Percorrer por autor "Paterson, A.D."
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- Convergence of genes and cellular pathways dysregulated in autism spectrum disordersPublication . 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.
- Functional impact of global rare copy number variation in autism spectrum disordersPublication . 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.; 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.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.
- Genome-wide linkage analyses of quantitative and categorical autism subphenotypesPublication . Liu, X.Q.; Paterson, A.D.; Szatmari, P.; Autism Genome Project ConsortiumThe search for susceptibility genes in autism and autism spectrum disorders (ASD) has been hindered by the possible small effects of individual genes and by genetic (locus) heterogeneity. To overcome these obstacles, one method is to use autism-related subphenotypes instead of the categorical diagnosis of autism since they may be more directly related to the underlying susceptibility loci. Another strategy is to analyze subsets of families that meet certain clinical criteria to reduce genetic heterogeneity.
- A genome-wide scan for common alleles affecting risk for autismPublication . 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.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.
- Individual common variants exert weak effects on the risk for autism spectrum disorderspiPublication . Anney, R.; Klei, L.; Pinto, D.; Almeida, J.; Bacchelli, E.; Baird, G.; Bolshakova, N.; Bölte, S.; Bolton, P.F.; Bourgeron, T.; Brennan, S.; Brian, J.; Casey, J.; Conroy, J.; Correia, C.; Corsello, C.; Crawford, E.L.; de Jonge, M.; Delorme, R.; Duketis, E.; Duque, F.; Estes, A.; Farrar, P.; Fernandez, B.A.; Folstein, S.E.; Fombonne, E.; Gilbert, J.; Gillberg, C.; Glessner, J.T.; Green, A.; Green, J.; Guter, S.J.; Heron, E.A.; Holt, R.; Howe, J.L.; Hughes, G.; Hus, V.; Igliozzi, R.; Jacob, S.; Kenny, G.P.; Kim, C.; Kolevzon, A.; Kustanovich, V.; Lajonchere, C.M.; Lamb, J.A.; Law-Smith, M.; Leboyer, M.; Le Couteur, A.; Leventhal, B.L.; Liu, X.Q.; Lombard, F.; Lord, C.; Lotspeich, L.; Lund, S.C.; Magalhaes, T.R.; Mantoulan, C.; McDougle, C.J.; Melhem, N.M.; Merikangas, A.; Minshew, N.J.; Mirza, G.K.; Munson, J.; Noakes, C.; Nygren, G.; Papanikolaou, K.; Pagnamenta, A.T.; Parrini, B.; Paton, T.; Pickles, A.; Posey, D.J.; Poustka, F.; Ragoussis, J.; Regan, R.; Roberts, W.; Roeder, K.; Roge, B.; Rutter, M.L.; Schlitt, S.; Shah, N.; Sheffield, V.C.; Soorya, L.; Sousa, I.; Stoppioni, V.; Sykes, N.; Tancredi, R.; Thompson, A.P.; Thomson, S.; Tryfon, A.; Tsiantis, J.; Van Engeland, H.; Vincent, J.B.; Volkmar, F.; Vorstman, J.; Wallace, S.; Wing, K.; Wittemeyer, K.; Wood, S.; Zurawiecki, D.; Zwaigenbaum, L.; Bailey, AJ; Battaglia, A.; Cantor, R.M.; Coon, H.; Cuccaro, M.L.; Dawson, G.; Ennis, S.; Freitag, C.M.; Geschwind, D.H.; Haines, J.L.; Klauck, S.M.; McMahon, W.M.; Maestrini, E.; Miller, J.; Monaco, A.P.; Nelson, S.F.; Nurnberger Jr, J.I.; Oliveira, G.; Parr, J.R.; Pericak-Vance, M.A.; Piven, J.; Schellenberg, G.D.; Scherer, S.W.; Vicente, A.M.; Wassink, T.H.; Wijsman, E.M.; Betancur, C.; Buxbaum, J.D.; Cook, E.H.; Gallagher, L.; Gill, M.; Hallmayer, J.; Paterson, A.D.; Sutcliffe, J.S.; Szatmari, P.; Vieland, V.J.; Hakonarson, H.; Devlin, B.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.
- Novel method for combined linkage and genome-wide association analysis finds evidence of distinct genetic architecture for two subtypes of autismPublication . Vieland, V.J.; Hallmayer, J.; Huang, Y.; Pagnamenta, A.T.; Pinto, D.; Khan, H.; Monaco, A.P.; Paterson, A.D.; Scherer, S.W.; Sutcliffe, J.S.; Szatmari, P.; The Autism Genome Project (AGP)The Autism Genome Project has assembled two large datasets originally designed for linkage analysis and genome-wide association analysis, respectively: 1,069 multiplex families genotyped on the Affymetrix 10 K platform, and 1,129 autism trios genotyped on the Illumina 1 M platform. We set out to exploit this unique pair of resources by analyzing the combined data with a novel statistical method, based on the PPL statistical framework, simultaneously searching for linkage and association to loci involved in autism spectrum disorders (ASD). Our analysis also allowed for potential differences in genetic architecture for ASD in the presence or absence of lower IQ, an important clinical indicator of ASD subtypes. We found strong evidence of multiple linked loci; however, association evidence implicating specific genes was low even under the linkage peaks. Distinct loci were found in the lower IQ families, and these families showed stronger and more numerous linkage peaks, while the normal IQ group yielded the strongest association evidence. It appears that presence/absence of lower IQ (LIQ) demarcates more genetically homogeneous subgroups of ASD patients, with not just different sets of loci acting in the two groups, but possibly distinct genetic architecture between them, such that the LIQ group involves more major gene effects (amenable to linkage mapping), while the normal IQ group potentially involves more common alleles with lower penetrances. The possibility of distinct genetic architecture across subtypes of ASD has implications for further research and perhaps for research approaches to other complex disorders as well.
- The impact of the metabotropic glutamate receptor and other gene family interaction networks on autismPublication . 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.