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Browsing by Author "Correia, C.T."

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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
  • Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism
    Publication . Correia, C.T.; Coutinho, A.M.; Sequeira, A.F.; Sousa, I.G.; Lourenço Venda, L.; Almeida, J.P.; Abreu, R.L.; Lobo, C.; Miguel, T.S.; Conroy, J.; Cochrane, L.; Gallagher, L.; Gill, M.; Ennis, S.; Oliveira, G.G.; Vicente, A.M.
    The brain-derived neurotrophic factor (BDNF), a neurotrophin fundamental for brain development and function, has previously been implicated in autism. In this study, the levels of BDNF in platelet-rich plasma were compared between autistic and control children, and the role of two genetic factors that might regulate this neurotrophin and contribute to autism etiology, BDNF and NTRK2, was examined. We found that BDNF levels in autistic children (n = 146) were significantly higher (t = 6.82; P < 0.0001) than in control children (n = 50) and were positively correlated with platelet serotonin distribution (r = 0.22; P = 0.004). Heritability of BDNF was estimated at 30% and therefore candidate genes BDNF and NTRK2 were tested for association with BDNF level distribution in this sample, and with autism in 469 trio families. Genetic association analysis provided no evidence for BDNF or NTRK2 as major determinants of the abnormally increased BDNF levels in autistic children. A significant association with autism was uncovered for six single nucleotide polymorphisms (SNPs) [0.004 (Z((1df)) = 2.85) < P < 0.039 (Z((1df)) = 2.06)] and multiple haplotypes [5 × 10(-4) (χ((3df)) = 17.77) < P < 0.042 (χ((9df)) = 17.450)] in the NTRK2 gene. These results do not withstand correction for multiple comparisons, however, reflect a trend toward association that supports a role of NTRK2 as a susceptibility factor for the disorder. Genetic variation in the BDNF gene had no impact on autism risk. By substantiating the previously observed increase in BDNF levels in autistic children in a larger patient set, and suggesting a genetic association between NTRK2 and autism, this study integrates evidence from multiple levels supporting the hypothesis that alterations in BDNF/tyrosine kinase B (TrkB) signaling contribute to an increased vulnerability to autism.
    2010-10Journal article Open access Show more
  • Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions
    Publication . Correia, C.T.; Almeida, J.P.; Santos, P.E.; Sequeira, A.F.; Marques, C.E.; Miguel, T.S.; Abreu, R.L.; Oliveira, G.G.; Vicente, A.M.
    Little has been reported on the factors, genetic or other, that underlie the variability in individual response, particularly for autism. In this study we simultaneously explored the effects of multiple candidate genes on clinical improvement and occurrence of adverse drug reactions, in 45 autistic patients who received monotherapy with risperidone up to 1 year. Candidate genes involved in the pharmacokinetics (CYP2D6 and ABCB1) and pharmacodynamics (HTR2A, HTR2C, DRD2, DRD3, HTR6) of the drug, and the brain-derived neurotrophic factor (BDNF) gene, were analysed. Using the generalized estimating equation method these genes were tested for association with drug efficacy, assessed with the Autism Treatment Evaluation Checklist, and with safety and tolerability measures, such as prolactin levels, body mass index (BMI), waist circumference and neurological adverse effects, including extrapyramidal movements. Our results confirm that risperidone therapy was very effective in reducing some autism symptoms and caused few serious adverse effects. After adjusting for confounding factors, the HTR2A c.-1438G>A, DRD3 Ser9Gly, HTR2C c.995G>A and ABCB1 1236C>T polymorphisms were predictors for clinical improvement with risperidone therapy. The HTR2A c.-1438G>A, HTR2C c.68G>C (p.C33S), HTR6 c.7154-2542C>T and BDNF c.196G>A (p.V66M) polymorphisms influenced prolactin elevation. HTR2C c.68G>C and CYP2D6 polymorphisms were associated with risperidone-induced increase in BMI or waist circumference. We thus identified for the first time several genes implicated in risperidone efficacy and safety in autism patients. Although association results require replication, given the small sample size, the study makes a preliminary contribution to the personalized therapy of risperidone in autism.
    2009-12-08Journal article Restricted access Show more
  • Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders
    Publication . Correia, C.T.; Conceição, I.C.; Oliveira, B.; Coelho, J.; Sousa, I.; Sequeira, A.F.; Almeida, J.; Café, C.; Duque, F; Mouga, S.; Roberts, W.; Gao, K.; Lowe, J.K.; Thiruvahindrapuram, B.; Walker, S.; Marshall, C.R.; Pinto, D.; Nurnberger, J.I.; Scherer, S.W.; Geschwind, D.H.; Oliveira, G.; Vicente, A.M.
    Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study.
    2014-04Journal article Open 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