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Browsing by Author "Casey, J.P."

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  • Convergence of genes and cellular pathways dysregulated in autism spectrum disorders
    Publication . 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.; Betancur, C.
    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.
    2014-05Journal article Restricted access Show more
  • Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders
    Publication . 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.; Buxbaum, J.D.; 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.; Gallagher, L.; Gill, M.; 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.; Jacob, S.
    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.
    2011-04-27Journal article Restricted access Show more
  • A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder
    Publication . 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.; Piven, J.; Posey, D.J.; Poustka, A.; Poustka, F.; Ragoussis, J.; Roge, B.; Rutter, M.L.; Sequeira, A.F.; Soorya, L.; Sousa, I.; Wittemeyer, K.; Sykes, N.; Stoppioni, V.; Tancredi, R.; Tauber, M.; Thompson, A.P.; Thomson, S.; Tsiantis, J.; Van Engeland, H.; Vincent, J.B.; Volkmar, F.; Yaspan, B.L.; Vorstman, J.A.; Wallace, S.; Wang, K.; Wassink, T.H.; White, K.; Wing, K.; Zwaigenbaum, L.; Betancur, C.; Buxbaum, J.D.; Cantor, R.M.; Cook, E.H.; Coon, H.; Cuccaro, M.L.; Geschwind, D.H.; Baird, G.; Haines, J.L.; Hallmayer, J.; Monaco, A.P.; Nurnberger, J.I. Jr; Pericak-Vance, M.A.; Schellenberg, G.D.; Scherer, S.W.; Sutcliffe, J.S.; Szatmari, P.; Vieland, V.J.; Battaglia, A.; Wijsman, E.M.; Green, A.; Gill, M.; Gallagher, L.; Vicente, A.M.; Ennis, S.; 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.; Le Couteur, A.; 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.
    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.
    2011-10-14Journal article Restricted access Show more
  • The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism
    Publication . 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.; Almeida, J.; Café, C.; Mouga, S.; Correia, C.; 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.; Betancur, C.; Scherer, S.W.
    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.
    2014-06-13Journal article Open access Show more