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PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder / J. PIJUAN in Autism Research, 14-6 (June 2021)
[article]
Titre : PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : J. PIJUAN, Auteur ; J. D. ORTIGOZA-ESCOBAR, Auteur ; J. ORTIZ, Auteur ; A. ALCALÁ, Auteur ; M. J. CALVO, Auteur ; M. CUBELLS, Auteur ; C. HERNANDO-DAVALILLO, Auteur ; F. PALAU, Auteur ; J. HOENICKA, Auteur Article en page(s) : p.1088-1100 Langues : Anglais (eng) Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics Autism Spectrum Disorder/genetics DNA Copy Number Variations Exome Genetic Predisposition to Disease/genetics Humans Nerve Tissue Proteins/genetics Receptors, Cell Surface Lrrc40 Plxna2 autism spectrum disorder diagnosis neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. En ligne : http://dx.doi.org/10.1002/aur.2502 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449
in Autism Research > 14-6 (June 2021) . - p.1088-1100[article] PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder [Texte imprimé et/ou numérique] / J. PIJUAN, Auteur ; J. D. ORTIGOZA-ESCOBAR, Auteur ; J. ORTIZ, Auteur ; A. ALCALÁ, Auteur ; M. J. CALVO, Auteur ; M. CUBELLS, Auteur ; C. HERNANDO-DAVALILLO, Auteur ; F. PALAU, Auteur ; J. HOENICKA, Auteur . - p.1088-1100.
Langues : Anglais (eng)
in Autism Research > 14-6 (June 2021) . - p.1088-1100
Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics Autism Spectrum Disorder/genetics DNA Copy Number Variations Exome Genetic Predisposition to Disease/genetics Humans Nerve Tissue Proteins/genetics Receptors, Cell Surface Lrrc40 Plxna2 autism spectrum disorder diagnosis neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. En ligne : http://dx.doi.org/10.1002/aur.2502 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449 An atlas of genetic correlations between gestational age and common psychiatric disorders / Yao YAO in Autism Research, 15-6 (June 2022)
[article]
Titre : An atlas of genetic correlations between gestational age and common psychiatric disorders Type de document : Texte imprimé et/ou numérique Auteurs : Yao YAO, Auteur ; Chun'e LI, Auteur ; Peilin MENG, Auteur ; Bolun CHENG, Auteur ; Shiqiang CHENG, Auteur ; Li LIU, Auteur ; Xuena YANG, Auteur ; Yumeng JIA, Auteur ; Yan WEN, Auteur ; Feng ZHANG, Auteur Article en page(s) : p.1008-1017 Langues : Anglais (eng) Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics Autism Spectrum Disorder/genetics Depressive Disorder, Major/genetics Female Genetic Predisposition to Disease Genome-Wide Association Study Gestational Age Humans Infant, Newborn Mendelian Randomization Analysis Premature Birth/genetics Proteomics genetic correlation linkage disequilibrium score regression psychiatric disorders Index. décimale : PER Périodiques Résumé : We aim to systematically explore the potential genetic correlations between five major psychiatric disorders and gestational ages. Genome-wide association study (GWAS) summary datasets of attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD) in discovery were downloaded from the Psychiatric GWAS Consortium (PGC) website. Suggestive (Raw p?0.05) genetic associations in the discovery phrase were further replicated in independent GWASs which downloaded from PGC, the FinnGen study or Integrative Psychiatric Research (iPSYCH) website. GWASs of gestational duration, preterm and post-term birth were derived from previous studies of infants from the Early Growth Genetics (EGG) Consortium, the iPSYCH study, and the Genomic and Proteomic Network for Preterm Birth Research (GPN). We calculated genetic correlations using linkage disequilibrium score (LDSC) regression. Mendelian randomization (MR) analyses were performed to investigate the causal effects. We identified four suggestive genetic correlations between psychiatric disorders and gestational age factors in discovery LDSC and two replicated in a confirmation LDSC: gestational duration and ADHD (r(g) = -0.1405, FDR p = 0.0406), post-term birth and SCZ (r(g) = -0.2003, FDR p = 0.0042). We also observed causal effect of post-term birth on SCZ by MR (P(Weighted median) = 0.037, P(Inverse variance weighted) = 0.007). Our analysis suggested no significant evidence of horizontal pleiotropy and heterogeneity. This study showed the genetic correlation evidences between gestational age phenotypes and psychiatric disorders, providing novel clues for understanding the pathogenic factors of common psychiatric disorders. LAY SUMMARY: Whereas gestational age factors were reported to be associated with psychiatric disorders, the genetic relationship and causality remain to be revealed. The present study reported the first large-scale genetic correlations investigation of the associations between gestational age phenotypes and psychiatric disorders. Results indicate causal relationships between post-term birth and schizophrenia (SCZ), as well as suggestive genetic correlations between gestational duration and attention deficit/hyperactivity disorder (ADHD). This study provided novel clues for understanding the pathogenic factors of common psychiatric disorders. En ligne : http://dx.doi.org/10.1002/aur.2719 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=476
in Autism Research > 15-6 (June 2022) . - p.1008-1017[article] An atlas of genetic correlations between gestational age and common psychiatric disorders [Texte imprimé et/ou numérique] / Yao YAO, Auteur ; Chun'e LI, Auteur ; Peilin MENG, Auteur ; Bolun CHENG, Auteur ; Shiqiang CHENG, Auteur ; Li LIU, Auteur ; Xuena YANG, Auteur ; Yumeng JIA, Auteur ; Yan WEN, Auteur ; Feng ZHANG, Auteur . - p.1008-1017.
Langues : Anglais (eng)
in Autism Research > 15-6 (June 2022) . - p.1008-1017
Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics Autism Spectrum Disorder/genetics Depressive Disorder, Major/genetics Female Genetic Predisposition to Disease Genome-Wide Association Study Gestational Age Humans Infant, Newborn Mendelian Randomization Analysis Premature Birth/genetics Proteomics genetic correlation linkage disequilibrium score regression psychiatric disorders Index. décimale : PER Périodiques Résumé : We aim to systematically explore the potential genetic correlations between five major psychiatric disorders and gestational ages. Genome-wide association study (GWAS) summary datasets of attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD) in discovery were downloaded from the Psychiatric GWAS Consortium (PGC) website. Suggestive (Raw p?0.05) genetic associations in the discovery phrase were further replicated in independent GWASs which downloaded from PGC, the FinnGen study or Integrative Psychiatric Research (iPSYCH) website. GWASs of gestational duration, preterm and post-term birth were derived from previous studies of infants from the Early Growth Genetics (EGG) Consortium, the iPSYCH study, and the Genomic and Proteomic Network for Preterm Birth Research (GPN). We calculated genetic correlations using linkage disequilibrium score (LDSC) regression. Mendelian randomization (MR) analyses were performed to investigate the causal effects. We identified four suggestive genetic correlations between psychiatric disorders and gestational age factors in discovery LDSC and two replicated in a confirmation LDSC: gestational duration and ADHD (r(g) = -0.1405, FDR p = 0.0406), post-term birth and SCZ (r(g) = -0.2003, FDR p = 0.0042). We also observed causal effect of post-term birth on SCZ by MR (P(Weighted median) = 0.037, P(Inverse variance weighted) = 0.007). Our analysis suggested no significant evidence of horizontal pleiotropy and heterogeneity. This study showed the genetic correlation evidences between gestational age phenotypes and psychiatric disorders, providing novel clues for understanding the pathogenic factors of common psychiatric disorders. LAY SUMMARY: Whereas gestational age factors were reported to be associated with psychiatric disorders, the genetic relationship and causality remain to be revealed. The present study reported the first large-scale genetic correlations investigation of the associations between gestational age phenotypes and psychiatric disorders. Results indicate causal relationships between post-term birth and schizophrenia (SCZ), as well as suggestive genetic correlations between gestational duration and attention deficit/hyperactivity disorder (ADHD). This study provided novel clues for understanding the pathogenic factors of common psychiatric disorders. En ligne : http://dx.doi.org/10.1002/aur.2719 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=476 DNA Methylation of the Oxytocin Receptor Across Neurodevelopmental Disorders / M. T. SIU in Journal of Autism and Developmental Disorders, 51-10 (October 2021)
[article]
Titre : DNA Methylation of the Oxytocin Receptor Across Neurodevelopmental Disorders Type de document : Texte imprimé et/ou numérique Auteurs : M. T. SIU, Auteur ; S. J. GOODMAN, Auteur ; I. YELLAN, Auteur ; D. T. BUTCHER, Auteur ; M. JANGJOO, Auteur ; D. GRAFODATSKAYA, Auteur ; R. RAJENDRAM, Auteur ; Y. LOU, Auteur ; R. ZHANG, Auteur ; C. ZHAO, Auteur ; R. NICOLSON, Auteur ; S. GEORGIADES, Auteur ; P. SZATMARI, Auteur ; Stephen SCHERER, Auteur ; W. ROBERTS, Auteur ; Evdokia ANAGNOSTOU, Auteur ; R. WEKSBERG, Auteur Article en page(s) : p.3610-3623 Langues : Anglais (eng) Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics Autism Spectrum Disorder/genetics DNA Methylation Female Humans Male Obsessive-Compulsive Disorder Oxytocin/metabolism Receptors, Oxytocin/genetics Adhd Asd Ocd Oxtr Index. décimale : PER Périodiques Résumé : Many neurodevelopmental disorders (NDDs) share common learning and behavioural impairments, as well as features such as dysregulation of the oxytocin hormone. Here, we examined DNA methylation (DNAm) in the 1st intron of the oxytocin receptor gene, OXTR, in patients with autism spectrum (ASD), attention deficit and hyperactivity (ADHD) and obsessive compulsive (OCD) disorders. DNAm of OXTR was assessed for cohorts of ASD (blood), ADHD (saliva), OCD (saliva), which uncovered sex-specific DNAm differences compared to neurotypical, tissue-matched controls. Individuals with ASD or ADHD exhibiting extreme DNAm values had lower IQ and more social problems, respectively, than those with DNAm within normative ranges. This suggests that OXTR DNAm patterns are altered across NDDs and may be correlated with common clinical outcomes. En ligne : http://dx.doi.org/10.1007/s10803-020-04792-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=453
in Journal of Autism and Developmental Disorders > 51-10 (October 2021) . - p.3610-3623[article] DNA Methylation of the Oxytocin Receptor Across Neurodevelopmental Disorders [Texte imprimé et/ou numérique] / M. T. SIU, Auteur ; S. J. GOODMAN, Auteur ; I. YELLAN, Auteur ; D. T. BUTCHER, Auteur ; M. JANGJOO, Auteur ; D. GRAFODATSKAYA, Auteur ; R. RAJENDRAM, Auteur ; Y. LOU, Auteur ; R. ZHANG, Auteur ; C. ZHAO, Auteur ; R. NICOLSON, Auteur ; S. GEORGIADES, Auteur ; P. SZATMARI, Auteur ; Stephen SCHERER, Auteur ; W. ROBERTS, Auteur ; Evdokia ANAGNOSTOU, Auteur ; R. WEKSBERG, Auteur . - p.3610-3623.
Langues : Anglais (eng)
in Journal of Autism and Developmental Disorders > 51-10 (October 2021) . - p.3610-3623
Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics Autism Spectrum Disorder/genetics DNA Methylation Female Humans Male Obsessive-Compulsive Disorder Oxytocin/metabolism Receptors, Oxytocin/genetics Adhd Asd Ocd Oxtr Index. décimale : PER Périodiques Résumé : Many neurodevelopmental disorders (NDDs) share common learning and behavioural impairments, as well as features such as dysregulation of the oxytocin hormone. Here, we examined DNA methylation (DNAm) in the 1st intron of the oxytocin receptor gene, OXTR, in patients with autism spectrum (ASD), attention deficit and hyperactivity (ADHD) and obsessive compulsive (OCD) disorders. DNAm of OXTR was assessed for cohorts of ASD (blood), ADHD (saliva), OCD (saliva), which uncovered sex-specific DNAm differences compared to neurotypical, tissue-matched controls. Individuals with ASD or ADHD exhibiting extreme DNAm values had lower IQ and more social problems, respectively, than those with DNAm within normative ranges. This suggests that OXTR DNAm patterns are altered across NDDs and may be correlated with common clinical outcomes. En ligne : http://dx.doi.org/10.1007/s10803-020-04792-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=453