mantoulan, C. McConachie, H. McDougle, C.J. McMahon, W.M. Marshall, C.R. Miller, J. Minshew, N.J. Monaco, A.P. Munson, J. Nurnberger Jr., J.I. Oliveira, G. Pagnamenta, A. Papanikolaou, K. Parr, J.R. Paterson, A.D. Pericak-Vance, M.A. Pickles, A. Pinto, D. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Regan, R. Reichert, J. Renshaw, K. Roberts, W. Roge, B. Rutter, M.L. Salt, J. Schellenberg, G.D. Scherer, S.W. Sheffield, V. Sutcliffe, J.S. Szatmari, P. Tansey, K. Thompson, A.P. Tsiantis, J. Van Engeland, H. Vicente, A.M. Vieland, V.J. Volkmar, F. Wallace, S. Wassink, T.H. Wijsman, E.M. Wing, K. Wittemeyer, K. Yaspan, B.L. Zwaigenbaum, L. Yoo, S.-Y. Hill, R.S. Mukaddes, N.M. Balkhy, S. Gascon, G. Al-Saad, S. Hashmi, A. Ware, J. Joseph, R.M. LeClair, E. Partlow, J.N. Barry, B. Walsh, C.A. Pauls, D. Moilanen, I. Ebeling, H. Mattila, M.-L. Kuusikko, S. Jussila, K. Ignatius, J. Tolouei, A. Ghadami, M. Rostami, M. Hosseinipour, A. Valujerdi, M. Andresen, K. Winkloski, B. Haddad, S. Kunkel, L. Kohane, Z. Tran, T. Won Kong, S. O'Neil, S.B. Hundley, R. Holm, I. Peters, H. Baroni, E. Cangialose, A. Jackson, L. Albers, L. Becker, R. Bridgemohan, C. Friedman, S. Munir, K. Nazir, R. Palfrey, J. Schonwald, A. Simmons, E. Rappaport, L.A. Gauthier, J. Mottron, L. Joober, R. Rouleau, G. Rehnstrom, K. Von Wendt, L. Peltonen, L.
Abstract: Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.
Published: 2009

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

Author: Waltes, R., Duketis, E., Knapp, M., Anney, R., Huguet, G., Schlitt, S., Jarczok, T., Sachse, M., Kämpfer, L., Kleinböck, T., Poustka, F., Bolte, Sven, Schmötzer, G., Voran, A., Huy, E., Meyer, J., Bourgeron, T., Klauck, S., Freitag, C., Chiocchetti, A., Waltes, R., Duketis, E., Knapp, M., Anney, R., Huguet, G., Schlitt, S., Jarczok, T., Sachse, M., Kämpfer, L., Kleinböck, T., Poustka, F., Bolte, Sven, Schmötzer, G., Voran, A., Huy, E., Meyer, J., Bourgeron, T., Klauck, S., Freitag, C., and Chiocchetti, A.
Abstract: Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (N = 192 and N = 254 families, respectively) and report association for rs7170637 (CYFIP1; set 1 and combined sets), rs6923492 (GRM1; combined sets), and rs25925 (CAMK4; combined sets). An additional risk score based on variants with an odds ratio (OR) > 1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11-1.53; P = 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the "Strict/European" ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75-0.96; P = 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04-1.64; P = 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD. © 2014 Springer-Verlag Berlin Heidelberg.
Published: 2014

16. Variants of the CNTNAP2 5′ promoter as risk factors for autism spectrum disorders: a genetic and functional approach

Author: Chiocchetti, A G, primary, Kopp, M, additional, Waltes, R, additional, Haslinger, D, additional, Duketis, E, additional, Jarczok, T A, additional, Poustka, F, additional, Voran, A, additional, Graab, U, additional, Meyer, J, additional, Klauck, S M, additional, Fulda, S, additional, and Freitag, C M, additional
Published: 2014
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17. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Author: Lee, Shermin, Ripke, S., Neale, B.M., Faraone, S.V., Purcell, S.M., Perlis, R.H., Mowry, B.J., Thapar, A., Goddard, M.E., Witte, J.S., Absher, D., Agartz, I., Akil, H., Amin, F., Andreassen, O.A., Anjorin, A., Anney, R., Anttila, V., Arking, D.E., Asherson, P., Azevedo, M.H., Backlund, L., Badner, J.A., Bailey, A.J., Banaschewski, T., Barchas, J.D., Barnes, M.R., Barrett, T.B., Bass, N., Battaglia, A., Bauer, M., Bayes, M., Bellivier, F., Bergen, S.E., Berrettini, W., Betancur, C., Bettecken, T., Biederman, J., Binder, E.B., Black, D.W., Blackwood, D.H., Bloss, C.S., Boehnke, M., Boomsma, D.I., Breen, G., Breuer, R., Bruggeman, R., Cormican, P., Buccola, N.G., Buitelaar, J.K., Bunney, W.E., Buxbaum, J.D., Byerley, W.F., Byrne, E.M., Caesar, S., Cahn, W., Cantor, R.M., Casas, M., Chakravarti, A., Chambert, K., Choudhury, K., Cichon, S., Cloninger, C.R., Collier, D.A., Cook, E.H., Coon, H., Cormand, B., Corvin, A., Coryell, W.H., Craig, D.W., Craig, I.W., Crosbie, J., Cuccaro, M.L., Curtis, D., Czamara, D., Datta, S., Dawson, G., Day, R., Geus, E.J. de, Degenhardt, F., Djurovic, S., Donohoe, G.J., Doyle, A.E., Duan, J., Dudbridge, F., Duketis, E., Ebstein, R.P., Edenberg, H.J., Elia, J., Ennis, S., Etain, B., Fanous, A., Farmer, A.E., Ferrier, I.N., Flickinger, M., Fombonne, E., Foroud, T., Frank, J., Franke, B., et al., Lee, Shermin, Ripke, S., Neale, B.M., Faraone, S.V., Purcell, S.M., Perlis, R.H., Mowry, B.J., Thapar, A., Goddard, M.E., Witte, J.S., Absher, D., Agartz, I., Akil, H., Amin, F., Andreassen, O.A., Anjorin, A., Anney, R., Anttila, V., Arking, D.E., Asherson, P., Azevedo, M.H., Backlund, L., Badner, J.A., Bailey, A.J., Banaschewski, T., Barchas, J.D., Barnes, M.R., Barrett, T.B., Bass, N., Battaglia, A., Bauer, M., Bayes, M., Bellivier, F., Bergen, S.E., Berrettini, W., Betancur, C., Bettecken, T., Biederman, J., Binder, E.B., Black, D.W., Blackwood, D.H., Bloss, C.S., Boehnke, M., Boomsma, D.I., Breen, G., Breuer, R., Bruggeman, R., Cormican, P., Buccola, N.G., Buitelaar, J.K., Bunney, W.E., Buxbaum, J.D., Byerley, W.F., Byrne, E.M., Caesar, S., Cahn, W., Cantor, R.M., Casas, M., Chakravarti, A., Chambert, K., Choudhury, K., Cichon, S., Cloninger, C.R., Collier, D.A., Cook, E.H., Coon, H., Cormand, B., Corvin, A., Coryell, W.H., Craig, D.W., Craig, I.W., Crosbie, J., Cuccaro, M.L., Curtis, D., Czamara, D., Datta, S., Dawson, G., Day, R., Geus, E.J. de, Degenhardt, F., Djurovic, S., Donohoe, G.J., Doyle, A.E., Duan, J., Dudbridge, F., Duketis, E., Ebstein, R.P., Edenberg, H.J., Elia, J., Ennis, S., Etain, B., Fanous, A., Farmer, A.E., Ferrier, I.N., Flickinger, M., Fombonne, E., Foroud, T., Frank, J., Franke, B., and et al.
Abstract: Item does not contain fulltext, Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 +/- 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 +/- 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 +/- 0.06 s.e.), and ADHD and major depressive disorder (0.32 +/- 0.07 s.e.), low between schizophrenia and ASD (0.16 +/- 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Published: 2013

18. 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

19. No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder.

Author: Curran, S., Bolton, P., Rozsnyai, K., Chiocchetti, A., Klauck, S.M., Duketis, E., Poustka, F., Schlitt, S., Freitag, C.M., Lee, I. van der, Muglia, P., Poot, M., Staal, W.G., Jonge, M.V. de, Ophoff, R.A., Lewis, C., Skuse, D., Mandy, W., Vassos, E., Fossdal, R., Magnusson, P., Hreidarsson, S., Saemundsen, E., Stefansson, H., Stefansson, K., Collier, D., Curran, S., Bolton, P., Rozsnyai, K., Chiocchetti, A., Klauck, S.M., Duketis, E., Poustka, F., Schlitt, S., Freitag, C.M., Lee, I. van der, Muglia, P., Poot, M., Staal, W.G., Jonge, M.V. de, Ophoff, R.A., Lewis, C., Skuse, D., Mandy, W., Vassos, E., Fossdal, R., Magnusson, P., Hreidarsson, S., Saemundsen, E., Stefansson, H., Stefansson, K., and Collier, D.
Abstract: 1 september 2011, Item does not contain fulltext, The Autism Genome Project (AGP) Consortium recently reported genome-wide significant association between autism and an intronic single nucleotide polymorphism marker, rs4141463, within the MACROD2 gene. In the present study we attempted to replicate this finding using an independent case-control design of 1,170 cases with autism spectrum disorder (ASD) (874 of which fulfilled narrow criteria for Autism (A)) from five centers within Europe (UK, Germany, the Netherlands, Italy, and Iceland), and 35,307 controls. The combined sample size gave us a non-centrality parameter (NCP) of 11.9, with 93% power to detect allelic association of rs4141463 at an alpha of 0.05 with odds ratio of 0.84 (the best odds ratio estimate of the AGP Consortium data), and for the narrow diagnosis of autism, an NCP of 8.9 and power of 85%. Our case-control data were analyzed for association, stratified by each center, and the summary statistics were combined using the meta-analysis program, GWAMA. This resulted in an odds ratio (OR) of 1.03 (95% CI 0.944-1.133), with a P-value of 0.5 for ASD and OR of 0.99 (95% CI 0.88-1.11) with P-value = 0.85 for the Autism (A) sub-group. Therefore, this study does not provide support for the reported association between rs4141463 and autism.
Published: 2011

20. Sex differences in cognitive domains and their clinical correlates in higher-functioning autism spectrum disorders

Author: Bölte, Sven, Duketis, E., Poustka, F., Holtmann, M., Bölte, Sven, Duketis, E., Poustka, F., and Holtmann, M.
Abstract: Despite the skewed sex ratio, few studies have addressed possible cognitive sex differences in autism spectrum disorders (ASDs). This study compared visual attention to detail (ATTD) and selected executive functions (EF) in 35 males and 21 females with higher-functioning ASD and unaffected sibling controls. Females with ASD outperformed males on EF as assessed by the Trail Making Test B-A. Males with ASD showed superior performance for ATTD as measured by the Block Design Test (BD) when compared with females. EF difficulties in males were correlated with more stereotypic behaviours and interests on the Autism Diagnostic Interview-Revised or the Autism Diagnostic Observation Schedule. The results indicated clinically meaningful cognitive sex differences in ASD, particularly an association between EF and stereotypic behaviours and interests. ATTD as a potential basis for specific cognitive strengths (e.g. scientific/savant skills) might be more pronounced in males with ASD.
Published: 2011

21. A genome-wide scan for common alleles affecting risk for autism

Author: Anney, R. Klei, L. Pinto, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Sykes, N. Pagnamenta, A.T. Almeida, J. Bacchelli, E. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Carson, A.R. Casallo, G. Casey, J. Chu, S.H. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Dawson, G. de Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Melhem, N.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Wing, K. Wittemeyer, K. Wood, S. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Betancur, C. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Miller, J. Monaco, A.P. Nurnberger Jr., J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Scherer, S.W. Sutcliffe, J.S. and Anney, R. Klei, L. Pinto, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Sykes, N. Pagnamenta, A.T. Almeida, J. Bacchelli, E. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Carson, A.R. Casallo, G. Casey, J. Chu, S.H. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Dawson, G. de Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Melhem, N.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Wing, K. Wittemeyer, K. Wood, S. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Betancur, C. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Miller, J. Monaco, A.P. Nurnberger Jr., J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Scherer, S.W. Sutcliffe, J.S.
Abstract: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 3 10-28. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10-28 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C. © The Author 2010. Published by Oxford University Press. All rights reserved.
Published: 2010

22. Functional impact of global rare copy number variation in autism spectrum disorders

Author: Pinto, D. Pagnamenta, A.T. Klei, L. Anney, R. Merico, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bader, G.D. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Bryson, S.E. Carson, A.R. Casallo, G. Casey, J. Chung, B.H.Y. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Cytrynbaum, C. Dawson, G. De Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, A. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Pilorge, M. Piven, J. Ponting, C.P. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Sequeira, A.F. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stein, O. Sykes, N. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Webber, C. Weksberg, R. Wing, K. Wittemeyer, K. Wood, S. Wu, J. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Devlin, B. Ennis, S. Gallagher, L. Geschwind, D.H. Gill, M. and Pinto, D. Pagnamenta, A.T. Klei, L. Anney, R. Merico, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bader, G.D. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Bryson, S.E. Carson, A.R. Casallo, G. Casey, J. Chung, B.H.Y. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Cytrynbaum, C. Dawson, G. De Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, A. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Pilorge, M. Piven, J. Ponting, C.P. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Sequeira, A.F. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stein, O. Sykes, N. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Webber, C. Weksberg, R. Wing, K. Wittemeyer, K. Wood, S. Wu, J. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Devlin, B. Ennis, S. Gallagher, L. Geschwind, D.H. Gill, M.
Abstract: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours 1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed the genome-wide characteristics of rare (<1%frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P=0.012), especially so for loci previously implicated in either ASDand/or intellectual disability (1.69 fold, P=3.4×310-4). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways. © 2010 Macmillan Publishers Limited. All rights reserved.
Published: 2010

23. A genome-wide linkage and association scan reveals novel loci for autism

Author: Weiss, L.A. Arking, D.E. Daly, M.J. Chakravarti, A. Brune, C.W. West, K. O'Connor, A. Hilton, G. Tomlinson, R.L. West, A.B. Cook Jr., E.H. Green, T. Chang, S.-C. Gabriel, S. Gates, C. Hanson, E.M. Kirby, A. Korn, J. Kuruvilla, F. McCarroll, S. Morrow, E.M. Neale, B. Purcell, S. Sasanfar, R. Sougnez, C. Stevens, C. Altshuler, D. Gusella, J. Santangelo, S.L. Sklar, P. Tanzi, R. Anney, R. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Betancur, C. Bölte, S. Bolton, P.F. Brian, J. Bryson, S.E. Buxbaum, J.D. Cabrito, I. Cai, G. Cantor, R.M. Coon, H. Conroy, J. Correia, C. Corsello, C. Crawford, E.L. Cuccaro, M.L. Dawson, G. De Jonge, M. Devlin, B. Duketis, E. Ennis, S. Estes, A. Farrar, P. Fombonne, E. Freitag, C.M. Gallagher, L. Geschwind, D.H. Gilbert, J. Gill, M. Gillberg, C. Goldberg, J. Green, A. Green, J. Guter, S.J. Haines, J.L. Hallmayer, J.F. Hus, V. Klauck, S.M. Korvatska, O. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventha, B.L. Liu, X.-Q. Lord, C. Lotspeich, L.J. Maestrini, E. Magalhaes, T. Mahoney, W. Mantoulan, C. McConachie, H. McDougle, C.J. McMahon, W.M. Marshall, C.R. Miller, J. Minshew, N.J. Monaco, A.P. Munson, J. Nurnberger Jr., J.I. Oliveira, G. Pagnamenta, A. Papanikolaou, K. Parr, J.R. Paterson, A.D. Pericak-Vance, M.A. Pickles, A. Pinto, D. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Regan, R. Reichert, J. Renshaw, K. Roberts, W. Roge, B. Rutter, M.L. Salt, J. Schellenberg, G.D. Scherer, S.W. Sheffield, V. Sutcliffe, J.S. Szatmari, P. Tansey, K. Thompson, A.P. Tsiantis, J. Van Engeland, H. Vicente, A.M. Vieland, V.J. Volkmar, F. Wallace, S. Wassink, T.H. Wijsman, E.M. Wing, K. Wittemeyer, K. Yaspan, B.L. Zwaigenbaum, L. Yoo, S.-Y. Hill, R.S. Mukaddes, N.M. Balkhy, S. Gascon, G. Al-Saad, S. Hashmi, A. Ware, J. Joseph, R.M. LeClair, E. Partlow, J.N. Barry, B. Walsh, C.A. Pauls, D. Moilanen, I. Ebeling, H. Mattila, M.-L. Kuusikko, S. Jussila, K. Ignatius, J. Tolouei, A. Ghadami, M. Rostami, M. Hosseinipour, A. Valujerdi, M. Andre and Weiss, L.A. Arking, D.E. Daly, M.J. Chakravarti, A. Brune, C.W. West, K. O'Connor, A. Hilton, G. Tomlinson, R.L. West, A.B. Cook Jr., E.H. Green, T. Chang, S.-C. Gabriel, S. Gates, C. Hanson, E.M. Kirby, A. Korn, J. Kuruvilla, F. McCarroll, S. Morrow, E.M. Neale, B. Purcell, S. Sasanfar, R. Sougnez, C. Stevens, C. Altshuler, D. Gusella, J. Santangelo, S.L. Sklar, P. Tanzi, R. Anney, R. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Betancur, C. Bölte, S. Bolton, P.F. Brian, J. Bryson, S.E. Buxbaum, J.D. Cabrito, I. Cai, G. Cantor, R.M. Coon, H. Conroy, J. Correia, C. Corsello, C. Crawford, E.L. Cuccaro, M.L. Dawson, G. De Jonge, M. Devlin, B. Duketis, E. Ennis, S. Estes, A. Farrar, P. Fombonne, E. Freitag, C.M. Gallagher, L. Geschwind, D.H. Gilbert, J. Gill, M. Gillberg, C. Goldberg, J. Green, A. Green, J. Guter, S.J. Haines, J.L. Hallmayer, J.F. Hus, V. Klauck, S.M. Korvatska, O. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventha, B.L. Liu, X.-Q. Lord, C. Lotspeich, L.J. Maestrini, E. Magalhaes, T. Mahoney, W. Mantoulan, C. McConachie, H. McDougle, C.J. McMahon, W.M. Marshall, C.R. Miller, J. Minshew, N.J. Monaco, A.P. Munson, J. Nurnberger Jr., J.I. Oliveira, G. Pagnamenta, A. Papanikolaou, K. Parr, J.R. Paterson, A.D. Pericak-Vance, M.A. Pickles, A. Pinto, D. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Regan, R. Reichert, J. Renshaw, K. Roberts, W. Roge, B. Rutter, M.L. Salt, J. Schellenberg, G.D. Scherer, S.W. Sheffield, V. Sutcliffe, J.S. Szatmari, P. Tansey, K. Thompson, A.P. Tsiantis, J. Van Engeland, H. Vicente, A.M. Vieland, V.J. Volkmar, F. Wallace, S. Wassink, T.H. Wijsman, E.M. Wing, K. Wittemeyer, K. Yaspan, B.L. Zwaigenbaum, L. Yoo, S.-Y. Hill, R.S. Mukaddes, N.M. Balkhy, S. Gascon, G. Al-Saad, S. Hashmi, A. Ware, J. Joseph, R.M. LeClair, E. Partlow, J.N. Barry, B. Walsh, C.A. Pauls, D. Moilanen, I. Ebeling, H. Mattila, M.-L. Kuusikko, S. Jussila, K. Ignatius, J. Tolouei, A. Ghadami, M. Rostami, M. Hosseinipour, A. Valujerdi, M. Andre
Abstract: Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.
Published: 2009

24. A genome-wide scan for common alleles affecting risk for autism

Author: Anney, R., primary, Klei, L., additional, Pinto, D., additional, Regan, R., additional, Conroy, J., additional, Magalhaes, T. R., additional, Correia, C., additional, Abrahams, B. S., additional, Sykes, N., additional, Pagnamenta, A. T., additional, Almeida, J., additional, Bacchelli, E., additional, Bailey, A. J., additional, Baird, G., additional, Battaglia, A., additional, Berney, T., additional, Bolshakova, N., additional, Bolte, S., additional, Bolton, P. F., additional, Bourgeron, T., additional, Brennan, S., additional, Brian, J., additional, Carson, A. R., additional, Casallo, G., additional, Casey, J., additional, Chu, S. H., additional, Cochrane, L., additional, Corsello, C., additional, Crawford, E. L., additional, Crossett, A., additional, Dawson, G., additional, de Jonge, M., additional, Delorme, R., additional, Drmic, I., additional, Duketis, E., additional, Duque, F., additional, Estes, A., additional, Farrar, P., additional, Fernandez, B. A., additional, Folstein, S. E., additional, Fombonne, E., additional, Freitag, C. M., additional, Gilbert, J., additional, Gillberg, C., additional, Glessner, J. T., additional, Goldberg, J., additional, Green, J., additional, Guter, S. J., additional, Hakonarson, H., additional, Heron, E. A., additional, Hill, M., additional, Holt, R., additional, Howe, J. L., additional, Hughes, G., additional, Hus, V., additional, Igliozzi, R., additional, Kim, C., additional, Klauck, S. M., additional, Kolevzon, A., additional, Korvatska, O., additional, Kustanovich, V., additional, Lajonchere, C. M., additional, Lamb, J. A., additional, Laskawiec, M., additional, Leboyer, M., additional, Le Couteur, A., additional, Leventhal, B. L., additional, Lionel, A. C., additional, Liu, X.-Q., additional, Lord, C., additional, Lotspeich, L., additional, Lund, S. C., additional, Maestrini, E., additional, Mahoney, W., additional, Mantoulan, C., additional, Marshall, C. R., additional, McConachie, H., additional, McDougle, C. J., additional, McGrath, J., additional, McMahon, W. M., additional, Melhem, N. M., additional, Merikangas, A., additional, Migita, O., additional, Minshew, N. J., additional, Mirza, G. K., additional, Munson, J., additional, Nelson, S. F., additional, Noakes, C., additional, Noor, A., additional, Nygren, G., additional, Oliveira, G., additional, Papanikolaou, K., additional, Parr, J. R., additional, Parrini, B., additional, Paton, T., additional, Pickles, A., additional, Piven, J., additional, Posey, D. J., additional, Poustka, A., additional, Poustka, F., additional, Prasad, A., additional, Ragoussis, J., additional, Renshaw, K., additional, Rickaby, J., additional, Roberts, W., additional, Roeder, K., additional, Roge, B., additional, Rutter, M. L., additional, Bierut, L. J., additional, Rice, J. P., additional, Salt, J., additional, Sansom, K., additional, Sato, D., additional, Segurado, R., additional, Senman, L., additional, Shah, N., additional, Sheffield, V. C., additional, Soorya, L., additional, Sousa, I., additional, Stoppioni, V., additional, Strawbridge, C., additional, Tancredi, R., additional, Tansey, K., additional, Thiruvahindrapduram, B., additional, Thompson, A. P., additional, Thomson, S., additional, Tryfon, A., additional, Tsiantis, J., additional, Van Engeland, H., additional, Vincent, J. B., additional, Volkmar, F., additional, Wallace, S., additional, Wang, K., additional, Wang, Z., additional, Wassink, T. H., additional, Wing, K., additional, Wittemeyer, K., additional, Wood, S., additional, Yaspan, B. L., additional, Zurawiecki, D., additional, Zwaigenbaum, L., additional, Betancur, C., additional, Buxbaum, J. D., additional, Cantor, R. M., additional, Cook, E. H., additional, Coon, H., additional, Cuccaro, M. L., additional, Gallagher, L., additional, Geschwind, D. H., additional, Gill, M., additional, Haines, J. L., additional, Miller, J., additional, Monaco, A. P., additional, Nurnberger, J. I., additional, Paterson, A. D., additional, Pericak-Vance, M. A., additional, Schellenberg, G. D., additional, Scherer, S. W., additional, Sutcliffe, J. S., additional, Szatmari, P., additional, Vicente, A. M., additional, Vieland, V. J., additional, Wijsman, E. M., additional, Devlin, B., additional, Ennis, S., additional, and Hallmayer, J., additional
Published: 2010
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25. A 16-Year-Old Boy with Severe Gamma-Butyrolactone (GBL) Withdrawal Delirium

Author: Zepf, F. D., primary, Holtmann, M., additional, Duketis, E., additional, Maier, J., additional, Radeloff, D., additional, Wagner, A., additional, Poustka, F., additional, and Wöckel, L., additional
Published: 2009
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26. Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

Author: Joana Almeida, Christian R. Marshall, Hakon Hakonarson, Bárbara Oliveira, Anthony J. Griswold, Jacob A. S. Vorstman, Bhooma Thiruvahindrapuram, Suma Jacob, Judith Conroy, Alistair T. Pagnamenta, Christelle Cabrol, Jeremy R. Parr, Daniel H. Geschwind, Nancy J. Minshew, Xiao Xu, Richard Anney, Sven Bölte, Zhuozhi Wang, Emily L. Crawford, Elsa Delaby, Margaret A. Pericak-Vance, Joachim Hallmayer, Jonathan L. Haines, Dalila Pinto, Susana Mouga, Alexander Kolevzon, Elena Bacchelli, Frederico Duque, Bernie Devlin, Latha Soorya, Cátia Café, Kirsty Wing, Jennifer K. Lowe, Ana Tryfon, Stephen J. Guter, Geraldine Dawson, Tiago R. Magalhaes, Anthony J. Bailey, Michael Gill, Peter Szatmari, Steven Gallinger, Marion Pilorge, James S. Sutcliffe, Bridget A. Fernandez, Herman van Engeland, Catalina Betancur, Guiomar Oliveira, Andrew Green, Eftichia Duketis, Bernadette Rogé, Ann Le Couteur, Evdokia Anagnostou, Michelle Cotterchio, Daniele Merico, Giovanna Pellecchia, Jonathan Green, Regina Regan, Jillian P. Casey, Guiqing Cai, Gerard D. Schellenberg, Jennifer L. Howe, Elena Maestrini, Andrew D. Paterson, L. Alison McInnes, Patrick Bolton, Edwin H. Cook, Richard Delorme, Lambertus Klei, Thomas Bourgeron, Gillian Baird, Christine M. Freitag, Beth A. Dombroski, Andreas G. Chiocchetti, Sabine M. Klauck, Susan E. Folstein, Mafalda Barbosa, Anthony P. Monaco, Marion Leboyer, Nadia Bolshakova, Fritz Poustka, Richard Holt, Kerstin Wittemeyer, Wendy Roberts, Lonnie Zwaigenbaum, Louise Gallagher, Susan G. McGrew, Joseph D. Buxbaum, Graham Casey, Simon Wallace, Catherine Lord, Sean Brennan, Robert Ziman, Alison K. Merikangas, John I. Nurnberger, Christopher Gillberg, Ellen M. Wijsman, Astrid M. Vicente, Inȇs C. Conceição, Sean Ennis, Patricia Jiménez González, Hilary Coon, Raphael Bernier, John R. Gilbert, Ann P. Thompson, Susanne Thomson, Agatino Battaglia, Maretha de Jonge, Michael L. Cuccaro, Catarina Correia, Veronica J. Vieland, Stephen W. Scherer, Pauline Chaste, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Department of Psychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Friedman Brain Institute, The Mindich Child Health and Development Institute, The Icahn Institute for Genomics and Multiscale Biology, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Trinity College Dublin-St. James's Hospital, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), McLaughlin Centre, University of Toronto, BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Department of Neurology, University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, Fisico-Quimica Biologica, Universidade Federal do Rio de Janeiro (UFRJ), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Department of Pathology, Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), Prevention & Cancer Control, Cancer Care Ontario, Department of Preventive Medicine, University of Southern California (USC), Department of Pediatrics, University of Alberta, School of Education, University of Birmingham [Birmingham], University of Oxford [Oxford]-Warneford Hospital, Octogone Unité de Recherche Interdisciplinaire (Octogone), Université Toulouse - Jean Jaurès (UT2J), Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Institute for Biomedical Imaging and Life Science, University of Coimbra [Portugal] (UC), Vanderbilt University [Nashville], Center for Autism and the Developing Brain (CADB), Weill Medical College of Cornell University [New York], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Institute of Health and Society, Newcastle University [Newcastle], Department of Child and Adolescent Psychiatry, Newcastle University [Newcastle]-Institute of Health & Society (Child & Adolescent Psychiatry), Child Developmental and Behavioral Unit, Hospital Nacional de Niños Dr Sáenz Herrera, Institute for Juvenile Research-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Manchester Academic Health Sciences Centre, Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Institute of Child Health, University College of London [London] (UCL), Memorial University of Newfoundland [St. John's], Disciplines of Genetics and Medicine, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Institute of Psychiatry, King‘s College London, Institute of psychiatry, University of Washington [Seattle], Paediatric Neurodisability, King‘s College London-King's Health Partners, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, University of British Columbia (UBC), Bloorview Research Institute, Division of Medical Genetics [Seattle], Departments of Biostatistics and Medicine, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Institute of Neuroscience [Newcastle] (ION), Institutes of Neuroscience and Health and Society, Indiana University School of Medicine, Indiana University System-Indiana University System, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Utah Autism Research Program, University of Utah Psychiatry Department, University of Miami School of Medicine, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford School of Medicine [Stanford], Institute for Juvenile Research, University of Illinois [Chicago] (UIC), Department of Neuroscience, Main funders of the Autism Genome Project: Autism Speaks (USA), the Health Research Board (Ireland, AUT/2006/1, AUT/2006/2, PD/2006/48), the Medical Research Council (UK), the Hilibrand Foundation (USA), Genome Canada, the Ontario Genomics Institute, and the Canadian Institutes of Health Research (CIHR), Autism Genome Project Consortium, Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), University of Pennsylvania, University of Oxford-Warneford Hospital, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), Betancur, Catalina, Instituto Nacional de Saude Dr Ricardo Jorge, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE - UMR 8587), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Università di Bologna [Bologna] (UNIBO), Mount Sinai Hospital (MSH), University of Toronto-The Hospital for Sick Children, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Gillberg Neuropsychiatry Centre, University of Gothenburg (GU), Stanford University Medical School, Stanford University School of Medicine [Stanford], Stanford University [Stanford], Université de Toulouse (UT)-Université de Toulouse (UT), Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, and Scherer SW.
Subjects: Male, INTELLECTUAL DISABILITY, pathways, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Bioinformatics, DUPLICATIONS, Intellectual disability, Gene Regulatory Networks, Genetics(clinical), Copy-number variation, 10. No inequality, Child, GDI1, Genetics (clinical), Sequence Deletion, COPY NUMBER VARIANTS, Genetics, gene networks, Copy Number Variation, 3. Good health, Pedigree, Fragile X syndrome, Multigene Family, Female, Metabolic Networks and Pathways, de novo, DNA Copy Number Variations, autism, Biology, rare CNV, PHENOTYPE ONTOLOGY, Article, Structural variation, mental disorders, medicine, Humans, ddc:610, FRAGILE-X-SYNDROME, GENOME-WIDE ASSOCIATION, Gene, [SDV.GEN]Life Sciences [q-bio]/Genetics, HDAC4, SETD5, medicine.disease, CHD2, inherited, STRUCTURAL VARIATION, DELETIONS, DE-NOVO MUTATIONS, Child Development Disorders, Pervasive, Autism
Abstract: International audience; Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
Published: 2014
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27. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Author: Anita Thapar, Lena Backlund, Lindsey Kent, Walter J. Muir, A. Jeremy Willsey, Sandra K. Loo, Michael Boehnke, Christa Lese Martin, Ania Korszun, Guiomar Oliveira, Veronica J. Vieland, Stephen W. Scherer, René S. Kahn, Darina Czamara, Jeremy R. Parr, Michael E. Goddard, Willem A. Nolen, Josep Antoni Ramos-Quiroga, Stephen Sanders, Karola Rehnstroem, Nelson B. Freimer, Erin N. Smith, Ann Olincy, Ingrid Melle, Myrna M. Weissman, James A. Knowles, William Byerley, Aravinda Chakravarti, Shaun Purcell, Jens Treutlein, Sebastian Zoellner, Hakon Hakonarson, Susanne Lucae, Markus M. Noethen, Ian B. Hickie, Marion Friedl, Srinivasa Thirumalai, Stephen Newhouse, Joseph Piven, Andrew M. McIntosh, Cathryn M. Lewis, Srdjan Djurovic, Francis J. McMahon, Ayman H. Fanous, Bernie Devlin, Steven A. McCarroll, Alan F. Schatzberg, Peter Szatmari, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Gerard van Grootheest, Phil Lee, Richard Anney, Elaine K. Green, Geraldine Dawson, Joseph A. Sergeant, Digby Quested, Magdalena Gross, Jack D. Barchas, Nicholas G. Martin, Timothy W. Yu, Jouke-Jan Hottenga, Mark Lathrop, Federica Tozzi, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Sandra Meier, Louise Gailagher, David A. Collier, Farooq Amin, Michael C. Neale, Martin Schalling, Lieuwe de Haan, Bru Cormand, Falk W. Lohoff, Jennifer Crosbie, Howard J. Edenberg, Aarno Palotie, Johannes H. Smit, Robert Freedman, Katherine Gordon-Smith, Michele L. Pergadia, Enda M. Byrne, Hans-Christoph Steinhausen, Benjamin M. Neale, Anjali K. Henders, Michele T. Pato, Manuel Mattheisen, Urban Ösby, Edward M. Scolnick, Evaristus A. Nwulia, Fritz Poustka, Gonneke Willemsen, Andrew C. Heath, David St. Cair, Emma M. Quinn, I. Nicol Ferrier, John R. Kelsoe, Vanessa Hus, Andrew McQuillin, John P. Rice, William M. McMahon, Joseph Biederman, Danyu Lin, Wolfgang Maier, Frans G. Zitman, Josephine Elia, Nicholas J. Schork, Stéphane Jamain, Lizzy Rossin, Jubao Duan, Ingrid Agartz, Devin Absher, Jordan W. Smoller, Matthew W. State, Richard M. Myers, Shrikant Mane, Carlos N. Pato, William E. Bunney, Marian L. Hamshere, Manfred Uhr, Nicholas John Craddock, Astrid M. Vicente, Tobias Banaschewski, David Curtis, Anne Farmer, Scott D. Gordon, Anna K. Kaehler, Eric M. Morrow, Marcella Rietschel, Patrik K. E. Magnusson, Klaus-Peter Lesch, Rebecca McKinney, Jana Strohmaier, Thomas F. Wienker, Pablo V. Gejman, Douglas Blackwood, Maria Helena Pinto de Azevedo, Tiffany A. Greenwood, Don H. Linszen, Daniel L. Koller, Richard Bruggeman, Vinay Puri, Naomi R. Wray, Stanley J. Watson, Elena Maestrini, Valentina Moskvina, Frank Dudbridge, Danielle Posthuma, Edward G. Jones, Lambertus Klei, Sarah E. Bergen, Fan Meng, Steven P. Hamilton, Guy A. Rouleau, Pierandrea Muglia, Mikael Landén, Stephanie H. Witt, Laramie E. Duncan, Stanley Zammit, Judith A. Badner, Florian Holsboer, Eco J. C. de Geus, Daniel Moreno-De-Luca, Benjamin S. Pickard, Gunnar Morken, Michael Conlon O'Donovan, Michael Steffens, Kathryn Roeder, Dorret I. Boomsma, Paul D. Shilling, Stephan Ripke, Nigel Williams, Jeremy M. Silverman, David Craig, Mark J. Daly, Michael Bauer, Detelina Grozeva, Markus J. Schwarz, Peter Holmans, Hugh Gurling, T. Scott Stroup, Aribert Rothenberger, Gary Donohoe, Eric Fombonne, Joseph D. Buxbaum, Matthew Flicldnger, Bryan J. Mowry, Thomas Hansen, Ina Giegling, Grant W. Montgomery, Caroline M. Nievergelt, Susan L. Smalley, Jung-Ying Tzeng, David H. Ledbetter, Christopher A. Walsh, Gerard D. Schellenberg, Sarah E. Medland, Robert D. Oades, James B. Potash, Dan E. Arking, Johannes Schumacher, Michael Gill, James J. McGough, Jennifer L. Moran, Donald W. Black, Sian Caesar, Neelroop N. Parikshak, Ian W. Craig, Sabine M. Klauck, Wade H. Berrettini, T. Foroud, Peter P. Zandi, Inez Myin-Germeys, Marcus Ising, Sven Cichon, Alexandre A. Todorov, Mònica Bayés, Thomas Werge, Susan L. Slager, Stanley I. Shyn, Jim van Os, Derek W. Morris, Douglas M. Ruderfer, Thomas W. Muehleisen, Matthew C. Keller, Susmita Datta, Ian Jones, John B. Vincent, James L. Kennedy, Anthony P. Monaco, Jianxin Shi, Dale R. Nyholt, Bruno Etain, Christine Fraser, Paul Cormican, Miguel Casas, Radhika Kandaswamy, Gerome Breen, Stephen V. Faraone, Jonna Kuntsi, Thomas Bettecken, Witte J.G. Hoogendijk, Nancy G. Buccola, Franziska Degenhardt, Lyudmila Georgieva, Marion Leboyer, Alan R. Sanders, John Strauss, Dan Rujescu, Russell Schachar, Helena Medeiros, Lisa Jones, Peter M. Visscher, Lauren A. Weiss, René Breuer, John I. Nurnberger, Andreas Reif, Phoenix Kwan, Vihra Milanova, Chunyu Liu, Martin A. Kohli, Donald J. MacIntyre, Nicholas Bass, Khalid Choudhury, Edwin H. Cook, Catherine Lord, Andrew D. Paterson, Jobst Meyer, Richard P. Ebstein, Zhaoming Zhao, Niklas Laengstroem, Thomas G. Schulze, Peter Propping, Wei Xu, Robert C. Thompson, Kimberly Chambert, Jonathan Pimm, Ivan Nikolov, Pamela A. F. Madden, Kevin A. McGhee, Jacob Lawrence, Jan K. Buitelaar, Andres Ingason, Christine M. Freitag, Robert Krasucki, Wiepke Cahn, Rita M. Cantor, Christina M. Hultman, Melvin G. McInnis, Catalina Betancur, Eftichia Duketis, Michael T. Murtha, Thomas H. Wassink, Philip Asherson, John S. Witte, Elaine Kenny, Edmund J.S. Sonuga-Barke, Lydia Krabbendam, Line Olsen, Agatino Battaglia, Laura J. Scott, Annette M. Hartmann, Yunjung Kim, Richard O. Day, Edwin J. C. G. van den Oord, Ole A. Andreassen, Herbert Roeyers, Michael John Owen, Colm O'Dushlaine, Peng Zhang, Morten Mattingsdal, Michael L. Cuccaro, Margaret A. Pericak-Vance, Joachim Hallmayer, Jun Li, Pamela B. Mahon, Elisabeth B. Binder, William A. Scheftner, Daniel H. Geschwind, Christel M. Middeldorp, Josef Frank, Keith Matthews, Jennifer K. Lowe, Paul Lichtenstein, Verneri Anttila, Pamela Sklar, Szabocls Szelinger, Roel A. Ophoff, Peter McGuffin, Stefan Herms, Bettina Konte, George Kirov, Hilary Coon, Maria Hipolito, Louise Frisén, Kenneth S. Kendler, Frank Bellivier, James S. Sutdiffe, Jeffrey A. Lieberman, Todd Lencz, Susanne Hoefels, Alan W. McLean, Barbara Franke, Huda Akil, Soumya Raychaudhuri, Ellen M. Wijsman, Vishwajit L. Nimgaonkar, Roy H. Perlis, Patrick J. McGrath, Susan L. Santangelo, William Coryell, Henrik B. Rasmussen, Weihua Guan, William Lawson, Elliot S. Gershon, Sean Ennis, Aiden Corvin, Allan H. Young, Thomas B. Barrett, Jonathan L. Haines, Douglas F. Levinson, Ana Miranda, Anil K. Malhotra, S. Hong Lee, Stan F. Nelson, Anthony J. Bailey, Patrick F. Sullivan, Dorothy E. Grice, Lefkos T. Middleton, Bertram Mueller-Myhsok, Michael R. Barnes, Adebayo Anjorin, O'Dushlaine, C, Rossin, L, Lee, Ph, Duncan, L, Parikshak, Nn, Newhouse, S, Ripke, S, Neale, Bm, Purcell, Sm, Posthuma, D, Nurnberger, Ji, Lee, Sh, Faraone, Sv, Perlis, Rh, Mowry, Bj, Thapar, A, Goddard, Me, Witte, J, Absher, D, Agartz, I, Akil, H, Amin, F, Andreassen, Oa, Anjorin, A, Anney, R, Anttila, V, Arking, De, Asherson, P, Azevedo, Mh, Backlund, L, Badner, Ja, Bailey, Aj, Banaschewski, T, Barchas, Jd, Barnes, Mr, Barrett, Tb, Bass, N, Battaglia, A, Bauer, M, Bayés, M, Bellivier, F, Bergen, Se, Berrettini, W, Betancur, C, Bettecken, T, Biederman, J, Binder, Eb, Black, Dw, Blackwood, Dh, Bloss, C, Boehnke, M, Boomsma, Di, Breuer, R, Bruggeman, R, Cormican, P, Buccola, Ng, Buitelaar, Jk, Bunney, We, Buxbaum, Jd, Byerley, Wf, Byrne, Em, Caesar, S, Cahn, W, Cantor, Rm, Casas, M, Chakravarti, A, Chambert, K, Choudhury, K, Cichon, S, Mattheisen, M, Cloninger, Cr, Collier, Da, Cook, Eh, Coon, H, Cormand, B, Corvin, A, Coryell, Wh, Craig, Dw, Craig, Iw, Crosbie, J, Cuccaro, Ml, Curtis, D, Czamara, D, Datta, S, Dawson, G, Day, R, De Geus, Ej, Degenhardt, F, Djurovic, S, Donohoe, Gj, Doyle, Ae, Duan, J, Dudbridge, F, Duketis, E, Ebstein, Rp, Edenberg, Hj, Elia, J, Ennis, S, Etain, B, Fanous, A, Farmer, Ae, Ferrier, In, Flickinger, M, Fombonne, E, Foroud, T, Frank, J, Franke, B, Fraser, C, Freedman, R, Freimer, Nb, Freitag, Cm, Friedl, M, Frisén, L, Gallagher, L, Gejman, Pv, Georgieva, L, Gershon, E, Giegling, I, Gill, M, Gordon, Sd, Gordon-Smith, K, Green, Ek, Greenwood, Ta, Grice, De, Gross, M, Grozeva, D, Guan, W, Gurling, H, De Haan, L, Haines, Jl, Hakonarson, H, Hallmayer, J, Hamilton, Sp, Hamshere, Ml, Hansen, Tf, Hartmann, Am, Hautzinger, M, Heath, Ac, Henders, Ak, Herms, S, Hickie, Ib, Hipolito, M, Hoefels, S, Holsboer, F, Hoogendijk, Wj, Hottenga, Jj, Hultman, Cm, Hus, V, Ingason, A, Ising, M, Jamain, S, Jones, Eg, Jones, I, Jones, L, Tzeng, Jy, Kähler, Ak, Kahn, R, Kandaswamy, R, Keller, Mc, Kennedy, Jl, Kenny, E, Kent, L, Kim, Y, Kirov, Gk, Klauck, Sm, Klei, L, Knowles, Ja, Kohli, Ma, Koller, Dl, Konte, B, Korszun, A, Krabbendam, L, Krasucki, R, Kuntsi, J, Kwan, P, Landén, M, Längström, N, Lathrop, M, Lawrence, J, Lawson, Wb, Leboyer, M, Ledbetter, Dh, Lencz, T, Lesch, Kp, Levinson, Df, Lewis, Cm, Li, J, Lichtenstein, P, Lieberman, Ja, Lin, Dy, Linszen, Dh, Liu, C, Lohoff, Fw, Loo, Sk, Lord, C, Lowe, Jk, Lucae, S, Macintyre, Dj, Madden, Pa, Maestrini, E, Magnusson, Pk, Mahon, Pb, Maier, W, Malhotra, Ak, Mane, Sm, Martin, Cl, Martin, Ng, Matthews, K, Mattingsdal, M, Mccarroll, Sa, Mcghee, Ka, Mcgough, Jj, Mcgrath, Pj, Mcguffin, P, Mcinnis, Mg, Mcintosh, A, Mckinney, R, Mclean, Aw, Mcmahon, Fj, Mcmahon, Wm, Mcquillin, A, Medeiros, H, Medland, Se, Meier, S, Melle, I, Meyer, J, Middeldorp, Cm, Middleton, L, Milanova, V, Miranda, A, Monaco, A, Montgomery, Gw, Moran, Jl, Moreno-De-Luca, D, Morken, G, Morris, Dw, Morrow, Em, Moskvina, V, Muglia, P, Mühleisen, Tw, Muir, Wj, Müller-Myhsok, B, Murtha, M, Myers, Rm, Myin-Germeys, I, Neale, Mc, Nelson, Sf, Nievergelt, Cm, Nikolov, I, Nimgaonkar, V, Nolen, Wa, Nöthen, Mm, Nwulia, Ea, Nyholt, Dr, Oades, Rd, Olincy, A, Oliveira, G, Olsen, L, Ophoff, Ra, Osby, U, Owen, Mj, Palotie, A, Parr, Jr, Paterson, Ad, Pato, Cn, Pato, Mt, Penninx, Bw, Pergadia, Ml, Pericak-Vance, Ma, Pickard, B, Pimm, J, Piven, J, Potash, Jb, Poustka, F, Propping, P, Puri, V, Quested, Dj, Quinn, Em, Ramos-Quiroga, Ja, Rasmussen, Hb, Raychaudhuri, S, Rehnström, K, Reif, A, Ribasés, M, Rice, Jp, Rietschel, M, Roeder, K, Roeyers, H, Rothenberger, A, Rouleau, G, Ruderfer, D, Rujescu, D, Sanders, Ar, Sanders, Sj, Santangelo, Sl, Sergeant, Ja, Schachar, R, Schalling, M, Schatzberg, Af, Scheftner, Wa, Schellenberg, Gd, Scherer, Sw, Schork, Nj, Schulze, Tg, Schumacher, J, Schwarz, M, Scolnick, E, Scott, Lj, Shi, J, Shilling, Pd, Shyn, Si, Silverman, Jm, Slager, Sl, Smalley, Sl, Smit, Jh, Smith, En, Sonuga-Barke, Ej, St Clair, D, State, M, Steffens, M, Steinhausen, Hc, Strauss, J, Strohmaier, J, Stroup, T, Sutcliffe, J, Szatmari, P, Szelinger, S, Thirumalai, S, Thompson, Rc, Todorov, Aa, Tozzi, F, Treutlein, J, Uhr, M, van den Oord, Jc, Van Grootheest, G, Van Os, J, Vicente, A, Vieland, Vj, Vincent, Jb, Visscher, Pm, Walsh, Ca, Wassink, Th, Watson, Sj, Weissman, Mm, Werge, T, Wienker, Tf, Wijsman, Em, Willemsen, G, Williams, N, Willsey, Aj, Witt, Sh, Xu, W, Young, Ah, Yu, Tw, Zammit, S, Zandi, Pp, Zhang, P, Zitman, Fg, Zöllner, S, Devlin, B, Kelsoe, Jr, Sklar, P, Daly, Mj, O'Donovan, Mc, Craddock, N, Kendler, K, Weiss, La, Wray, Nr, Zhao, Z, Geschwind, Dh, Sullivan, Pf, Smoller, Jw, Holmans, Pa, Breen, G., Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Human genetics, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Gastroenterology & Hepatology, Hematology, University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), RS: MHeNs - R2 - Mental Health, ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Universitat de Barcelona, Perceptual and Cognitive Neuroscience (PCN), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Complex Trait Genetics, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), O'Dushlaine, Colm, Rossin, Lizzy, Lee, Phil H, Duncan, Laramie, Lee, S Hong, Breen, Gerome, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, and Myin-Germeys, Inez
Subjects: Netherlands Twin Register (NTR), Statistical methods, Autism, Medizin, LOCI, Genome-wide association study, heritability, Genome-wide association studies, Histones, Genètica mèdica, 0302 clinical medicine, Histone methylation, Databases, Genetic, 2.1 Biological and endogenous factors, Psychology, GWAS, Aetiology, Psychiatric genetics, R2C, bipolar disorder, Psychiatry, 0303 health sciences, Disorders, Loci, Depression, General Neuroscience, Mental Disorders, Medical genetics, METHYLATION, Brain, 3rd-DAS, Serious Mental Illness, Psychiatric Disorders, 3. Good health, Histone, Mental Health, Schizophrenia, Mental Disorder, Cognitive Sciences, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Promoters, BDC, BURDEN, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Human, Signal Transduction, medicine.medical_specialty, DISORDERS, Genomics, Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium, Burden, Biology, Methylation, Article, Biological pathway, PROMOTERS, 03 medical and health sciences, Databases, Genetic, medicine, Genetics, Humans, Genetic Predisposition to Disease, histone methylation, Bipolar disorder, Psiquiatria, AUTISM, 030304 developmental biology, Genetic association, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, Neuroscience (all), Human Genome, Neurosciences, medicine.disease, Brain Disorders, Good Health and Well Being, DE-NOVO MUTATIONS, Perturbações do Desenvolvimento Infantil e Saúde Mental, RC0321, Genome-wide Association Studies, De-novo mutations, major depression, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: G.B. and S.N. acknowledge funding support for this work from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. P.H.L. is supported by US National Institute of Mental Health (NIMH) grant K99MH101367. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders. Postprint
Published: 2015
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28. Joint Analysis of Psychiatric Disorders Increases Accuracy of Risk Prediction for Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

Author: Robert Maier, Gerhard Moser, Guo-Bo Chen, Stephan Ripke, William Coryell, James B. Potash, William A. Scheftner, Jianxin Shi, Myrna M. Weissman, Christina M. Hultman, Mikael Landén, Douglas F. Levinson, Kenneth S. Kendler, Jordan W. Smoller, Naomi R. Wray, S. Hong Lee, Devin Absher, Ingrid Agartz, Huda Akil, Farooq Amin, Ole A. Andreassen, Adebayo Anjorin, Richard Anney, Dan E. Arking, Philip Asherson, Maria H. Azevedo, Lena Backlund, Judith A. Badner, Anthony J. Bailey, Tobias Banaschewski, Jack D. Barchas, Michael R. Barnes, Thomas B. Barrett, Nicholas Bass, Agatino Battaglia, Michael Bauer, Mònica Bayés, Frank Bellivier, Sarah E. Bergen, Wade Berrettini, Catalina Betancur, Thomas Bettecken, Joseph Biederman, Elisabeth B. Binder, Donald W. Black, Douglas H.R. Blackwood, Cinnamon S. Bloss, Michael Boehnke, Dorret I. Boomsma, Gerome Breen, René Breuer, Richard Bruggeman, Nancy G. Buccola, Jan K. Buitelaar, William E. Bunney, Joseph D. Buxbaum, William F. Byerley, Sian Caesar, Wiepke Cahn, Rita M. Cantor, Miguel Casas, Aravinda Chakravarti, Kimberly Chambert, Khalid Choudhury, Sven Cichon, C. Robert Cloninger, David A. Collier, Edwin H. Cook, Hilary Coon, Bru Cormand, Paul Cormican, Aiden Corvin, William H. Coryell, Nicholas Craddock, David W. Craig, Ian W. Craig, Jennifer Crosbie, Michael L. Cuccaro, David Curtis, Darina Czamara, Mark J. Daly, Susmita Datta, Geraldine Dawson, Richard Day, Eco J. De Geus, Franziska Degenhardt, Bernie Devlin, Srdjan Djurovic, Gary J. Donohoe, Alysa E. Doyle, Jubao Duan, Frank Dudbridge, Eftichia Duketis, Richard P. Ebstein, Howard J. Edenberg, Josephine Elia, Sean Ennis, Bruno Etain, Ayman Fanous, Stephen V. Faraone, Anne E. Farmer, I. Nicol Ferrier, Matthew Flickinger, Eric Fombonne, Tatiana Foroud, Josef Frank, Barbara Franke, Christine Fraser, Robert Freedman, Nelson B. Freimer, Christine M. Freitag, Marion Friedl, Louise Frisén, Louise Gallagher, Pablo V. Gejman, Lyudmila Georgieva, Elliot S. Gershon, Daniel H. Geschwind, Ina Giegling, Michael Gill, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Tiffany A. Greenwood, Dorothy E. Grice, Magdalena Gross, Detelina Grozeva, Weihua Guan, Hugh Gurling, Lieuwe De Haan, Jonathan L. Haines, Hakon Hakonarson, Joachim Hallmayer, Steven P. Hamilton, Marian L. Hamshere, Thomas F. Hansen, Annette M. Hartmann, Martin Hautzinger, Andrew C. Heath, Anjali K. Henders, Stefan Herms, Ian B. Hickie, Maria Hipolito, Susanne Hoefels, Peter A. Holmans, Florian Holsboer, Witte J. Hoogendijk, Jouke-Jan Hottenga, Vanessa Hus, Andrés Ingason, Marcus Ising, Stéphane Jamain, Ian Jones, Lisa Jones, Anna K. Kähler, René S. Kahn, Radhika Kandaswamy, Matthew C. Keller, John R. Kelsoe, James L. Kennedy, Elaine Kenny, Lindsey Kent, Yunjung Kim, George K. Kirov, Sabine M. Klauck, Lambertus Klei, James A. Knowles, Martin A. Kohli, Daniel L. Koller, Bettina Konte, Ania Korszun, Lydia Krabbendam, Robert Krasucki, Jonna Kuntsi, Phoenix Kwan, Niklas Långström, Mark Lathrop, Jacob Lawrence, William B. Lawson, Marion Leboyer, David H. Ledbetter, Phil H. Lee, Todd Lencz, Klaus-Peter Lesch, Cathryn M. Lewis, Jun Li, Paul Lichtenstein, Jeffrey A. Lieberman, Dan-Yu Lin, Don H. Linszen, Chunyu Liu, Falk W. Lohoff, Sandra K. Loo, Catherine Lord, Jennifer K. Lowe, Susanne Lucae, Donald J. MacIntyre, Pamela A.F. Madden, Elena Maestrini, Patrik K.E. Magnusson, Pamela B. Mahon, Wolfgang Maier, Anil K. Malhotra, Shrikant M. Mane, Christa L. Martin, Nicholas G. Martin, Manuel Mattheisen, Keith Matthews, Morten Mattingsdal, Steven A. McCarroll, Kevin A. McGhee, James J. McGough, Patrick J. McGrath, Peter McGuffin, Melvin G. McInnis, Andrew McIntosh, Rebecca McKinney, Alan W. McLean, Francis J. McMahon, William M. McMahon, Andrew McQuillin, Helena Medeiros, Sarah E. Medland, Sandra Meier, Ingrid Melle, Fan Meng, Jobst Meyer, Christel M. Middeldorp, Lefkos Middleton, Vihra Milanova, Ana Miranda, Anthony P. Monaco, Grant W. Montgomery, Jennifer L. Moran, Daniel Moreno-De-Luca, Gunnar Morken, Derek W. Morris, Eric M. Morrow, Valentina Moskvina, Bryan J. Mowry, Pierandrea Muglia, Thomas W. Mühleisen, Bertram Müller-Myhsok, Michael Murtha, Richard M. Myers, Inez Myin-Germeys, Benjamin M. Neale, Stan F. Nelson, Caroline M. Nievergelt, Ivan Nikolov, Vishwajit Nimgaonkar, Willem A. Nolen, Markus M. Nöthen, John I. Nurnberger, Evaristus A. Nwulia, Dale R. Nyholt, Michael C. O’Donovan, Colm O’Dushlaine, Robert D. Oades, Ann Olincy, Guiomar Oliveira, Line Olsen, Roel A. Ophoff, Urban Osby, Michael J. Owen, Aarno Palotie, Jeremy R. Parr, Andrew D. Paterson, Carlos N. Pato, Michele T. Pato, Brenda W. Penninx, Michele L. Pergadia, Margaret A. Pericak-Vance, Roy H. Perlis, Benjamin S. Pickard, Jonathan Pimm, Joseph Piven, Danielle Posthuma, Fritz Poustka, Peter Propping, Shaun M. Purcell, Vinay Puri, Digby J. Quested, Emma M. Quinn, Josep Antoni Ramos-Quiroga, Henrik B. Rasmussen, Soumya Raychaudhuri, Karola Rehnström, Andreas Reif, Marta Ribasés, John P. Rice, Marcella Rietschel, Kathryn Roeder, Herbert Roeyers, Lizzy Rossin, Aribert Rothenberger, Guy Rouleau, Douglas Ruderfer, Dan Rujescu, Alan R. Sanders, Stephan J. Sanders, Susan L. Santangelo, Russell Schachar, Martin Schalling, Alan F. Schatzberg, Gerard D. Schellenberg, Stephen W. Scherer, Nicholas J. Schork, Thomas G. Schulze, Johannes Schumacher, Markus Schwarz, Edward Scolnick, Laura J. Scott, Joseph A. Sergeant, Paul D. Shilling, Stanley I. Shyn, Jeremy M. Silverman, Pamela Sklar, Susan L. Slager, Susan L. Smalley, Johannes H. Smit, Erin N. Smith, Edmund J.S. Sonuga-Barke, David St Clair, Matthew State, Michael Steffens, Hans-Christoph Steinhausen, John S. Strauss, Jana Strohmaier, T. Scott Stroup, Patrick F. Sullivan, James Sutcliffe, Peter Szatmari, Szabocls Szelinger, Anita Thapar, Srinivasa Thirumalai, Robert C. Thompson, Alexandre A. Todorov, Federica Tozzi, Jens Treutlein, Jung-Ying Tzeng, Manfred Uhr, Edwin J.C.G. van den Oord, Gerard Van Grootheest, Jim Van Os, Astrid M. Vicente, Veronica J. Vieland, John B. Vincent, Peter M. Visscher, Christopher A. Walsh, Thomas H. Wassink, Stanley J. Watson, Lauren A. Weiss, Thomas Werge, Thomas F. Wienker, Durk Wiersma, Ellen M. Wijsman, Gonneke Willemsen, Nigel Williams, A. Jeremy Willsey, Stephanie H. Witt, Wei Xu, Allan H. Young, Timothy W. Yu, Stanley Zammit, Peter P. Zandi, Peng Zhang, Frans G. Zitman, Sebastian Zöllner, University of Zurich, Lee, S Hong, Epidemiology and Data Science, Psychiatry, EMGO - Mental health, NCA - Neurobiology of mental health, Human genetics, NCA - Brain mechanisms in health and disease, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Maier, Robert, Moser, Gerhard, Chen, Guo-Bo, Ripke, Stephan, Coryell, William, Potash, James B, Scheftner, William A, Shi, Jianxin, Weissman, Myrna M, Hultman, Christina M, Landen, Mikael, Levinson, Douglas F, Kendler, Kenneth S, Smoller, Jordan, Wray, Naomi R, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Oades, Robert D. (Beitragende*r), Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Maier R., Moser G., Chen G.-B., Ripke S., Coryell W., Potash J.B., Scheftner W.A., Shi J., Weissman M.M., Hultman C.M., Landen M., Levinson D.F., Kendler K.S., Smoller J.W., Wray N.R., Lee S.H., Absher D., Agartz I., Akil H., Amin F., Andreassen O.A., Anjorin A., Anney R., Arking D.E., Asherson P., Azevedo M.H., Backlund L., Badner J.A., Bailey A.J., Banaschewski T., Barchas J.D., Barnes M.R., Barrett T.B., Bass N., Battaglia A., Bauer M., Bayes M., Bellivier F., Bergen S.E., Berrettini W., Betancur C., Bettecken T., Biederman J., Binder E.B., Black D.W., Blackwood D.H.R., Bloss C.S., Boehnke M., Boomsma D.I., Breen G., Breuer R., Bruggeman R., Buccola N.G., Buitelaar J.K., Bunney W.E., Buxbaum J.D., Byerley W.F., Caesar S., Cahn W., Cantor R.M., Casas M., Chakravarti A., Chambert K., Choudhury K., Cichon S., Robert Cloninger C., Collier D.A., Cook E.H., Coon H., Cormand B., Cormican P., Corvin A., Coryell W.H., Craddock N., Craig D.W., Craig I.W., Crosbie J., Cuccaro M.L., Curtis D., Czamara D., Daly M.J., Datta S., Dawson G., Day R., De Geus E.J., Degenhardt F., Devlin B., Djurovic S., Donohoe G.J., Doyle A.E., Duan J., Dudbridge F., Duketis E., Ebstein R.P., Edenberg H.J., Elia J., Ennis S., Etain B., Fanous A., Faraone S.V., Farmer A.E., Nicol Ferrier I., Flickinger M., Fombonne E., Foroud T., Frank J., Franke B., Fraser C., Freedman R., Freimer N.B., Freitag C.M., Friedl M., Frisen L., Gallagher L., Gejman P.V., Georgieva L., Gershon E.S., Geschwind D.H., Giegling I., Gill M., Gordon S.D., Gordon-Smith K., Green E.K., Greenwood T.A., Grice D.E., Gross M., Grozeva D., Guan W., Gurling H., De Haan L., Haines J.L., Hakonarson H., Hallmayer J., Hamilton S.P., Hamshere M.L., Hansen T.F., Hartmann A.M., Hautzinger M., Heath A.C., Henders A.K., Herms S., Hickie I.B., Hipolito M., Hoefels S., Holmans P.A., Holsboer F., Hoogendijk W.J., Hottenga J.-J., Hus V., Ingason A., Ising M., Jamain S., Jones I., Jones L., Kahler A.K., Kahn R.S., Kandaswamy R., Keller M.C., Kelsoe J.R., Kennedy J.L., Kenny E., Kent L., Kim Y., Kirov G.K., Klauck S.M., Klei L., Knowles J.A., Kohli M.A., Koller D.L., Konte B., Korszun A., Krabbendam L., Krasucki R., Kuntsi J., Kwan P., Langstrom N., Lathrop M., Lawrence J., Lawson W.B., Leboyer M., Ledbetter D.H., Lee P.H., Lencz T., Lesch K.-P., Lewis C.M., Li J., Lichtenstein P., Lieberman J.A., Lin D.-Y., Linszen D.H., Liu C., Lohoff F.W., Loo S.K., Lord C., Lowe J.K., Lucae S., MacIntyre D.J., Madden P.A.F., Maestrini E., Magnusson P.K.E., Mahon P.B., Maier W., Malhotra A.K., Mane S.M., Martin C.L., Martin N.G., Mattheisen M., Matthews K., Mattingsdal M., McCarroll S.A., McGhee K.A., McGough J.J., McGrath P.J., McGuffin P., McInnis M.G., McIntosh A., McKinney R., McLean A.W., McMahon F.J., McMahon W.M., McQuillin A., Medeiros H., Medland S.E., Meier S., Melle I., Meng F., Meyer J., Middeldorp C.M., Middleton L., Milanova V., Miranda A., Monaco A.P., Montgomery G.W., Moran J.L., Moreno-De-Luca D., Morken G., Morris D.W., Morrow E.M., Moskvina V., Mowry B.J., Muglia P., Muhleisen T.W., Muller-Myhsok B., Murtha M., Myers R.M., Myin-Germeys I., Neale B.M., Nelson S.F., Nievergelt C.M., Nikolov I., Nimgaonkar V., Nolen W.A., Nothen M.M., Nurnberger J.I., Nwulia E.A., Nyholt D.R., O'Donovan M.C., O'Dushlaine C., Oades R.D., Olincy A., Oliveira G., Olsen L., Ophoff R.A., Osby U., Owen M.J., Palotie A., Parr J.R., Paterson A.D., Pato C.N., Pato M.T., Penninx B.W., Pergadia M.L., Pericak-Vance M.A., Perlis R.H., Pickard B.S., Pimm J., Piven J., Posthuma D., Poustka F., Propping P., Purcell S.M., Puri V., Quested D.J., Quinn E.M., Ramos-Quiroga J.A., Rasmussen H.B., Raychaudhuri S., Rehnstrom K., Reif A., Ribases M., Rice J.P., Rietschel M., Roeder K., Roeyers H., Rossin L., Rothenberger A., Rouleau G., Ruderfer D., Rujescu D., Sanders A.R., Sanders S.J., Santangelo S.L., Schachar R., Schalling M., Schatzberg A.F., Schellenberg G.D., Scherer S.W., Schork N.J., Schulze T.G., Schumacher J., Schwarz M., Scolnick E., Scott L.J., Sergeant J.A., Shilling P.D., Shyn S.I., Silverman J.M., Sklar P., Slager S.L., Smalley S.L., Smit J.H., Smith E.N., Sonuga-Barke E.J.S., St Clair D., State M., Steffens M., Steinhausen H.-C., Strauss J.S., Strohmaier J., Scott Stroup T., Sullivan P.F., Sutcliffe J., Szatmari P., Szelinger S., Thapar A., Thirumalai S., Thompson R.C., Todorov A.A., Tozzi F., Treutlein J., Tzeng J.-Y., Uhr M., van den Oord E.J.C.G., Van Grootheest G., Van Os J., Vicente A.M., Vieland V.J., Vincent J.B., Visscher P.M., Walsh C.A., Wassink T.H., Watson S.J., Weiss L.A., Werge T., Wienker T.F., Wiersma D., Wijsman E.M., Willemsen G., Williams N., Jeremy Willsey A., Witt S.H., Xu W., Young A.H., Yu T.W., Zammit S., Zandi P.P., Zhang P., Zitman F.G., and Zollner S.
Subjects: Netherlands Twin Register (NTR), Multifactorial Inheritance, Multivariate analysis, Bipolar Disorder, genome annotation, Medizin, R Medicine (General), Medical and Health Sciences, Genome-wide association studies, 0302 clinical medicine, 2.5 Research design and methodologies (aetiology), GWAS, Genetics(clinical), Aetiology, Multivariate Analysi, Genetics (clinical), Genetics & Heredity, bipolar disorder, 0303 health sciences, education.field_of_study, Depression, Mental Disorders, Single Nucleotide, 3rd-DAS, Biological Sciences, 10058 Department of Child and Adolescent Psychiatry, Serious Mental Illness, Psychiatric Disorders, 3. Good health, Mental Health, Schizophrenia, Mental Disorder, Linear Model, Major depressive disorder, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Risk assessment, Human, medicine.medical_specialty, 2716 Genetics (clinical), Genetics, Medical, Population, SNP, 610 Medicine & health, QH426 Genetics, Best linear unbiased prediction, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, 1311 Genetics, Medical, Report, medicine, Genetics, Humans, Bipolar disorder, Genetic Testing, Polymorphism, education, Psychiatry, QH426, 030304 developmental biology, Depressive Disorder, Depressive Disorder, Major, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Prevention, Human Genome, Major, medicine.disease, genetic risk prediction, R1, Brain Disorders, schizophrenia, Sample size determination, Perturbações do Desenvolvimento Infantil e Saúde Mental, Multivariate Analysis, Linear Models, business, depressive disorders, 030217 neurology & neurosurgery
Abstract: Cross-Disorder Working Group of the Psychiatric Genomics Consortium - Vicente A.M. Acessível em: http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25640677/ Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk
Published: 2015
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29. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Author: Laura J. Scott, Bernie Devlin, Steven A. McCarroll, James S. Sutcliffe, Stefan Herms, Yunjung Kim, Richard O. Day, Thomas F. Wienker, Frank Dudbridge, I. Nicol Ferrier, Bettina Konte, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Detelina Grozeva, Herbert Roeyers, Peter Holmans, Colm O'Dushlaine, Scott D. Gordon, Sarah E. Bergen, Fan Meng, Morten Mattingsdal, Hugh Gurling, Ina Giegling, Gerard van Grootheest, Ania Korszun, Markus J. Schwarz, George Kirov, Sebastian Zöllner, Kenneth S. Kendler, Nicholas G. Martin, Michael Conlon O'Donovan, Michael C. Neale, Jim van Os, Aravinda Chakravarti, Timothy W. Yu, Mikael Landén, Inez Myin-Germeys, Markus M. Nöthen, Kathryn Roeder, James B. Potash, Alan W. McLean, Louise Gallagher, Anna K. Kähler, Thomas Bettecken, Nigel Williams, Frank Bellivier, Joseph D. Buxbaum, Derek W. Morris, Susan L. Smalley, Jung-Ying Tzeng, Martin Schalling, Douglas M. Ruderfer, Caroline M. Nievergelt, T. Scott Stroup, David H. Ledbetter, Jennifer Crosbie, Anita Thapar, Barbara Franke, Jeffrey A. Lieberman, Huda Akil, Miguel Casas, Daniel H. Geschwind, Paul Cormican, Bertram Müller-Myhsok, Lyudmila Georgieva, Robert Krasucki, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Gerard D. Schellenberg, Todd Lencz, Melvin G. McInnis, Catalina Betancur, Josep Antoni Ramos-Quiroga, Stephen Sanders, Eftichia Duketis, Don H. Linszen, Matthew W. State, Richard M. Myers, Soumya Raychaudhuri, Lizzy Rossin, Howard J. Edenberg, Michael E. Goddard, S. Hong Lee, Elisabeth B. Binder, Pablo V. Gejman, William A. Scheftner, Wolfgang Maier, Judith A. Badner, Christel M. Middeldorp, Maria Helena Pinto de Azevedo, Johannes H. Smit, Willem A. Nolen, Lieuwe de Haan, Gonneke Willemsen, Keith Matthews, Ellen M. Wijsman, Jennifer K. Lowe, Rebecca McKinney, Magdalena Gross, Dorothy E. Grice, James A. Knowles, Andrew C. Heath, Jana Strohmaier, Vishwajit L. Nimgaonkar, William Byerley, William E. Bunney, Dan E. Arking, Andrew McQuillin, William M. McMahon, Manuel Mattheisen, Hans-Christoph Steinhausen, Joseph Biederman, Guy A. Rouleau, James J. McGough, Sian Caesar, Edward M. Scolnick, Lefkos T. Middleton, Jack D. Barchas, Ian B. Hickie, Danyu Lin, Patrik K. E. Magnusson, Douglas Blackwood, Francis J. McMahon, Ingrid Agartz, Elena Maestrini, Marian L. Hamshere, Lindsey Kent, Walter J. Muir, Stephan Ripke, Lydia Krabbendam, Christine Fraser, Maria Hipolito, Louise Frisén, Eric Fombonne, Emma M. Quinn, Michael Bauer, Richard P. Ebstein, Michael Steffens, Jordan W. Smoller, Stanley J. Watson, Michael Boehnke, Philip Asherson, Agatino Battaglia, Elliot S. Gershon, Russell Schachar, Marcus Ising, Peng Zhang, Margaret A. Pericak-Vance, Joachim Hallmayer, Sean Ennis, Radhika Kandaswamy, René S. Kahn, Susanne Hoefels, Thomas W. Mühleisen, Pamela Sklar, Paul Lichtenstein, Verneri Anttila, Michael L. Cuccaro, Florian Holsboer, René Breuer, Eric M. Morrow, Vinay Puri, Naomi R. Wray, Szabocls Szelinger, Sabine M. Klauck, John B. Vincent, Shrikant Mane, Aribert Rothenberger, Marion Friedl, Ian Jones, Khalid Choudhury, Michael R. Barnes, Adebayo Anjorin, Edwin H. Cook, William Lawson, Allan H. Young, Lambertus Klei, Bryan J. Mowry, Johannes Schumacher, Michael Gill, James L. Kennedy, Marcella Rietschel, Aiden Corvin, Henrik B. Rasmussen, Susmita Datta, Kimberly Chambert, Daniel Moreno-De-Luca, Benjamin S. Pickard, Stan F. Nelson, Veronica J. Vieland, Stephen W. Scherer, Peter M. Visscher, John Strauss, Andreas Reif, Andrew D. Paterson, Ann Olincy, Phoenix Kwan, Anthony J. Bailey, Patrick F. Sullivan, Pierandrea Muglia, Gunnar Morken, Susanne Lucae, Ayman H. Fanous, Jacob Lawrence, Donald J. MacIntyre, Nancy G. Buccola, Rita M. Cantor, Christina M. Hultman, Weihua Guan, Anthony P. Monaco, Jouke-Jan Hottenga, Elaine Kenny, Jianxin Shi, Dale R. Nyholt, Kevin A. McGhee, Falk W. Lohoff, Jonna Kuntsi, Niklas Långström, John I. Nurnberger, Nelson B. Freimer, Erin N. Smith, John P. Rice, Michael T. Murtha, Thomas H. Wassink, Alexandre A. Todorov, Edmund J.S. Sonuga-Barke, Dan Rujescu, Roy H. Perlis, John S. Witte, Christopher A. Walsh, Matthew C. Keller, Pamela B. Mahon, Patrick J. McGrath, Susan L. Santangelo, Annette M. Hartmann, Ole A. Andreassen, Tatiana Foroud, Shaun Purcell, Josef Frank, Douglas F. Levinson, William Coryell, Ana Miranda, Alan F. Schatzberg, Peter Szatmari, Jun Li, Gerome Breen, Stephen V. Faraone, Anil K. Malhotra, Helena Medeiros, Martin A. Kohli, Nicholas Bass, Catherine Lord, Peter Propping, Wei Xu, Federica Tozzi, Ivan Nikolov, Jan K. Buitelaar, Thomas G. Schulze, Katherine Gordon-Smith, Michele L. Pergadia, Fritz Poustka, Valentina Moskvina, David Curtis, Tobias Banaschewski, Devin Absher, Danielle Posthuma, Stanley Zammit, Gary Donohoe, Ingrid Melle, Karola Rehnström, Thomas Hansen, Myrna M. Weissman, Stanley I. Shyn, Hakon Hakonarson, Christa Lese Martin, Digby Quested, Darina Czamara, Jeremy R. Parr, Pamela A. F. Madden, Jens Treutlein, Aarno Palotie, Robert Freedman, Sandra Meier, Bru Cormand, Nicholas J. Schork, Michele T. Pato, John R. Kelsoe, Vanessa Hus, Frans G. Zitman, Josephine Elia, David St Clair, Roel A. Ophoff, Peter McGuffin, Jonathan Pimm, Jonathan L. Haines, Wiepke Cahn, Matthew Flickinger, Steven P. Hamilton, Michael John Owen, Paul D. Shilling, Jeremy M. Silverman, David Craig, Mark J. Daly, Sarah E. Medland, Robert D. Oades, Marion Leboyer, Alan R. Sanders, Vihra Milanova, Chunyu Liu, Jobst Meyer, Dorret I. Boomsma, Evaristus A. Nwulia, Thomas B. Barrett, Jennifer L. Moran, Donald W. Black, Mònica Bayés, Witte J.G. Hoogendijk, Franziska Degenhardt, Benjamin M. Neale, Daniel L. Koller, Carlos N. Pato, Nicholas John Craddock, Richard Bruggeman, Enda M. Byrne, Edward G. Jones, Eco J. C. de Geus, Stéphane Jamain, Jubao Duan, Anne Farmer, Astrid M. Vicente, Grant W. Montgomery, Thomas Werge, Cathryn M. Lewis, Srdjan Djurovic, Phil Lee, Richard Anney, Elaine K. Green, Wade H. Berrettini, Peter P. Zandi, Susan L. Slager, Stephanie H. Witt, Ian W. Craig, Lisa Jones, Sven Cichon, Bruno Etain, Mark Lathrop, Hilary Coon, Robert C. Thompson, Lena Backlund, A. Jeremy Willsey, Andres Ingason, Christine M. Freitag, Sandra K. Loo, Guiomar Oliveira, Line Olsen, Edwin J. C. G. van den Oord, Geraldine Dawson, Joseph A. Sergeant, David A. Collier, Farooq Amin, Srinivasa Thirumalai, Manfred Uhr, Joseph Piven, Andrew M. McIntosh, Anjali K. Henders, Urban Ösby, Klaus-Peter Lesch, Tiffany A. Greenwood, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Lee, S Hong, Ripke, Stephan, Neale, Benjamin M, Faraone, Stephen V, Wray, Naomi R, Cross-Disorder Group of the Psychiatric Genomics Consortium, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Queensland Brain Institute, University of Queensland [Brisbane], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], SUNY Upstate Medical University, State University of New York (SUNY), Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Psychiatric and Neurodevelopmental Genetics Unit, Queensland Centre for Mental Health Research, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], New South Wales Department of Primary Industries (NSW DPI), Faculty of Land and Food Resources, University of Melbourne, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Diakonhjemmet Hospital, University of Michigan [Ann Arbor], University of Michigan System, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan System-University of Michigan System, Emory University [Atlanta, GA], Oslo University Hospital [Oslo], University College of London [London] (UCL), Trinity College Dublin, Johns Hopkins University School of Medicine [Baltimore], MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, King's College London, University of Coimbra [Portugal] (UC), Karolinska Institutet [Stockholm], University of Chicago, University of British Columbia (UBC), Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim], Universität Heidelberg [Heidelberg] = Heidelberg University, Weill Medical College of Cornell University [New York], GlaxoSmithKline, Glaxo Smith Kline, Portland Veterans Administration Medical Center, Windeyer Institute for Medical Sciences, IRCCS Fondazione Stella Maris [Pisa], University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - 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Georg-August-Universität Göttingen, Yale University School of Medicine, Georg-August-University [Göttingen], ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayés M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisén L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kähler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landén M, Långström N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Mühleisen TW, Muir WJ, Müller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nöthen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O'Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnström K, Reif A, Ribasés M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zöllner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O'Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR, Cardiff University-Medical Research Council (MRC), HudsonAlpha Institute for Biotechnology, The Institute of Psychiatry-King‘s College London, Cornell University-Weill Medical College of Cornell University [New York], Stanford University Medical School, Technische Universität Dresden (TUD)-University Hospital Carl Gustav Carus, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, McGill University-Montreal Children's Hospital, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Eberhard Karls Universität Tübingen, Friedrich Alexander University [Erlangen-Nürnberg], Università di Bologna [Bologna] (UNIBO), University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Washington University School of Medicine, Ghent University [Belgium] (UGENT), University of Goettingen, CHUM Research Center, Psychiatry and Behavioral Science, Stanford University School of Medicine [CA, USA], Aalborg Psychiatric Hospital, Aarhus University Hospital, Washington University in St Louis, Instituto Nacional de Saude Dr Ricardo Jorge, Oades, Robert D., Guellaen, Georges, Medical Oncology, Epidemiology, Child and Adolescent Psychiatry / Psychology, and Hematology
Subjects: Netherlands Twin Register (NTR), Medizin, Inheritance Patterns, Social Sciences, AUTISM SPECTRUM DISORDERS, nosology, heritability, COMMON SNPS, 0302 clinical medicine, Crohn Disease, SCHIZOPHRENIA, Child, Psychiatric genetics, Genetics & Heredity, MAJOR DEPRESSIVE DISORDER, RISK, 0303 health sciences, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, 120 000 Neuronal Coherence, Mental Disorders, Variants, BIPOLAR DISORDER, ASSOCIATION, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], Psychiatric Disorders, CROHNS-DISEASE, 3. Good health, Schizophrenia, genetic association study, Medical genetics, Major depressive disorder, SNPs, Adult, medicine.medical_specialty, genetic etiology, medical genetics, DEFICIT HYPERACTIVITY DISORDER, Biology, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Heritability, Genetic Heterogeneity, 03 medical and health sciences, Prevalence of mental disorders, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, ddc:61, Humans, Attention deficit hyperactivity disorder, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DCN PAC - Perception action and control NCEBP 9 - Mental health, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Bipolar disorder, Psychiatry, 030304 developmental biology, Depressive Disorder, Major, Genome, Human, Genetic heterogeneity, medicine.disease, schizophrenia, Attention Deficit Disorder with Hyperactivity, Child Development Disorders, Pervasive, Perturbações do Desenvolvimento Infantil e Saúde Mental, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Published: 2013
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30. Individual common variants exert weak effects on the risk for autism spectrum disorderspi

Author: Naisha Shah, William M. McMahon, Barbara Parrini, Jeremy R. Parr, Thomas Bourgeron, Vanessa Hus, Gudrun Nygren, Sabine M. Klauck, John B. Vincent, Nadine M. Melhem, Jillian P. Casey, Christina Corsello, Jonathan L. Haines, Andrew D. Paterson, Raffaella Tancredi, Alistair T. Pagnamenta, Jonathan Green, Richard Delorme, Geraldine Dawson, Andrew Pickles, Carine Mantoulan, Alexander Kolevzon, Bridget A. Fernandez, Frederico Duque, Inês Sousa, Tara Paton, Kathryn Roeder, Joana Almeida, Richard Anney, Margaret A. Pericak-Vance, Joachim Hallmayer, Gerard D. Schellenberg, Sabata C. Lund, Rita M. Cantor, Daniel H. Geschwind, Janine A. Lamb, Annette Estes, Sven Bölte, Hakon Hakonarson, Gillian Hughes, Gillian Baird, John I. Nurnberger, Jessica Brian, Bernie Devlin, Roberta Igliozzi, Vera Stoppioni, Jiannis Ragoussis, Peter Szatmari, Ghazala Mirza, Eric Fombonne, Thomas H. Wassink, Emily L. Crawford, Nuala Sykes, Danielle Zurawiecki, Graham Kenny, David J. Posey, Elena Maestrini, Vlad Kustanovich, Elena Bacchelli, Veronica J. Vieland, Stephen W. Scherer, Guiomar Oliveira, Simon Wallace, John R. Gilbert, Latha Soorya, Sean Brennan, Tiago R. Magalhaes, Hilary Coon, Elizabeth A. Heron, Sabine Schlitt, Fritz Poustka, Astrid M. Vicente, Patrick Bolton, Linda Lotspeich, Nancy J. Minshew, Val C. Sheffield, Bennett L. Leventhal, Xiao-Qing Liu, Andrew Green, Joseph D. Buxbaum, Shawn Wood, Susan E. Folstein, Sean Ennis, Catarina Correia, James S. Sutcliffe, Carolyn Noakes, Ann Le Couteur, Marion Leboyer, Ann P. Thompson, Christine M. Freitag, Fred R. Volkmar, Katerina Papanikolaou, Dalila Pinto, Agatino Battaglia, Frances Lombard, Joseph Piven, Maretha de Jonge, Michael Rutter, Clara Lajonchere, Kerstin Wittemeyer, Herman van Engeland, Michael L. Cuccaro, Richard Holt, Lonnie Zwaigenbaum, Louise Gallagher, Jeff Munson, Ana Tryfon, John Tsiantis, Lambertus Klei, Christopher Gillberg, Penny Farrar, Joseph T. Glessner, Ellen M. Wijsman, Anthony P. Monaco, Wendy Roberts, Nadia Bolshakova, Cecilia Kim, Judith Miller, Stephen J. Guter, Susanne Thomson, Catherine Lord, Anthony J. Bailey, Miriam Law-Smith, Michael Gill, Christopher J. McDougle, Bernadette Rogé, Alison K. Merikangas, Jacob A. S. Vorstman, Suma Jacob, Judith Conroy, Kirsty Wing, Regina Regan, Jennifer L. Howe, Stanley F. Nelson, Edwin H. Cook, Catalina Betancur, Eftichia Duketis, Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), The Centre for Applied Genomics, Toronto, University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Newcomen Centre, Guy's Hospital [London], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Department of Child and Adolescent Psychiatry, Institute of psychiatry, Molecular and Cellular Neurobiology, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Autism and Communicative Disorders Centre, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Psychiatry, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Speech and Hearing Sciences [Washington], University of Washington [Seattle], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Disciplines of Genetics and Medicine, Memorial University of Newfoundland [St. John's], University of Miami School of Medicine, John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Research Unit on Children's Psychosocial Maladjustment, Université Laval [Québec] (ULaval)-Department of Psychology, University of Gothenburg (GU), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Manchester Academic Health Sciences Centre, Department of Disability and Human Development, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), Autism Genetic Resource Exchange, Autism Speaks, Centre for Integrated Genomic Medical Research, Manchester, University of Manchester [Manchester], Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, European Network of Bipolar Research Expert Centres (ENBREC), ENBREC, Newcastle University [Newcastle]-Institute of Health & Society (Child & Adolescent Psychiatry), New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Centre de Référence du Syndrome de Prader-Willi, CHU Toulouse [Toulouse], Indiana University School of Medicine, Indiana University System-Indiana University System, Department of Psychiatry and Behavioral Sciences, University Department of Child Psychiatry, National and Kapodistrian University of Athens (NKUA), Department of Medicine, Manchester, University of Manchester [Manchester]-School of Epidemiology and Health Science, Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Octogone Unité de Recherche Interdisciplinaire (Octogone), Université Toulouse - Jean Jaurès (UT2J), Social, Genetic and Developmental Psychiatry Centre, Department of Pediatrics, University of Iowa [Iowa City]-Howard Hughes Medical-Institute Carver College of Medicine, Neuropsichiatria Infantile, Ospedale Santa Croce, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, University of Toronto, Child Study Centre, Yale University School of Medicine, University of Oxford [Oxford]-Warneford Hospital, University of Alberta, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), The Institute of Psychiatry-King‘s College London, Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California-University of California [Los Angeles] (UCLA), University of California-University of California, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Autism Speaks and the Department of Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Department of Neurology, University of California-University of California-David Geffen School of Medicine [Los Angeles], Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institutes of Neuroscience and Health and Society, Newcastle University [Newcastle], Carolina Institute for Developmental Disabilities, Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Departments of Biostatistics and Medicine, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Stanford School of Medicine [Stanford], Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Children’s Hospital of Philadelphia (CHOP )-Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Yale School of Medicine [New Haven, Connecticut] (YSM), King‘s College London-The Institute of Psychiatry, University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Casey J, Conroy J, Correia C, Corsello C, Crawford EL, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Gilbert J, Gillberg C, Glessner JT, Green A, Green J, Guter SJ, Heron EA, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Jacob S, Kenny GP, Kim C, Kolevzon A, Kustanovich V, Lajonchere CM, Lamb JA, Law-Smith M, Leboyer M, Le Couteur A, Leventhal BL, Liu XQ, Lombard F, Lord C, Lotspeich L, Lund SC, Magalhaes TR, Mantoulan C, McDougle CJ, Melhem NM, Merikangas A, Minshew NJ, Mirza GK, Munson J, Noakes C, Nygren G, Papanikolaou K, Pagnamenta AT, Parrini B, Paton T, Pickles A, Posey DJ, Poustka F, Ragoussis J, Regan R, Roberts W, Roeder K, Roge B, Rutter ML, Schlitt S, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Sykes N, Tancredi R, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman J, Wallace S, Wing K, Wittemeyer K, Wood S, Zurawiecki D, Zwaigenbaum L, Bailey AJ, Battaglia A, Cantor RM, Coon H, Cuccaro ML, Dawson G, Ennis S, Freitag CM, Geschwind DH, Haines JL, Klauck SM, McMahon WM, Maestrini E, Miller J, Monaco AP, Nelson SF, Nurnberger JI Jr, Oliveira G, Parr JR, Pericak-Vance MA, Piven J, Schellenberg GD, Scherer SW, Vicente AM, Wassink TH, Wijsman EM, Betancur C, Buxbaum JD, Cook EH, Gallagher L, Gill M, Hallmayer J, Paterson AD, Sutcliffe JS, Szatmari P, Vieland VJ, Hakonarson H, Devlin B, University of Oxford, Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University of Oxford-Warneford Hospital, University of Pennsylvania, University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), Betancur, Catalina, and Université de Toulouse (UT)-Université de Toulouse (UT)
Subjects: Male, CNTNAP2, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Nerve Tissue Proteins, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Language Development, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, autism spectrum disorders (ASDs), Gene Frequency, Risk Factors, mental disorders, Genetics, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Allele, GENOME-WIDE ASSOCIATION, Child, Molecular Biology, Allele frequency, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Association Studies Articles, Membrane Proteins, General Medicine, medicine.disease, Genetic architecture, Child Development Disorders, Pervasive, common variant, Perturbações do Desenvolvimento Infantil e Saúde Mental, Autism, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: International audience; 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
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31. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders

Author: Christian Proepper, Dominique Bonneau, Catalina Betancur, Sarah Curran, Astrid M. Vicente, Henrik Anckarsäter, Elena Bacchelli, Sabine M. Klauck, Eftichia Duketis, Guiomar Oliveira, Fabien Fauchereau, Richard Delorme, Irma Järvelä, I. Carina Gillberg, Marina Konyukh, Stephen W. Scherer, Pauline Chaste, Elena Maestrini, Guillaume Huguet, Dalila Pinto, David Skuse, Marie-Christine Mouren, Béatrice Regnault, Nathalie Lemière, Jonas Melke, Christopher Gillberg, Bárbara Oliveira, Maria Råstam, Thomas Bourgeron, Marnie Kopp, Marc Delepine, Oriane Mercati, Raija Vanhala, Luigi Mazzone, Marion Leboyer, Richard Holt, Agatino Battaglia, Fiorella Minopoli, Katri Kantojärvi, Diana Zelenika, Liliana Ruta, Roberto Toro, Ana Filipa Sequeira, Françoise Devillard, Brigitte Assouline, Martin Poot, Elodie Ey, Regina Waltes, Vincent Guinchat, Tobias M. Boeckers, Jutta Heinrich, Anthony P. Monaco, Gudrun Nygren, Fritz Poustka, Mark Lathrop, David A. Collier, Claire S. Leblond, Patrick Bolton, Christine M. Freitag, Andreas G. Chiocchetti, Betancur, Catalina, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Universität Ulm - Ulm University [Ulm, Allemagne], Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Forensic Psychiatry, Lund University [Lund], Department of Pharmacology, Génotypage des Eucaryotes (Plate-Forme), Institut Pasteur [Paris] (IP), Behavioural and Brain Sciences Unit, Institute of Child Health, University College of London [London] (UCL), University Medical Center [Utrecht], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King‘s College London, Social, Genetic and Developmental Psychiatry Centre (SGDP), Institute of psychiatry, Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Institute of Biotechnology, Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Division of Child Neurology and Psychiatry, Department of Paediatrics, Università degli studi di Catania = University of Catania (Unict), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire Intégrée (BNVI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Pédopsychiatrique et Neuropédiatrique de Diagnostic et d'Evaluation des Troubles Envahissants du Développement, Centre Alpin de DIagnostic Précoce de l'Autisme - CADIPA-Centre Hospitalier Alpes Isère, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institute for Anatomy and Cell Biology, Department of Medical and Clinical Genetics, Leblond C.S., Heinrich J., Delorme R., Proepper C., Betancur C., Huguet G., Konyukh M., Chaste P| Ey E., Rastam M., Anckarsäter H., Nygren G., Gillberg IC., Melke J., Toro R., Regnault B., Fauchereau F., Mercati O., Lemière N., Skuse D., Poot M., Holt R., Monaco A.P., Järvelä I., Kantojärvi K., Vanhala R., Curran S., Collier D.A., Bolton P., Chiocchetti A., Klauck S.M., Poustka F., Freitag C.M., Waltes R., Kopp M., Duketis E., Bacchelli E., Minopoli F., Ruta L., Battaglia A., Mazzone L., Maestrini E., Sequeira A.F., Oliveira B., Vicente A., Oliveira G., Pinto D., Scherer S.W., Zelenika D., Delepine M., Lathrop M., Bonneau D., Guinchat V., Devillard F., Assouline B., Mouren M.C., Leboyer M., Gillberg C., Boeckers T.M., Bourgeron T., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Anatomy and Cell Biology, Ulm University, University of Lund, Institut Pasteur [Paris], University of Oxford [Oxford], University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Università degli studi di Catania [Catania], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10
Subjects: Male, Gene Dosage, Receptors, Nicotinic, MESH: Protein Isoforms, HIDDEN-MARKOV MODEL, 0302 clinical medicine, MESH: Child, Protein Isoforms, Tissue Distribution, MESH: Nerve Tissue Proteins, Child, Neurons, 0303 health sciences, MESH: Alternative Splicing, PSYCHIATRIC-DISORDERS, CHRNA7, MESH: Sequence Deletion, 3. Good health, Autism spectrum disorder, Child, Preschool, Medicine, Adaptor Proteins, Signal Transducing, Adult, Alternative Splicing, Cell Line, Child Development Disorders, Pervasive, Female, Gene Expression Regulation, Humans, Nerve Tissue Proteins, RNA Splice Sites, Sequence Deletion, Synapses, alpha7 Nicotinic Acetylcholine Receptor, Child Development Disorders, education, COPY-NUMBER VARIATION, Molecular Genetics, 03 medical and health sciences, Genetics, AUTISM, MESH: Tissue Distribution, Molecular Biology, Biology, SNP GENOTYPING DATA, Ecology, Evolution, Behavior and Systematics, Pervasive, MESH: Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, RECURRENT MICRODELETIONS, MESH: Child, Preschool, Signal Transducing, MESH: Adult, SCAFFOLDING PROTEIN SHANK3, medicine.disease, Human genetics, MESH: Cell Line, MESH: Female, 030217 neurology & neurosurgery, Neuroscience, Cancer Research, MESH: Neurons, MESH: RNA Splice Sites, [SDV.GEN] Life Sciences [q-bio]/Genetics, Bioinformatics, Nicotinic, MESH: Child Development Disorders, Pervasive, MESH: Gene Dosage, MESH: Synapses, POSTSYNAPTIC DENSITY, Receptors, Copy-number variation, Genetics (clinical), Psychiatry, Adaptor Proteins, MESH: Gene Expression Regulation, Settore MED/39 - Neuropsichiatria Infantile, SHANK2, Mental Health, MESH: Receptors, Nicotinic, Research Article, lcsh:QH426-470, 15Q13.3 MICRODELETIONS, Genetic variation, mental disorders, medicine, ddc:610, Preschool, Gene, 030304 developmental biology, MESH: Male, lcsh:Genetics, DE-NOVO MUTATIONS, Perturbações do Desenvolvimento Infantil e Saúde Mental, biology.protein, Autism, 3111 Biomedicine, MENTAL-RETARDATION
Abstract: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23–4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11–q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the “multiple hit model” for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD., Author Summary Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While mutations in several genes have been identified in patients with ASD, little is known about their effects on neuronal function and their interaction with other genetic variations. Using a combination of genetic and functional approaches, we identified novel SHANK2 mutations including a de novo loss of one copy of the SHANK2 gene in a patient with autism and several mutations observed in patients that reduced neuronal cell contacts in vitro. Further genomic analysis of three patients carrying de novo SHANK2 deletions identified additional rare genomic imbalances previously associated with neuropsychiatric disorders. Taken together, these results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the “multiple hit model” for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
Published: 2012
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32. A genome-wide scan for common alleles affecting risk for autism

Author: Veronica J. Vieland, Stephen W. Scherer, Elizabeth A. Heron, Barbara Parrini, Jeremy R. Parr, Louise Gallagher, Jeff Munson, Annemarie Poustka, Susan E. Folstein, Irene Drmic, Gudrun Nygren, John P. Rice, Jeff Salt, Simon Wallace, Geraldine Dawson, Daniel H. Geschwind, Annette Estes, Sean Brennan, Alistair T. Pagnamenta, Nancy J. Minshew, Christina Corsello, Jonathan Green, William M. McMahon, Christopher Gillberg, Kathryn Roeder, Lambertus Klei, Anath C. Lionel, Bridget A. Fernandez, Thomas Bourgeron, Ellen M. Wijsman, Gerard D. Schellenberg, Wendy Roberts, Jeremy Goldberg, Frederico Duque, Ghazala Mirza, Sean Ennis, Joana Almeida, Nadine M. Melhem, Jillian P. Casey, Roberta Igliozzi, Ricardo Segurado, Carine Mantoulan, Katy Renshaw, Kai Wang, Andrew D. Paterson, Raffaella Tancredi, Matthew Nicholas Hill, Richard Anney, Christian R. Marshall, Anthony P. Monaco, Linda Lotspeich, Marion Leboyer, Richard Holt, Andrew Pickles, Vlad Kustanovich, William M. Mahoney, Jessica Brian, Inês Sousa, Peter Szatmari, Vanessa Hus, Janine A. Lamb, Hakon Hakonarson, Lonnie Zwaigenbaum, John Tsiantis, David J. Posey, Olena Korvatska, Guillermo Casallo, Rita M. Cantor, Bhooma Thiruvahindrapduram, Nadia Bolshakova, Sven Bölte, Alison K. Merikangas, Brian L. Yaspan, Cecilia Kim, Andrew Crossett, Fritz Poustka, Danielle Zurawiecki, Agatino Battaglia, Sabata C. Lund, Ann P. Thompson, Bennett L. Leventhal, Jessica Rickaby, Zhouzhi Wang, John I. Nurnberger, Astrid M. Vicente, Maretha de Jonge, Tiago R. Magalhaes, Michael L. Cuccaro, Val C. Sheffield, Nuala Sykes, Elena Maestrini, Guiomar Oliveira, Joseph D. Buxbaum, Fred R. Volkmar, Shawn Wood, Magdalena Laskawiec, Katherine Sansom, Herman van Engeland, Jane McGrath, Thomas H. Wassink, Su H. Chu, Elena Bacchelli, Carolyn Noakes, Ann Le Couteur, Catarina Correia, Ohsuke Migita, Bernie Devlin, Hilary Coon, Gillian Baird, Joseph Piven, Tom Berney, Ana Tryfon, Abdul Noor, Patrick Bolton, Latha Soorya, Vera Stoppioni, Stephen J. Guter, Joseph T. Glessner, Michael Gill, Christopher J. McDougle, Anthony J. Bailey, Margaret A. Pericak-Vance, Joachim Hallmayer, Christine M. Freitag, Penny Farrar, Kirsty Wing, Katherine E. Tansey, Bernadette Rogé, Michael Rutter, Christina Strawbridge, Brett S. Abrahams, Kerstin Wittemeyer, Laura J. Bierut, Tara Paton, Emily L. Crawford, Jonathan L. Haines, Alexander Kolevzon, Gillian Hughes, Lili Senman, James S. Sutcliffe, John B. Gilbert, Katerina Papanikolaou, Andrew R. Carson, Lynne E Cochrane, Regina Regan, Judith Miller, Susanne Thomson, Helen McConachie, Daisuke Sato, Richard Delorme, Jiannis Ragoussis, Eric Fombonne, Clara Lajonchere, Judith Conroy, Dalila Pinto, Aparna Prasad, Naisha Shah, Stanley F. Nelson, Sabine M. Klauck, Catalina Betancur, John B. Vincent, Eftichia Duketis, Jennifer L. Howe, Edwin H. Cook, Xiao-Qing Liu, Catherine Lord, Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Department of Neurology, University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Psychiatry, University of Oxford [Oxford]-Warneford Hospital, Newcomen Centre, Guy's Hospital [London], Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Child and Adolescent Mental Health, Newcastle University [Newcastle], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Department of Child and Adolescent Psychiatry, Institute of psychiatry, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Autism Research Unit, University of Toronto-The Hospital for sick children [Toronto] (SickKids), Autism and Communicative Disorders Centre, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Scientific Affairs, Autism Speaks, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Department of Speech and Hearing Sciences [Washington], University of Washington [Seattle], Disciplines of Genetics and Medicine, Memorial University of Newfoundland [St. John's], John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Department of Child Psychiatry, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), University of Gothenburg (GU), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario], Manchester Academic Health Sciences Centre, Institute for Juvenile Research-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), Department of Medicine, Autism Genetic Resource Exchange, Centre for Integrated Genomic Medical Research, Manchester, University of Manchester [Manchester], Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Nathan Kline Institute for Psychiatric Research (NKI), Nathan Kline Institute for Psychiatric Research, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU)-NYU Child Study Center, Centre d'Etudes et de Recherches en PsychoPathologie, Université Toulouse - Jean Jaurès (UT2J), Indiana University School of Medicine, Indiana University System-Indiana University System, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Departments of Psychiatry and Neurology, Department of Psychiatry and Behavioral Sciences, Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), Centre for Addiction and Mental Health, Clarke Institute, University Department of Child Psychiatry, National and Kapodistrian University of Athens (NKUA), Institutes of Neuroscience and Health and Society, Department of Medicine, Manchester, University of Manchester [Manchester]-School of Epidemiology and Health Science, Carolina Institute for Developmental Disabilities, Social, Genetic and Developmental Psychiatry Centre, Washington University in Saint Louis (WUSTL), Howard Hughes Medical-Institute Carver College of Medicine-University of Iowa [Iowa City], Neuropsichiatria Infantile, Ospedale Santa Croce, Child Study Centre, Yale University School of Medicine, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], University of Alberta, Physiopathologie des Maladies du Système Nerveux Central, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Departments of Biostatistics and Medicine, This research was primarily supported by Autism Speaks (USA), the Health Research Board (HRB, Ireland), The Medical Research Council (MRC, UK), Genome Canada/Ontario Genomics Institute, and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health [HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH057881, MH061009, MH06359, MH066673, MH077930, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261], the Canadian Institutes for Health Research (CIHR), Assistance Publique-Hôpitaux de Paris (France), Autistica, Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche Forschungsgemeinschaft (grant: Po 255/17-4) (Germany), EC Sixth FP AUTISM MOLGEN, Fundação Calouste Gulbenkian (Portugal), Fondation de France, Fondation FondaMental (France), Fondation Orange (France), Fondation pour la Recherche Médicale (France), Fundação para a Ciência e Tecnologia (Portugal), GlaxoSmithKline-CIHR Pathfinder Chair (Canada), the Hospital for Sick Children Foundation and University of Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian Ministry of Health [convention 181 of 19.10.2001], the John P Hussman Foundation (USA), McLaughlin Centre (Canada), Netherlands Organization for Scientific Research [Rubicon 825.06.031], Ontario Ministry of Research and Innovation (Canada), Royal Netherlands Academy of Arts and Sciences [TMF/DA/5801], the Seaver Foundation (USA), the Swedish Science Council, The Centre for Applied Genomics (Canada), the Utah Autism Foundation (USA) and the Wellcome Trust core award [075491/Z/04 UK]. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422)., University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), University of Iowa [Iowa City]-Howard Hughes Medical-Institute Carver College of Medicine, Yale School of Medicine [New Haven, Connecticut] (YSM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, University of Oxford-Warneford Hospital, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), Université de Toulouse (UT)-Université de Toulouse (UT), University of Pennsylvania, Betancur, Catalina, Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu SH, Cochrane L, Corsello C, Crawford EL, Crossett A, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Melhem NM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Piven J, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Wing K, Wittemeyer K, Wood S, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Gallagher L, Geschwind DH, Gill M, Haines JL, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Devlin B, Ennis S, and Hallmayer J.
Subjects: Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Genotype, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Databases, Genetic, Copy-number variation, MESH: Genetic Variation, Genetics (clinical), MESH: Databases, Genetic, Genetics, 0303 health sciences, education.field_of_study, MESH: Polymorphism, Single Nucleotide, Association Studies Articles, MESH: Genetic Predisposition to Disease, General Medicine, MESH: European Continental Ancestry Group, Autism spectrum disorders, MESH: DNA Copy Number Variations, Genotyping, DNA Copy Number Variations, Genotype, Population, MESH: Autistic Disorder, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Genetic variation, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Autistic Disorder, SNP association, education, Molecular Biology, Alleles, MESH: Genome, Human, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Genome, Human, MESH: Alleles, Haplotype, Genetic Variation, Genetic architecture, Perturbações do Desenvolvimento Infantil e Saúde Mental, MESH: Genome-Wide Association Study, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C. Author has checked copyright TS 14.06.13 The subscript characters from the abstract have not copied across properly. TS
Published: 2010
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33. A genome-wide linkage and association scan reveals novel loci for autism

Author: Zak Kohane, Jeremy Goldberg, Carine Mantoulan, Shaun Purcell, Jessica Brian, Magdalena Laskawiec, Christopher A. Walsh, Irma Moilanen, Ridha Joober, Peter Szatmari, Olena Korvatska, Kerim Munir, James F. Gusella, Rudolph E. Tanzi, David L. Pauls, Generoso G. Gascon, Christine Stevens, Linda Lotspeich, John I. Nurnberger, Ramzi Nazir, Jonathan Green, Brian L. Yaspan, Marion Leboyer, Ann P. Thompson, Shun-Chiao Chang, Carolyn Bridgemohan, Louise Gallagher, Jeff Munson, Michael Gill, Guiqing Cai, Fritz Poustka, Regina Regan, Aislyn Cangialose, Gerard D. Schellenberg, Christopher J. McDougle, Christina Corsello, Wendy Roberts, Thomas H. Wassink, Majid Ghadami, Ellen M. Hanson, Benjamin M. Neale, Stacey Gabriel, Lonnie Zwaigenbaum, John Tsiantis, Hanna Ebeling, Sabine M. Klauck, Elaine LeClair, Bernie Devlin, Steven A. McCarroll, Ashley O'Connor, Andrew Pickles, Emily L. Crawford, Katja Jussila, Helen McConachie, Christopher Gillberg, Brenda E. Barry, Lou Kunkel, Seung Yun Yoo, Jennifer N. Partlow, Stephanie Brewster O'Neil, Ingrid A. Holm, Judith Miller, Guy A. Rouleau, Val C. Sheffield, Catherine Lord, Judith S. Palfrey, Ellen M. Wijsman, Astrid M. Vicente, Azam Hosseinipour, Ronald E. Becker, James S. Sutcliffe, Fred R. Volkmar, Marja Leena Mattila, Katerina Papanikolaou, Jennifer Reichert, Edwin H. Cook, Pamela Sklar, Elena Maestrini, Hilary Coon, Sek Won Kong, Stephen A. Haddad, Todd Green, Gillian Baird, Andrew Kirby, Patrick Bolton, Robert Sean Hill, Eric M. Morrow, Tom Berney, Jonathan L. Haines, Maryam Valujerdi, Casey Gates, David J. Posey, Karola Rehnström, Alistair T. Pagnamenta, Christine M. Freitag, Eric Fombonne, Janice Ware, Christian R. Marshall, Janine A. Lamb, Lauren A. Weiss, Agatino Battaglia, Nancy J. Minshew, Roksana Sasanfar, Elizabeth Baroni, Maretha de Jonge, Lennart von Wendt, Gina Hilton, Dalila Pinto, Nahit Motavalli Mukaddes, Ala Tolouei, Catalina Betancur, Michael Rutter, Tram Tran, Eftichia Duketis, Laurent Mottron, Margaret A. Pericak-Vance, Kristen West, Joachim Hallmayer, Kirsty Wing, Kerstin Wittemeyer, Rachel J. Hundley, Herman van Engeland, Judith Conroy, Mark J. Daly, Asif Hashmi, Michael L. Cuccaro, Geraldine Dawson, Sanna Kuusikko, Richard Anney, Anthony P. Monaco, Brian Winkloski, Samira Al-Saad, Dan E. Arking, Veronica J. Vieland, Stephen W. Scherer, Soher Balkhy, Kara Andresen, Rebecca L. Tomlinson, Joseph D. Buxbaum, Aravinda Chakravarti, Xiao-Qing Liu, Lindsay Jackson, Jaakko Ignatius, Catarina Correia, Leonard Rappaport, Heather Peters, Julie Gauthier, John R. Gilbert, Jeremy R. Parr, Carrie Sougnez, Katherine E. Tansey, Bennett L. Leventha, Annemarie Poustka, Daniel H. Geschwind, Annette Estes, Leena Peltonen, Maryam Rostami, Jeff Salt, David Altshuler, Simon Wallace, Susan E. Bryson, William M. Mahoney, Katy Renshaw, Robert M. Joseph, Lisa H. Albers, Inês Cabrito, Sean Ennis, Vanessa Hus, Guiomar Oliveira, Ann Le Couteur, Joseph Piven, Sandra L. Friedman, Penny Farrar, Joshua M. Korn, Sven Bölte, Camille W. Brune, Esau Simmons, Susan L. Santangelo, Andrew D. Paterson, Rita M. Cantor, Andrew B. West, Finny G Kuruvilla, Tiago R. Magalhaes, Andrew Green, Alison Schonwald, Stephen J. Guter, Anthony J. Bailey, Bernadette Rogé, William M. McMahon, Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Johns Hopkins University (JHU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Betancur, Catalina, University of Helsinki, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), WEISS LA, ARKING DE, and GENE DISCOVERY PROJECT OF JOHNS HOPKINS & THE AUTISM CONSORTIUM, DALY MJ, CHAKRAVARTI A, BRUNE CW, WEST K, O'CONNOR A, HILTON G, TOMLINSON RL, WEST AB, COOK EH JR, CHAKRAVARTI A, WEISS LA, GREEN T, CHANG SC, GABRIEL S, GATES C, HANSON EM, KIRBY A, KORN J, KURUVILLA F, MCCARROLL S, MORROW EM, NEALE B, PURCELL S, SASANFAR R, SOUGNEZ C, STEVENS C, ALTSHULER D, GUSELLA J, SANTANGELO SL, SKLAR P, TANZI R, DALY MJ, ANNEY R, BAILEY AJ, BAIRD G, BATTAGLIA A, BERNEY T, BETANCUR C, BÖLTE S, BOLTON PF, BRIAN J, BRYSON SE, BUXBAUM JD, CABRITO I, CAI G, CANTOR RM, COOK EH JR, COON H, CONROY J, CORREIA C, CORSELLO C, CRAWFORD EL, CUCCARO ML, DAWSON G, DE JONGE M, DEVLIN B, DUKETIS E, ENNIS S, ESTES A, FARRAR P, FOMBONNE E, FREITAG CM, GALLAGHER L, GESCHWIND DH, GILBERT J, GILL M, GILLBERG C, GOLDBERG J, GREEN A, GREEN J, GUTER SJ, HAINES JL, HALLMAYER JF, HUS V, KLAUCK SM, KORVATSKA O, LAMB JA, LASKAWIEC M, LEBOYER M, COUTEUR AL, LEVENTHAL BL, LIU XQ, LORD C, LOTSPEICH LJ, MAESTRINI E, MAGALHAES T, MAHONEY W, MANTOULAN C, MCCONACHIE H, MCDOUGLE CJ, MCMAHON WM, MARSHALL CR, MILLER J, MINSHEW NJ, MONACO AP, MUNSON J, NURNBERGER JI JR, OLIVEIRA G, PAGNAMENTA A, PAPANIKOLAOU K, PARR JR, PATERSON AD, PERICAK-VANCE MA, PICKLES A, PINTO D, PIVEN J, POSEY DJ, POUSTKA A, POUSTKA F, REGAN R, REICHERT J, RENSHAW K, ROBERTS W, ROGE B, RUTTER ML, SALT J, SCHELLENBERG GD, SCHERER SW, SHEFFIELD V, SUTCLIFFE JS, SZATMARI P, TANSEY K, THOMPSON AP, TSIANTIS J, VAN ENGELAND H, VICENTE AM, VIELAND VJ, VOLKMAR F, WALLACE S, WASSINK TH, WIJSMAN EM, WING K, WITTEMEYER K, YASPAN BL, ZWAIGENBAUM L, MORROW EM, YOO SY, HILL RS, MUKADDES NM, BALKHY S, GASCON G, AL-SAAD S, HASHMI A, WARE J, JOSEPH RM, LECLAIR E, PARTLOW JN, BARRY B, WALSH CA, PAULS D, MOILANEN I, EBELING H, MATTILA ML, KUUSIKKO S, JUSSILA K, IGNATIUS J, SASANFAR R, TOLOUEI A, GHADAMI M, ROSTAMI M, HOSSEINIPOUR A, VALUJERDI M, SANTANGELO SL, ANDRESEN K, WINKLOSKI B, HADDAD S, KUNKEL L, KOHANE Z, TRAN T, KONG SW, O'NEIL SB, HANSON EM, HUNDLEY R, HOLM I, PETERS H, BARONI E, CANGIALOSE A, JACKSON L, ALBERS L, BECKER R, BRIDGEMOHAN C, FRIEDMAN S, MUNIR K, NAZIR R, PALFREY J, SCHONWALD A, SIMMONS E, RAPPAPORT LA, GAUTHIER J, MOTTRON L, JOOBER R, FOMBONNE E, ROULEAU G, REHNSTROM K, VON WENDT L, PELTONEN L.
Subjects: Perturbação Autística, Internationality, Genetic Linkage, Genome-wide association study, MESH: Semaphorins, Semaphorins, [SDV.GEN] Life Sciences [q-bio]/Genetics, 0302 clinical medicine, Neurodevelopmental disorder, Heritability of autism, MESH: Nerve Tissue Proteins, Association mapping, Genetics, 0303 health sciences, Multidisciplinary, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Brain, Chromosome Mapping, Chromosomes, Human, Pair 5, MESH: Membrane Proteins, MESH: Chromosomes, Human, Pair 5, MESH: Autistic Disorder, MESH: Genetic Linkage, Single-nucleotide polymorphism, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, MESH: Brain, Genetic linkage, medicine, Humans, Genetic Predisposition to Disease, Autistic Disorder, MESH: Sample Size, 030304 developmental biology, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Membrane Proteins, medicine.disease, Sample Size, Perturbações do Desenvolvimento Infantil e Saúde Mental, MESH: Genome-Wide Association Study, MESH: Internationality, Autism, MESH: Chromosome Mapping, Predisposição Genética para Doença, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Member of the Autism Genome Project Consortium: Astrid M. Vicente Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 x 10(-7)). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.
Published: 2009
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34. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Author: Veronica J. Vieland, Stephen W. Scherer, Alison K. Merikangas, Naisha Shah, Edwin H. Cook, William M. McMahon, Kirsty Wing, Sabata C. Lund, Jacob A. S. Vorstman, Judith Conroy, Sabine M. Klauck, John B. Vincent, Astrid M. Vicente, Carine Mantoulan, Barbara Parrini, Jeremy R. Parr, Herman van Engeland, Jane McGrath, Guiomar Oliveira, Jonathan Green, James S. Sutcliffe, Peter Szatmari, Ann Le Couteur, Katerina Papanikolaou, Joseph Piven, Andrew Pickles, Gillian Baird, Inês Sousa, Gerard D. Schellenberg, Catarina Correia, Bennett L. Leventhal, Helen McConachie, Joseph T. Glessner, Fritz Poustka, Alistair T. Pagnamenta, Marion Leboyer, Nuala Sykes, Elena Maestrini, Penny Farrar, Maïté Tauber, Suzanne Foley, Richard Holt, Lonnie Zwaigenbaum, David J. Posey, John Tsiantis, Alexander Kolevzon, Agatino Battaglia, Maretha de Jonge, Hilary Coon, Gillian Hughes, John R. Gilbert, Patrick Bolton, Louise Gallagher, Jeff Munson, Kathy White, Michael L. Cuccaro, Annemarie Poustka, Daniel H. Geschwind, Richard Delorme, Annette Estes, Christine M. Freitag, Jillian P. Casey, Joana Almeida, Dalila Pinto, Simon Wallace, Sean Brennan, Stephen J. Guter, Stanley F. Nelson, Michael Rutter, Ghazala Mirza, Anthony J. Bailey, Christina Corsello, Kerstin Wittemeyer, Christian R. Marshall, Janine A. Lamb, Catherine Lord, Hakon Hakonarson, Jiannis Ragoussis, Catalina Betancur, Geraldine Dawson, Eftichia Duketis, Sean Ennis, Fiorella Minopoli, Christopher Gillberg, Vera Stoppioni, Bridget A. Fernandez, Frederico Duque, Eric Fombonne, Ellen M. Wijsman, Bernadette Rogé, Vanessa Hus, Susan E. Folstein, Jonathan L. Haines, Denis C. Shields, Tiago R. Magalhaes, Andrew Green, Thomas Bourgeron, Brian L. Yaspan, Ann P. Thompson, Gudrun Nygren, Judith Miller, Susanne Thomson, Roberta Igliozzi, Ana Filipa Sequeira, Kai Wang, Brett S. Abrahams, John I. Nurnberger, Michael Gill, Thomas H. Wassink, Christopher J. McDougle, Marc N. Coutanche, Anthony P. Monaco, Nadia Bolshakova, Cecilia Kim, Raffaella Tancredi, Rita M. Cantor, Phil Cali, Fred R. Volkmar, Tom Berney, Margaret A. Pericak-Vance, Joachim Hallmayer, Joseph D. Buxbaum, Elena Bacchelli, Latha Soorya, Richard Anney, Regina Regan, University of Bologna, Open University of Israël, IRCCS Fondazione Stella Maris [Pisa], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Goethe-University Frankfurt am Main, Memorial University of Newfoundland [St. John's], McGill University = Université McGill [Montréal, Canada], Johns Hopkins University (JHU), Autism Research Centre and Section of Developmental Psychiatry, University of Cambridge [UK] (CAM), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Psychiatrie génétique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Mondor de Recherche Biomédicale, The Hospital for sick children [Toronto] (SickKids), University of Toronto, Australian Resources Research Centre, Kensington, Sécurité et Qualité des Produits d'Origine Végétale (SQPOV), Avignon Université (AU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital des Enfants, CHU Toulouse [Toulouse], School of Chemistry, Dalhousie University [Halifax], DLR Institut für Planetenforschung, Deutsches Zentrum für Luft- und Raumfahrt [Berlin] (DLR), Department of Human Genetics, University of Chicago, University of Alberta, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), University of Koblenz-Landau, McMaster University [Hamilton, Ontario], The authors acknowledge the families participating in the study and the main funders of the Autism Genome Project Consortium (AGP): Autism Speaks (USA), the Health Research Board (HRB, Ireland), The Medical Research Council (MRC, UK), Genome Canada/Ontario Genomics Institute, and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health (NIH grants HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH57881, MH061009, MH06359, MH066673, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261), the Canadian Institute for Advanced Research (CIFAR), the Canadian Institutes for Health Research (CIHR), Assistance Publique–Hôpitaux de Paris (France), Autistica, Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche Forschungsgemeinschaft (grant Po 255/17-4) (Germany), EC Sixth FP AUTISM MOLGEN, Fundação Calouste Gulbenkian (Portugal), Fondation de France, Fondation FondaMental (France), Fondation Orange (France), Fondation pour la Recherche Médicale (France), Fundação para a Ciência e Tecnologia (Portugal), the Hospital for Sick Children Foundation and University of Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian Ministry of Health (convention 181 of 19.10.2001), the John P. Hussman Foundation (USA), McLaughlin Centre (Canada), Ontario Ministry of Research and Innovation (Canada), the Seaver Foundation (USA), the Swedish Science Council, The Centre for Applied Genomics (Canada), the Utah Autism Foundation (USA) and the Wellcome Trust core award 075491/Z/04 (UK). We acknowledge support from the Autism Genetic Resource Exchange (AGRE) and Autism Speaks. We gratefully acknowledge the resources provided by the AGRE consortium and the participating AGRE families. AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). We wish to acknowledge the National Children’s Research Centre Our Lady’s Children’s Hospital Crumlin Ireland for providing additional support and the Wellcome Trust Case–Control Consortium for providing data sets that were used as part of this study. J.P.C is supported by an EMBARK postgraduate award from the Irish Research Council for Science, Engineering and Technology (IRCSET)., The AGRE Consortium, Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, Shields DC, Abrahams BS, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolton PF, Bourgeron T, Brennan S, Cali P, Correia C, Corsello C, Coutanche M, Dawson G, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Foley S, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Green J, Guter SJ, Hakonarson H, Holt R, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Lamb JA, Leboyer M, Le Couteur A, Leventhal BL, Lord C, Lund SC, Maestrini E, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Miller J, Minopoli F, Mirza GK, Munson J, Nelson SF, Nygren G, Oliveira G, Pagnamenta AT, Papanikolaou K, Parr JR, Parrini B, Pickles A, Pinto D, Piven J, Posey DJ, Poustka A, Poustka F, Ragoussis J, Roge B, Rutter ML, Sequeira AF, Soorya L, Sousa I, Sykes N, Stoppioni V, Tancredi R, Tauber M, Thompson AP, Thomson S, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman JA, Wallace S, Wang K, Wassink TH, White K, Wing K, Wittemeyer K, Yaspan BL, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Geschwind DH, Haines JL, Hallmayer J, Monaco AP, Nurnberger JI Jr, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vieland VJ, Wijsman EM, Green A, Gill M, Gallagher L, Vicente A, Ennis S., McGill University, Institut National de la Recherche Agronomique (INRA)-Avignon Université (AU), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of Bologna/Università di Bologna, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Candidate gene, Genome-wide association study, Linkage Disequilibrium, MESH: Child Development Disorders, Pervasive, Cohort Studies, MESH: Genotype, 0302 clinical medicine, MESH: Child, Cluster Analysis, Genetics(clinical), Copy-number variation, Child, MESH: Cohort Studies, Genetics (clinical), Original Investigation, SNPS, Genetics, 0303 health sciences, education.field_of_study, MESH: Middle Aged, MESH: Nuclear Family, MESH: Polymorphism, Single Nucleotide, Homozygote, MESH: Genetic Predisposition to Disease, Middle Aged, Autism spectrum disorder (ASD), 3. Good health, MESH: Linkage Disequilibrium, Female, MESH: DNA Copy Number Variations, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Homozygote, Adult, DNA Copy Number Variations, Genotype, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Nuclear Family, 03 medical and health sciences, HOMOZYGOSITY MAPPING, mental disorders, medicine, Humans, Genetic Predisposition to Disease, ddc:610, AUTISM, GENOME-WIDE ASSOCIATION, education, 030304 developmental biology, MESH: Humans, Genetic heterogeneity, Haplotype, MESH: Adult, MESH: Haplotypes, medicine.disease, MESH: Cluster Analysis, MESH: Male, Haplotypes, Child Development Disorders, Pervasive, Perturbações do Desenvolvimento Infantil e Saúde Mental, MESH: Genome-Wide Association Study, Autism, MESH: Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data. Electronic supplementary material The online version of this article (doi:10.1007/s00439-011-1094-6) contains supplementary material, which is available to authorized users.
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35. Quantitative genome-wide association study of six phenotypic subdomains identifies novel genome-wide significant variants in autism spectrum disorder.

Author: Yousaf A, Waltes R, Haslinger D, Klauck SM, Duketis E, Sachse M, Voran A, Biscaldi M, Schulte-Rüther M, Cichon S, Nöthen M, Ackermann J, Koch I, Freitag CM, and Chiocchetti AG
Subjects: Humans, Autism Spectrum Disorder genetics, Genome-Wide Association Study
Abstract: Autism spectrum disorders (ASD) are highly heritable and are characterized by deficits in social communication and restricted and repetitive behaviors. Twin studies on phenotypic subdomains suggest a differing underlying genetic etiology. Studying genetic variation explaining phenotypic variance will help to identify specific underlying pathomechanisms. We investigated the effect of common variation on ASD subdomains in two cohorts including >2500 individuals. Based on the Autism Diagnostic Interview-Revised (ADI-R), we identified and confirmed six subdomains with a SNP-based genetic heritability h 2 SNP = 0.2-0.4. The subdomains nonverbal communication (NVC), social interaction (SI), and peer interaction (PI) shared genetic risk factors, while the subdomains of repetitive sensory-motor behavior (RB) and restricted interests (RI) were genetically independent of each other. The polygenic risk score (PRS) for ASD as categorical diagnosis explained 2.3-3.3% of the variance of SI, joint attention (JA), and PI, 4.5% for RI, 1.2% of RB, but only 0.7% of NVC. We report eight genome-wide significant hits-partially replicating previous findings-and 292 known and novel candidate genes. The underlying biological mechanisms were related to neuronal transmission and development. At the SNP and gene level, all subdomains showed overlap, with the exception of RB. However, no overlap was observed at the functional level. In summary, the ADI-R algorithm-derived subdomains related to social communication show a shared genetic etiology in contrast to restricted and repetitive behaviors. The ASD-specific PRS overlapped only partially, suggesting an additional role of specific common variation in shaping the phenotypic expression of ASD subdomains.
Published: 2020
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36. Common functional variants of the glutamatergic system in Autism spectrum disorder with high and low intellectual abilities.

Author: Chiocchetti AG, Yousaf A, Bour HS, Haslinger D, Waltes R, Duketis E, Jarczok T, Sachse M, Biscaldi M, Degenhardt F, Herms S, Cichon S, Ackermann J, Koch I, Klauck SM, and Freitag CM
Subjects: Child, Female, Humans, Intellectual Disability genetics, Intelligence Tests, Male, Polymorphism, Single Nucleotide, Autism Spectrum Disorder genetics, Genetic Association Studies, Glutamic Acid genetics
Abstract: The genetic architecture underlying Autism spectrum disorder (ASD) has been suggested to differ between individuals with lower (IQ ≤ 70; LIQ) and higher intellectual abilities (IQ > 70; HIQ). Among the identified pathomechanisms, the glutamatergic signalling pathway is of specific interest in ASD. We investigated 187 common functional variants of this neurotransmitter system for association with ASD and with symptom severity in two independent samples, a German (German-ALL: N = 583 families) and the Autism Genome Project cohort (AGP-ALL: N = 2001 families), split into HIQ, and LIQ subgroups. We did not identify any association withstanding correction for multiple testing. However, we report a replicated nominal significant under-transmission (OR < 0.79, p < 0.04) of the AKAP13 rs745191-T allele in both LIQ cohorts, but not in the much larger HIQ cohorts. At the phenotypic level, we nominally replicated associations of CAMK2A-rs2241694 with non-verbal communication in both combined LIQ and HIQ ASD cohorts. Variants PLD1-rs2124147 and ADCY1-rs2461127 were nominally associated with impaired non-verbal abilities and AKAP2-rs3739456 with repetitive behaviour in both LIQ cohorts. All four LIQ-associated genes are involved in G-protein coupled signal transduction, a downstream pathway of metabotropic glutamate receptor activation. We conclude that functional common variants of glutamatergic genes do not have a strong impact on ASD, but seem to moderately affect ASD risk and phenotypic expression. Since most of our nominally replicated hits were identified in the LIQ cohort, further investigation of the glutamatergic system in this subpopulation might be warranted.
Published: 2018
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37. Lack of replication of previous autism spectrum disorder GWAS hits in European populations.

Author: Torrico B, Chiocchetti AG, Bacchelli E, Trabetti E, Hervás A, Franke B, Buitelaar JK, Rommelse N, Yousaf A, Duketis E, Freitag CM, Caballero-Andaluz R, Martinez-Mir A, Scholl FG, Ribasés M, Battaglia A, Malerba G, Delorme R, Benabou M, Maestrini E, Bourgeron T, Cormand B, and Toma C
Subjects: Case-Control Studies, Europe, Female, Genome-Wide Association Study methods, Humans, Male, Reproducibility of Results, Autism Spectrum Disorder genetics, Genome-Wide Association Study statistics & numerical data
Abstract: Common variants contribute significantly to the genetics of autism spectrum disorder (ASD), although the identification of individual risk polymorphisms remains still elusive due to their small effect sizes and limited sample sizes available for association studies. During the last decade several genome-wide association studies (GWAS) have enabled the detection of a few plausible risk variants. The three main studies are family-based and pointed at SEMA5A (rs10513025), MACROD2 (rs4141463) and MSNP1 (rs4307059). In our study we attempted to replicate these GWAS hits using a case-control association study in five European populations of ASD patients and gender-matched controls, all Caucasians. Results showed no association of individual variants with ASD in any of the population groups considered or in the combined European sample. We performed a meta-analysis study across five European populations for rs10513025 (1,904 ASD cases and 2,674 controls), seven European populations for rs4141463 (2,855 ASD cases and 36,177 controls) and five European populations for rs4307059 (2,347 ASD cases and 2,764 controls). The results showed an odds ratio (OR) of 1.05 (95% CI = 0.84-1.32) for rs10513025, 1.0002 (95% CI = 0.93-1.08) for rs4141463 and 1.01 (95% CI = 0.92-1.1) for rs4307059, with no significant P-values (rs10513025, P = 0.73; rs4141463, P = 0.95; rs4307059, P = 0.9). No association was found when we considered either only high functioning autism (HFA), genders separately or only multiplex families. Ongoing GWAS projects with larger ASD cohorts will contribute to clarify the role of common variation in the disorder and will likely identify risk variants of modest effect not detected previously. Autism Res 2017, 10: 202-211. © 2016 International Society for Autism Research, Wiley Periodicals, Inc., (© 2016 International Society for Autism Research, Wiley Periodicals, Inc.)
Published: 2017
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38. Meta-analysis and association of two common polymorphisms of the human oxytocin receptor gene in autism spectrum disorder.

Author: Kranz TM, Kopp M, Waltes R, Sachse M, Duketis E, Jarczok TA, Degenhardt F, Görgen K, Meyer J, Freitag CM, and Chiocchetti AG
Subjects: Alleles, Child, Genotype, Humans, Autism Spectrum Disorder genetics, Polymorphism, Single Nucleotide genetics, Receptors, Oxytocin genetics
Abstract: Neuropeptides such as oxytocin (OXT) are known facilitators of social behavior across species. Variants of the OXT receptor gene (OXTR) have been tested for association with autism spectrum disorder (ASD) across manifold ethnicities, yielding both positive and negative findings. A recent meta-analysis, comprising 16 single nucleotide polymorphisms (SNPs), has corroborated the implication of OXTR in the etiology of ASD. Here, we genotyped and tested two additional variants (rs237889 and rs237897) for association with ASD in two German predominantly high-functioning ASD samples. We found nominal over-transmission (OR = 1.48, CI95 = 1.06-2.08, P = 0.022) for the minor A allele of variant rs237889G>A in sample 1 (N = 135 complete parent-offspring trios, 29 parent child duos), but not in sample 2 (362 trios, 69 duos). Still, in a meta-analysis comprising four different studies including the two unreported German data sets (N = 542 families), this finding was confirmed (OR = 1.12; CI95 = 1.01-1.24, random effects P = 0.012). In addition, carriers of the minor risk allele rs237889-A showed significantly increased severity scores, as assessed through the autism diagnostic interview - revised (ADI-R), with highly significant increases in social interaction deficits. Our results corroborate the implication of common OXTR variants in the etiology of ASD. There is a need for functional studies to delineate the neurobiological implications of this and other association findings. (172/250). Autism Res 2016, 9: 1036-1045. © 2016 International Society for Autism Research, Wiley Periodicals, Inc., (© 2016 International Society for Autism Research, Wiley Periodicals, Inc.)
Published: 2016
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39. Synaptic, transcriptional and chromatin genes disrupted in autism.

Author: De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, and Buxbaum JD
Subjects: Amino Acid Sequence, Child Development Disorders, Pervasive pathology, Chromatin metabolism, Chromatin Assembly and Disassembly, Exome genetics, Female, Germ-Line Mutation genetics, Humans, Male, Molecular Sequence Data, Mutation, Missense genetics, Nerve Net metabolism, Odds Ratio, Child Development Disorders, Pervasive genetics, Chromatin genetics, Genetic Predisposition to Disease genetics, Mutation genetics, Synapses metabolism, Transcription, Genetic genetics
Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
Published: 2014
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40. Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders.

Author: Waltes R, Duketis E, Knapp M, Anney RJ, Huguet G, Schlitt S, Jarczok TA, Sachse M, Kämpfer LM, Kleinböck T, Poustka F, Bölte S, Schmötzer G, Voran A, Huy E, Meyer J, Bourgeron T, Klauck SM, Freitag CM, and Chiocchetti AG
Subjects: Adaptor Proteins, Signal Transducing metabolism, Adolescent, Alleles, Calcium-Calmodulin-Dependent Protein Kinase Type 4 metabolism, Child, Child Development Disorders, Pervasive ethnology, Child Development Disorders, Pervasive metabolism, Child Development Disorders, Pervasive pathology, Child, Preschool, Female, Fragile X Mental Retardation Protein metabolism, Gene Expression Regulation, Genotyping Techniques, Humans, Male, Neuronal Plasticity genetics, Protein Binding, Risk Factors, Signal Transduction, White People, Adaptor Proteins, Signal Transducing genetics, Calcium-Calmodulin-Dependent Protein Kinase Type 4 genetics, Child Development Disorders, Pervasive genetics, Fragile X Mental Retardation Protein genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
Abstract: Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (N = 192 and N = 254 families, respectively) and report association for rs7170637 (CYFIP1; set 1 and combined sets), rs6923492 (GRM1; combined sets), and rs25925 (CAMK4; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11-1.53; P = 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the "Strict/European" ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75-0.96; P = 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04-1.64; P = 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD.
Published: 2014
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41. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

Author: Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayés M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisén L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kähler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landén M, Långström N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Mühleisen TW, Muir WJ, Müller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nöthen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O'Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnström K, Reif A, Ribasés M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zöllner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O'Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, and Wray NR
Subjects: Adult, Attention Deficit Disorder with Hyperactivity genetics, Bipolar Disorder genetics, Child, Child Development Disorders, Pervasive genetics, Crohn Disease genetics, Depressive Disorder, Major genetics, Genetic Heterogeneity, Genome, Human, Humans, Inheritance Patterns, Schizophrenia genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Mental Disorders genetics, Polymorphism, Single Nucleotide
Abstract: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Published: 2013
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42. 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 S, Bolton PF, Bourgeron T, Brennan S, Brian J, Casey J, Conroy J, Correia C, Corsello C, Crawford EL, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Gilbert J, Gillberg C, Glessner JT, Green A, Green J, Guter SJ, Heron EA, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Jacob S, Kenny GP, Kim C, Kolevzon A, Kustanovich V, Lajonchere CM, Lamb JA, Law-Smith M, Leboyer M, Le Couteur A, Leventhal BL, Liu XQ, Lombard F, Lord C, Lotspeich L, Lund SC, Magalhaes TR, Mantoulan C, McDougle CJ, Melhem NM, Merikangas A, Minshew NJ, Mirza GK, Munson J, Noakes C, Nygren G, Papanikolaou K, Pagnamenta AT, Parrini B, Paton T, Pickles A, Posey DJ, Poustka F, Ragoussis J, Regan R, Roberts W, Roeder K, Roge B, Rutter ML, Schlitt S, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Sykes N, Tancredi R, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman JA, Wallace S, Wing K, Wittemeyer K, Wood S, Zurawiecki D, Zwaigenbaum L, Bailey AJ, Battaglia A, Cantor RM, Coon H, Cuccaro ML, Dawson G, Ennis S, Freitag CM, Geschwind DH, Haines JL, Klauck SM, McMahon WM, Maestrini E, Miller J, Monaco AP, Nelson SF, Nurnberger JI Jr, Oliveira G, Parr JR, Pericak-Vance MA, Piven J, Schellenberg GD, Scherer SW, Vicente AM, Wassink TH, Wijsman EM, Betancur C, Buxbaum JD, Cook EH, Gallagher L, Gill M, Hallmayer J, Paterson AD, Sutcliffe JS, Szatmari P, Vieland VJ, Hakonarson H, and Devlin B
Subjects: Alleles, Child, Child Development Disorders, Pervasive physiopathology, Female, Gene Frequency, Genotype, Humans, Language Development, Male, Polymorphism, Single Nucleotide, Risk Factors, Child Development Disorders, Pervasive genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Membrane Proteins genetics, Nerve Tissue Proteins genetics
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
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43. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.

Author: Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G, Konyukh M, Chaste P, Ey E, Rastam M, Anckarsäter H, Nygren G, Gillberg IC, Melke J, Toro R, Regnault B, Fauchereau F, Mercati O, Lemière N, Skuse D, Poot M, Holt R, Monaco AP, Järvelä I, Kantojärvi K, Vanhala R, Curran S, Collier DA, Bolton P, Chiocchetti A, Klauck SM, Poustka F, Freitag CM, Waltes R, Kopp M, Duketis E, Bacchelli E, Minopoli F, Ruta L, Battaglia A, Mazzone L, Maestrini E, Sequeira AF, Oliveira B, Vicente A, Oliveira G, Pinto D, Scherer SW, Zelenika D, Delepine M, Lathrop M, Bonneau D, Guinchat V, Devillard F, Assouline B, Mouren MC, Leboyer M, Gillberg C, Boeckers TM, and Bourgeron T
Subjects: Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Adult, Alternative Splicing genetics, Cell Line, Child, Child, Preschool, Female, Gene Dosage genetics, Gene Expression Regulation, Humans, Male, Neurons cytology, Protein Isoforms genetics, Protein Isoforms metabolism, RNA Splice Sites genetics, Receptors, Nicotinic genetics, Receptors, Nicotinic metabolism, Synapses pathology, Tissue Distribution, alpha7 Nicotinic Acetylcholine Receptor, Child Development Disorders, Pervasive genetics, Nerve Tissue Proteins genetics, Sequence Deletion genetics, Synapses genetics
Abstract: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD., Competing Interests: The authors have declared that no competing interests exist.
Published: 2012
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44. No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder.

Author: Curran S, Bolton P, Rozsnyai K, Chiocchetti A, Klauck SM, Duketis E, Poustka F, Schlitt S, Freitag CM, Lee I, Muglia P, Poot M, Staal W, de Jonge MV, Ophoff RA, Lewis C, Skuse D, Mandy W, Vassos E, Fossdal R, Magnusson P, Hreidarsson S, Saemundsen E, Stefansson H, Stefansson K, and Collier D
Subjects: Case-Control Studies, Europe, Genetic Predisposition to Disease, Genotype, Humans, Autistic Disorder genetics, Genome-Wide Association Study, Polymorphism, Single Nucleotide
Abstract: The Autism Genome Project (AGP) Consortium recently reported genome-wide significant association between autism and an intronic single nucleotide polymorphism marker, rs4141463, within the MACROD2 gene. In the present study we attempted to replicate this finding using an independent case-control design of 1,170 cases with autism spectrum disorder (ASD) (874 of which fulfilled narrow criteria for Autism (A)) from five centers within Europe (UK, Germany, the Netherlands, Italy, and Iceland), and 35,307 controls. The combined sample size gave us a non-centrality parameter (NCP) of 11.9, with 93% power to detect allelic association of rs4141463 at an alpha of 0.05 with odds ratio of 0.84 (the best odds ratio estimate of the AGP Consortium data), and for the narrow diagnosis of autism, an NCP of 8.9 and power of 85%. Our case-control data were analyzed for association, stratified by each center, and the summary statistics were combined using the meta-analysis program, GWAMA. This resulted in an odds ratio (OR) of 1.03 (95% CI 0.944-1.133), with a P-value of 0.5 for ASD and OR of 0.99 (95% CI 0.88-1.11) with P-value = 0.85 for the Autism (A) sub-group. Therefore, this study does not provide support for the reported association between rs4141463 and autism., (Copyright © 2011 Wiley-Liss, Inc.)
Published: 2011
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45. Sex differences in cognitive domains and their clinical correlates in higher-functioning autism spectrum disorders.

Author: Bölte S, Duketis E, Poustka F, and Holtmann M
Subjects: Adolescent, Attention, Case-Control Studies, Child, Executive Function, Female, Humans, Male, Neuropsychological Tests, Psychological Tests, Sex Factors, Stereotyped Behavior, Child Development Disorders, Pervasive psychology, Cognition
Abstract: Despite the skewed sex ratio, few studies have addressed possible cognitive sex differences in autism spectrum disorders (ASDs). This study compared visual attention to detail (ATTD) and selected executive functions (EF) in 35 males and 21 females with higher-functioning ASD and unaffected sibling controls. Females with ASD outperformed males on EF as assessed by the Trail Making Test B-A. Males with ASD showed superior performance for ATTD as measured by the Block Design Test (BD) when compared with females. EF difficulties in males were correlated with more stereotypic behaviours and interests on the Autism Diagnostic Interview-Revised or the Autism Diagnostic Observation Schedule. The results indicated clinically meaningful cognitive sex differences in ASD, particularly an association between EF and stereotypic behaviours and interests. ATTD as a potential basis for specific cognitive strengths (e.g. scientific/savant skills) might be more pronounced in males with ASD.
Published: 2011
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46. Functional impact of global rare copy number variation in autism spectrum disorders.

Author: Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Pilorge M, Piven J, Ponting CP, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Sequeira AF, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stein O, Sykes N, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Webber C, Weksberg R, Wing K, Wittemeyer K, Wood S, Wu J, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, and Betancur C
Subjects: Case-Control Studies, Cell Movement, Child, Child Development Disorders, Pervasive pathology, Cytoprotection, Europe ethnology, Genome-Wide Association Study, Humans, Signal Transduction, Social Behavior, Child Development Disorders, Pervasive genetics, Child Development Disorders, Pervasive physiopathology, DNA Copy Number Variations genetics, Gene Dosage genetics, Genetic Predisposition to Disease genetics
Abstract: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Published: 2010
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47. Bipolar disorder in children and adolescents in Germany: national trends in the rates of inpatients, 2000-2007.

Author: Holtmann M, Duketis E, Poustka L, Zepf FD, Poustka F, and Bölte S
Subjects: Adolescent, Age Factors, Bipolar Disorder diagnosis, Child, Conduct Disorder diagnosis, Conduct Disorder epidemiology, Depressive Disorder diagnosis, Depressive Disorder epidemiology, Female, Germany epidemiology, Humans, Hyperkinesis diagnosis, Hyperkinesis epidemiology, Male, Mental Disorders diagnosis, Mental Disorders epidemiology, Patient Admission statistics & numerical data, Prevalence, Psychotic Disorders diagnosis, Psychotic Disorders epidemiology, Time Factors, Young Adult, Bipolar Disorder epidemiology, Inpatients statistics & numerical data, Patient Admission trends
Abstract: Objectives: Increasing admission and prevalence rates of bipolar disorder (BD) are a matter of controversy in international child and adolescent psychiatry. We seek to contribute to this discussion by presenting data obtained in a population of German children and adolescents., Methods: Nationwide, whole population changes in inpatient admissions of BD and other psychiatric disorders between 2000 and 2007 were analyzed in individuals aged up to 19 years using registry data from the German Federal Health Monitoring System., Results: Inpatient admissions for BD in individuals aged up to 19 years increased from 1.13 to 1.91 per 100,000 or 68.5% between 2000 and 2007 (odds ratio: 1.69; 95% confidence interval: 1.41-2.02), with a nonsignificant decline in children less than 15 years and the largest relative increase in adolescents aged 15-19 years. Inpatient rates for depressive disorders increased by 219.6% and for hyperkinetic disorder by 111.3%. Conduct disorders increased by 18.1%, considerably less than the 38.1% general rise for all mental disorders in children and adolescents. The only significant decline in a diagnostic category occurred for psychotic disorders (-11.8%). BD inpatient admission represented only 0.22% of all mental disorder admissions in 2000 and 0.27% in 2007., Conclusions: An elevation of inpatient admissions of BD in Germany in adolescents was detected, exceeding the general trend for increased mental disorder admissions. The results may indicate a higher clinical awareness and appreciation of mood symptoms at earlier ages and, in part, a reconceptualization of previously diagnosed psychotic disorders in youth. However, a diagnosis of BD in youngsters is still extremely rare in Germany. Diagnoses were based on the judgment of the treating physician. A correction for multiple admissions in the data set is not possible.
Published: 2010
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48. Genetics of autistic disorders: review and clinical implications.

Author: Freitag CM, Staal W, Klauck SM, Duketis E, and Waltes R
Subjects: Adolescent, Child, Child Development Disorders, Pervasive diagnosis, Child Development Disorders, Pervasive psychology, Chromosome Mapping, Cytogenetic Analysis, DNA Copy Number Variations physiology, Genetic Counseling, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Humans, Child Development Disorders, Pervasive genetics, DNA Mutational Analysis, Diseases in Twins genetics, Genetic Markers genetics
Abstract: Twin and family studies in autistic disorders (AD) have elucidated a high heritability of AD. In this literature review, we will present an overview on molecular genetic studies in AD and highlight the most recent findings of an increased rate of copy number variations in AD. An extensive literature search in the PubMed database was performed to obtain English published articles on genetic findings in autism. Results of linkage, (genome wide) association and cytogenetic studies are presented, and putative aetiopathological pathways are discussed. Implications of the different genetic findings for genetic counselling and genetic testing at present will be described. The article ends with a prospectus on future directions.
Published: 2010
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49. Severe affective and behavioral dysregulation in youth is associated with increased serum TSH.

Author: Holtmann M, Duketis E, Goth K, Poustka L, and Boelte S
Subjects: Adolescent, Aggression psychology, Antisocial Personality Disorder diagnosis, Antisocial Personality Disorder epidemiology, Antisocial Personality Disorder psychology, Anxiety Disorders diagnosis, Anxiety Disorders epidemiology, Anxiety Disorders psychology, Attention Deficit Disorder with Hyperactivity diagnosis, Attention Deficit Disorder with Hyperactivity epidemiology, Attention Deficit Disorder with Hyperactivity psychology, Bipolar Disorder diagnosis, Bipolar Disorder epidemiology, Bipolar Disorder psychology, Child, Child, Preschool, Comorbidity, Cross-Sectional Studies, Depressive Disorder diagnosis, Depressive Disorder epidemiology, Depressive Disorder psychology, Female, Germany, Humans, Hypothyroidism blood, Hypothyroidism diagnosis, Hypothyroidism epidemiology, Hypothyroidism psychology, Male, Thyroid Function Tests, Thyroxine blood, Triiodothyronine blood, Aggression physiology, Antisocial Personality Disorder blood, Anxiety Disorders blood, Attention Deficit Disorder with Hyperactivity blood, Bipolar Disorder blood, Depressive Disorder blood, Thyrotropin blood
Abstract: Background: The relationship of bipolar disorder (BD) and altered thyroid function is increasingly recognized. Recently, a behavioral phenotype of co-occurring deviance on the Anxious/Depressed (A/D), Attention Problems (AP), and Aggressive Behavior (AB) syndrome scales has been identified as the Child Behavior Checklist Dysregulation Profile (CBCL-DP), which itself has been linked to BD. This study tested for differences in thyroid function within a sample of n=114 psychiatric children and adolescents with and without the CBCL-DP., Method: A CBCL-DP score was generated based on the composite of the crucial CBCL syndrome scales (A/D, AP, AB). Participants with a CBCL-DP score >or=2.5 SDs above average constituted the CBCL-DP subgroup (n=53). Those with CBCL-DP scores of 1 SD or less above average percentile were regarded as controls (n=61). Groups were compared regarding serum levels of TSH, fT3 and fT4., Results: In participants showing the CBCL-DP, basal serum TSH was elevated compared to controls. More CBCL-DP subjects than controls showed subclinical hypothyroidism. No differences were observed for serum fT3 and fT4 levels., Conclusions: This is the first study to demonstrate associations between CBCL-DP and subclinical hypothyroidism. Future research should address the long-term outcome of CBCL-DP with coexisting hypothyroidism, the potential benefits of supplementation with thyroid hormone, and the association between severe dysregulation and the bipolar spectrum., (2009 Elsevier B.V. All rights reserved.)
Published: 2010
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50. Validation of the Hypomania Checklist (HCL-32) in a nonclinical sample of German adolescents.

Author: Holtmann M, Pörtner F, Duketis E, Flechtner HH, Angst J, and Lehmkuhl G
Subjects: Adolescent, Attention Deficit Disorder with Hyperactivity, Conduct Disorder, Factor Analysis, Statistical, Female, Germany, Humans, Male, Substance-Related Disorders, Bipolar Disorder physiopathology, Psychometrics, Surveys and Questionnaires standards
Abstract: We tested the psychometric properties of the Hypomania Checklist (HCL-32) in a sample of nonclinical adolescents, examined the association with current psychopathology, and tested if "hypomanic" adolescents differ from other participants regarding HCL-scores and psychopathology. A total of 294 students completed the HCL-32 and the SDQ, a screening for psychopathology. In adolescence, the internal structure of hypomania seems to be represented by a triple structure. The first factor "active-elated" is an indicator of symptoms related to energy and activity. The adult factor "irritable-risk taking" is better reflected by two separate factors ("disinhibited/stimulation-seeking" and "irritable-erratic"). These factors were associated with externalizing problems. "Hypomanic" adolescents showed higher HCL total and disinhibited/stimulation-seeking scores and reported more conduct problems than "non-hypomanic" youngsters. The internal structure of the HCL in adolescents mirrors the association of juvenile bipolarity with substance use and symptoms of ADHD and conduct disorder and presents preliminary evidence for its validity.
Published: 2009
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