Common variation contributes to the genetic architecture of social communication traits / Beate ST POURCAIN in Molecular Autism, (September 2013)  

Public ISBD [article]  inMolecular Autism > (September 2013) Titre : Common variation contributes to the genetic architecture of social communication traits Type de document : Texte imprimé et/ou numérique Auteurs : Beate ST POURCAIN, Auteur ; Andrew J. O. WHITEHOUSE, Auteur ; Wei ANG, Auteur ; Nicole WARRINGTON, Auteur ; Joseph GLESSNER, Auteur ; Kai WANG, Auteur ; Nicholas TIMPSON, Auteur ; David EVANS, Auteur ; John KEMP, Auteur ; Susan RING, Auteur ; Wendy MCARDLE, Auteur ; Jean GOLDING, Auteur ; Hakon HAKONARSON, Auteur ; Craig E. PENNELL, Auteur ; George SMITH, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype. We performed a genome-wide association study on parent-reported social communication problems using items of the children's communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364). Two of our seven independent top signals (P-discovery 1.0E-05) were replicated (0.009 P-replication [less than or equal to]0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta-P = 2.5E-07) and 14q22.1 (rs2352908, meta-P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27. This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region.Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027). Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes. En ligne : http://dx.doi.org/10.1186/2040-2392-4-34 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Common variation contributes to the genetic architecture of social communication traits [Texte imprimé et/ou numérique] / Beate ST POURCAIN, Auteur ; Andrew J. O. WHITEHOUSE, Auteur ; Wei ANG, Auteur ; Nicole WARRINGTON, Auteur ; Joseph GLESSNER, Auteur ; Kai WANG, Auteur ; Nicholas TIMPSON, Auteur ; David EVANS, Auteur ; John KEMP, Auteur ; Susan RING, Auteur ; Wendy MCARDLE, Auteur ; Jean GOLDING, Auteur ; Hakon HAKONARSON, Auteur ; Craig E. PENNELL, Auteur ; George SMITH, Auteur. Langues : Anglais (eng) in Molecular Autism > (September 2013) Index. décimale : PER Périodiques Résumé : Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype. We performed a genome-wide association study on parent-reported social communication problems using items of the children's communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364). Two of our seven independent top signals (P-discovery 1.0E-05) were replicated (0.009 P-replication [less than or equal to]0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta-P = 2.5E-07) and 14q22.1 (rs2352908, meta-P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27. This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region.Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027). Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes. En ligne : http://dx.doi.org/10.1186/2040-2392-4-34 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence / Beate ST POURCAIN in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence Type de document : Texte imprimé et/ou numérique Auteurs : Beate ST POURCAIN, Auteur ; David SKUSE, Auteur ; William MANDY, Auteur ; Kai WANG, Auteur ; Hakon HAKONARSON, Auteur ; Nicholas TIMPSON, Auteur ; David EVANS, Auteur ; John KEMP, Auteur ; Susan RING, Auteur ; Wendy MCARDLE, Auteur ; Jean GOLDING, Auteur ; George DAVEY SMITH, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence. Social-communication difficulties were ascertained at ages 8, 11, 14 and 17years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N[less than or equal to]5,628) using mother-reported Social Communication Disorder Checklist scores. Genome-wide Complex Trait Analysis (GCTA) was conducted for all phenotypes. The time-points with the highest GCTA heritability were subsequently analysed for single SNP association genome-wide. Type I error in the presence of measurement relatedness and the likelihood of observing SNP signals near known autism susceptibility loci (co-location) were assessed via large-scale, genome-wide permutations. Association signals (P[less than or equal to]105) were also followed up in Autism Genetic Resource Exchange pedigrees (N=793) and the Autism Case Control cohort (Ncases/Ncontrols=1,204/6,491). GCTA heritability was strongest in childhood (h2(8 years)=0.24) and especially in later adolescence (h2(17 years)=0.45), with a marked drop during early to middle adolescence (h2(11 years)=0.16 and h2(14 years)=0.08). Genome-wide screens at ages 8 and 17years identified for the latter time-point evidence for association at 3p22.2 near SCN11A (rs4453791, P=9.3x109; genome-wide empirical P=0.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P=7.9x108; genome-wide empirical P=0.085). None of these signals contributed to risk for autism. However, the co-location of population-based signals and autism susceptibility loci harbouring rare mutations, such as PLCB1, is unlikely to be due to chance (genome-wide empirical Pco-location=0.007). Our findings suggest that measurable common genetic effects for social-communication difficulties vary developmentally and that these changes may affect detectable overlaps with the autism spectrum. En ligne : http://dx.doi.org/10.1186/2040-2392-5-18 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence [Texte imprimé et/ou numérique] / Beate ST POURCAIN, Auteur ; David SKUSE, Auteur ; William MANDY, Auteur ; Kai WANG, Auteur ; Hakon HAKONARSON, Auteur ; Nicholas TIMPSON, Auteur ; David EVANS, Auteur ; John KEMP, Auteur ; Susan RING, Auteur ; Wendy MCARDLE, Auteur ; Jean GOLDING, Auteur ; George DAVEY SMITH, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence. Social-communication difficulties were ascertained at ages 8, 11, 14 and 17years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N[less than or equal to]5,628) using mother-reported Social Communication Disorder Checklist scores. Genome-wide Complex Trait Analysis (GCTA) was conducted for all phenotypes. The time-points with the highest GCTA heritability were subsequently analysed for single SNP association genome-wide. Type I error in the presence of measurement relatedness and the likelihood of observing SNP signals near known autism susceptibility loci (co-location) were assessed via large-scale, genome-wide permutations. Association signals (P[less than or equal to]105) were also followed up in Autism Genetic Resource Exchange pedigrees (N=793) and the Autism Case Control cohort (Ncases/Ncontrols=1,204/6,491). GCTA heritability was strongest in childhood (h2(8 years)=0.24) and especially in later adolescence (h2(17 years)=0.45), with a marked drop during early to middle adolescence (h2(11 years)=0.16 and h2(14 years)=0.08). Genome-wide screens at ages 8 and 17years identified for the latter time-point evidence for association at 3p22.2 near SCN11A (rs4453791, P=9.3x109; genome-wide empirical P=0.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P=7.9x108; genome-wide empirical P=0.085). None of these signals contributed to risk for autism. However, the co-location of population-based signals and autism susceptibility loci harbouring rare mutations, such as PLCB1, is unlikely to be due to chance (genome-wide empirical Pco-location=0.007). Our findings suggest that measurable common genetic effects for social-communication difficulties vary developmentally and that these changes may affect detectable overlaps with the autism spectrum. En ligne : http://dx.doi.org/10.1186/2040-2392-5-18 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

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