Development of the pupillary light reflex from 9 to 24 months: association with common autism spectrum disorder (ASD) genetic liability and 3-year ASD diagnosis / Laurel A. FISH in Journal of Child Psychology and Psychiatry, 62-11 (November 2021)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 62-11 (November 2021) . - p.1308-1319 Titre : Development of the pupillary light reflex from 9 to 24 months: association with common autism spectrum disorder (ASD) genetic liability and 3-year ASD diagnosis Type de document : texte imprimé Auteurs : Laurel A. FISH, Auteur ; P. NYSTROM, Auteur ; Teodora GLIGA, Auteur ; Anna GUI, Auteur ; Jannath BEGUM-ALI, Auteur ; Luke MASON, Auteur ; Shruti GARG, Auteur ; Jonathan GREEN, Auteur ; Mark Henry JOHNSON, Auteur ; Tony CHARMAN, Auteur ; Rebecca HARRISON, Auteur ; Emma MEABURN, Auteur ; Terje FALCK-YTTER, Auteur ; Emily Jane Harrison JONES, Auteur Article en page(s) : p.1308-1319 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/diagnosis/genetics  Humans  Infant  Phenotype  Reflex  Autism spectrum disorder  infancy  neurodevelopment  pupillary light reflex Index. décimale : PER Périodiques Résumé : BACKGROUND: Although autism spectrum disorder (ASD) is heritable, the mechanisms through which genes contribute to symptom emergence remain unclear. Investigating candidate intermediate phenotypes such as the pupillary light reflex (PLR) prospectively from early in development could bridge genotype and behavioural phenotype. METHODS: Using eye tracking, we longitudinally measured the PLR at 9, 14 and 24 months in a sample of infants (N = 264) enriched for a family history of ASD; 27 infants received an ASD diagnosis at 3 years. We examined the 9- to 24-month developmental trajectories of PLR constriction latency (onset; ms) and amplitude (%) and explored their relation to categorical 3-year ASD outcome, polygenic liability for ASD and dimensional 3-year social affect (SA) and repetitive/restrictive behaviour (RRB) traits. Polygenic scores for ASD (PGS(ASD) ) were calculated for 190 infants. RESULTS: While infants showed a decrease in latency between 9 and 14 months, higher PGS(ASD) was associated with a smaller decrease in latency in the first year (β = -.16, 95% CI = -0.31, -0.002); infants with later ASD showed a significantly steeper decrease in latency (a putative 'catch-up') between 14 and 24 months relative to those with other outcomes (typical: β = .54, 95% CI = 0.08, 0.99; other: β = .53, 95% CI = 0.02, 1.04). Latency development did not associate with later dimensional variation in ASD-related traits. In contrast, change in amplitude was not related to categorical ASD or genetics, but decreasing 9- to 14-month amplitude was associated with higher SA (β = .08, 95% CI = 0.01, 0.14) and RRB (β = .05, 95% CI = 0.004, 0.11) traits. CONCLUSIONS: These findings corroborate PLR development as possible intermediate phenotypes being linked to both genetic liability and phenotypic outcomes. Future work should incorporate alternative measures (e.g. functionally informed structural and genetic measures) to test whether distinct neural mechanisms underpin PLR alterations. En ligne : http://dx.doi.org/10.1111/jcpp.13518 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=456 [article] Development of the pupillary light reflex from 9 to 24 months: association with common autism spectrum disorder (ASD) genetic liability and 3-year ASD diagnosis [texte imprimé] / Laurel A. FISH, Auteur ; P. NYSTROM, Auteur ; Teodora GLIGA, Auteur ; Anna GUI, Auteur ; Jannath BEGUM-ALI, Auteur ; Luke MASON, Auteur ; Shruti GARG, Auteur ; Jonathan GREEN, Auteur ; Mark Henry JOHNSON, Auteur ; Tony CHARMAN, Auteur ; Rebecca HARRISON, Auteur ; Emma MEABURN, Auteur ; Terje FALCK-YTTER, Auteur ; Emily Jane Harrison JONES, Auteur . - p.1308-1319. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 62-11 (November 2021) . - p.1308-1319 Mots-clés : Autism Spectrum Disorder/diagnosis/genetics  Humans  Infant  Phenotype  Reflex  Autism spectrum disorder  infancy  neurodevelopment  pupillary light reflex Index. décimale : PER Périodiques Résumé : BACKGROUND: Although autism spectrum disorder (ASD) is heritable, the mechanisms through which genes contribute to symptom emergence remain unclear. Investigating candidate intermediate phenotypes such as the pupillary light reflex (PLR) prospectively from early in development could bridge genotype and behavioural phenotype. METHODS: Using eye tracking, we longitudinally measured the PLR at 9, 14 and 24 months in a sample of infants (N = 264) enriched for a family history of ASD; 27 infants received an ASD diagnosis at 3 years. We examined the 9- to 24-month developmental trajectories of PLR constriction latency (onset; ms) and amplitude (%) and explored their relation to categorical 3-year ASD outcome, polygenic liability for ASD and dimensional 3-year social affect (SA) and repetitive/restrictive behaviour (RRB) traits. Polygenic scores for ASD (PGS(ASD) ) were calculated for 190 infants. RESULTS: While infants showed a decrease in latency between 9 and 14 months, higher PGS(ASD) was associated with a smaller decrease in latency in the first year (β = -.16, 95% CI = -0.31, -0.002); infants with later ASD showed a significantly steeper decrease in latency (a putative 'catch-up') between 14 and 24 months relative to those with other outcomes (typical: β = .54, 95% CI = 0.08, 0.99; other: β = .53, 95% CI = 0.02, 1.04). Latency development did not associate with later dimensional variation in ASD-related traits. In contrast, change in amplitude was not related to categorical ASD or genetics, but decreasing 9- to 14-month amplitude was associated with higher SA (β = .08, 95% CI = 0.01, 0.14) and RRB (β = .05, 95% CI = 0.004, 0.11) traits. CONCLUSIONS: These findings corroborate PLR development as possible intermediate phenotypes being linked to both genetic liability and phenotypic outcomes. Future work should incorporate alternative measures (e.g. functionally informed structural and genetic measures) to test whether distinct neural mechanisms underpin PLR alterations. En ligne : http://dx.doi.org/10.1111/jcpp.13518 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=456

Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients / Hannah BROADBENT in Journal of Neurodevelopmental Disorders, 6-1 (December 2014)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.18 Titre : Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients Type de document : texte imprimé Auteurs : Hannah BROADBENT, Auteur ; Emily K. FARRAN, Auteur ; Esther CHIN, Auteur ; Kay METCALFE, Auteur ; May TASSABEHJI, Auteur ; Peter TURNPENNY, Auteur ; Francis SANSBURY, Auteur ; Emma MEABURN, Auteur ; Annette KARMILOFF-SMITH, Auteur Article en page(s) : p.18 Langues : Anglais (eng) Mots-clés : Gtf2i  Gtf2ird1  Limk1  Navigation  Visuospatial cognition  Williams syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive. METHODS: WE REPORT ON VISUOSPATIAL COGNITION IN TWO INDIVIDUALS WITH CONTRASTING PARTIAL DELETIONS IN THE WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted. RESULTS: Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB's atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion. CONCLUSIONS: Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed. En ligne : http://dx.doi.org/10.1186/1866-1955-6-18 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346 [article] Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients [texte imprimé] / Hannah BROADBENT, Auteur ; Emily K. FARRAN, Auteur ; Esther CHIN, Auteur ; Kay METCALFE, Auteur ; May TASSABEHJI, Auteur ; Peter TURNPENNY, Auteur ; Francis SANSBURY, Auteur ; Emma MEABURN, Auteur ; Annette KARMILOFF-SMITH, Auteur . - p.18. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.18 Mots-clés : Gtf2i  Gtf2ird1  Limk1  Navigation  Visuospatial cognition  Williams syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive. METHODS: WE REPORT ON VISUOSPATIAL COGNITION IN TWO INDIVIDUALS WITH CONTRASTING PARTIAL DELETIONS IN THE WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted. RESULTS: Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB's atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion. CONCLUSIONS: Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed. En ligne : http://dx.doi.org/10.1186/1866-1955-6-18 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346

In search of genes associated with risk for psychopathic tendencies in children: a two-stage genome-wide association study of pooled DNA / Essi VIDING in Journal of Child Psychology and Psychiatry, 51-7 (July 2010)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 51-7 (July 2010) . - p.780-788 Titre : In search of genes associated with risk for psychopathic tendencies in children: a two-stage genome-wide association study of pooled DNA Type de document : texte imprimé Auteurs : Essi VIDING, Auteur ; Robert PLOMIN, Auteur ; Oliver S.P. DAVIS, Auteur ; Ken B. HANSCOMBE, Auteur ; Charles J.C. CURTIS, Auteur ; Emma MEABURN, Auteur Année de publication : 2010 Article en page(s) : p.780-788 Langues : Anglais (eng) Mots-clés : Antisocial-behaviour psychopathy callous-unemotional-traits genome-wide genetics behavioural-genetics twins Index. décimale : PER Périodiques Résumé : Background: Quantitative genetic data from our group indicates that antisocial behaviour (AB) is strongly heritable when coupled with psychopathic, callous-unemotional (CU) personality traits. We have also demonstrated that the genetic influences for AB and CU overlap considerably. We conducted a genome-wide association scan that capitalises on these findings in an attempt to identify quantitative trait loci (QTLs) that may increase risk for psychopathic tendencies (AB+/CU+). Methods: Teacher ratings at age 7 were used to screen 8374 twins with available DNA samples for individuals that were high vs. low on both AB and CU. In Stage 1, we screened for allele frequency differences in 642,432 autosomal single-nucleotide polymorphisms (SNPs) using the Affymetrix 6.0 GeneChip with pooled DNA for high-scoring (AB+/CU+) versus low-scoring children (N = ∼300/group). In Stage 2, we tested the 3000 most strongly associated SNPs from Stage 1 for association in the same direction in a second sample of high- versus low-scoring children from the same twin study (18% co-twins). Results: Using allele frequencies estimated from pooled DNA, we found suggestive evidence for enrichment of association in the second stage of our two-stage genome-wide association design and focus on reporting the 30 top-ranking SNPs nominally associated with psychopathic tendencies. These SNPs include neurodevelopmental genes such as ROBO2. Conclusions: Although none of the SNPs reached genome-wide statistical significance we have generated a list of SNPs that are potentially associated with psychopathic tendencies, which we believe warrant verification and replication in large independent and clinical samples. En ligne : http://dx.doi.org/10.1111/j.1469-7610.2010.02236.x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=101 [article] In search of genes associated with risk for psychopathic tendencies in children: a two-stage genome-wide association study of pooled DNA [texte imprimé] / Essi VIDING, Auteur ; Robert PLOMIN, Auteur ; Oliver S.P. DAVIS, Auteur ; Ken B. HANSCOMBE, Auteur ; Charles J.C. CURTIS, Auteur ; Emma MEABURN, Auteur . - 2010 . - p.780-788. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 51-7 (July 2010) . - p.780-788 Mots-clés : Antisocial-behaviour psychopathy callous-unemotional-traits genome-wide genetics behavioural-genetics twins Index. décimale : PER Périodiques Résumé : Background: Quantitative genetic data from our group indicates that antisocial behaviour (AB) is strongly heritable when coupled with psychopathic, callous-unemotional (CU) personality traits. We have also demonstrated that the genetic influences for AB and CU overlap considerably. We conducted a genome-wide association scan that capitalises on these findings in an attempt to identify quantitative trait loci (QTLs) that may increase risk for psychopathic tendencies (AB+/CU+). Methods: Teacher ratings at age 7 were used to screen 8374 twins with available DNA samples for individuals that were high vs. low on both AB and CU. In Stage 1, we screened for allele frequency differences in 642,432 autosomal single-nucleotide polymorphisms (SNPs) using the Affymetrix 6.0 GeneChip with pooled DNA for high-scoring (AB+/CU+) versus low-scoring children (N = ∼300/group). In Stage 2, we tested the 3000 most strongly associated SNPs from Stage 1 for association in the same direction in a second sample of high- versus low-scoring children from the same twin study (18% co-twins). Results: Using allele frequencies estimated from pooled DNA, we found suggestive evidence for enrichment of association in the second stage of our two-stage genome-wide association design and focus on reporting the 30 top-ranking SNPs nominally associated with psychopathic tendencies. These SNPs include neurodevelopmental genes such as ROBO2. Conclusions: Although none of the SNPs reached genome-wide statistical significance we have generated a list of SNPs that are potentially associated with psychopathic tendencies, which we believe warrant verification and replication in large independent and clinical samples. En ligne : http://dx.doi.org/10.1111/j.1469-7610.2010.02236.x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=101

Look duration at the face as a developmental endophenotype: elucidating pathways to autism and ADHD / Anna GUI in Development and Psychopathology, 32-4 (October 2020)  

Public ISBD [article]  inDevelopment and Psychopathology > 32-4 (October 2020) . - p.1303-1322 Titre : Look duration at the face as a developmental endophenotype: elucidating pathways to autism and ADHD Type de document : texte imprimé Auteurs : Anna GUI, Auteur ; Luke MASON, Auteur ; Teodora GLIGA, Auteur ; Alexandra HENDRY, Auteur ; Jannath BEGUM-ALI, Auteur ; Greg PASCO, Auteur ; Elizabeth SHEPHARD, Auteur ; Charles CURTIS, Auteur ; Tony CHARMAN, Auteur ; Mark H. JOHNSON, Auteur ; Emma MEABURN, Auteur ; Emily J.H. JONES, Auteur Article en page(s) : p.1303-1322 Langues : Anglais (eng) Mots-clés : attention  endophenotypes  eye-tracking  infant siblings  polygenic score Index. décimale : PER Périodiques Résumé : Identifying developmental endophenotypes on the pathway between genetics and behavior is critical to uncovering the mechanisms underlying neurodevelopmental conditions. In this proof-of-principle study, we explored whether early disruptions in visual attention are a unique or shared candidate endophenotype of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We calculated the duration of the longest look (i.e., peak look) to faces in an array-based eye-tracking task for 335 14-month-old infants with and without first-degree relatives with ASD and/or ADHD. We leveraged parent-report and genotype data available for a proportion of these infants to evaluate the relation of looking behavior to familial (n = 285) and genetic liability (using polygenic scores, n = 185) as well as ASD and ADHD-relevant temperament traits at 2 years of age (shyness and inhibitory control, respectively, n = 272) and ASD and ADHD clinical traits at 6 years of age (n = 94).Results showed that longer peak looks at the face were associated with elevated polygenic scores for ADHD (β = 0.078, p = .023), but not ASD (β = 0.002, p = .944), and with elevated ADHD traits in mid-childhood (F(1,88) = 6.401, p = .013, $\eta _p^2$=0.068; ASD: F (1,88) = 3.218, p = .076), but not in toddlerhood (ps > 0.2). This pattern of results did not emerge when considering mean peak look duration across face and nonface stimuli. Thus, alterations in attention to faces during spontaneous visual exploration may be more consistent with a developmental endophenotype of ADHD than ASD. Our work shows that dissecting paths to neurodevelopmental conditions requires longitudinal data incorporating polygenic contribution, early neurocognitive function, and clinical phenotypic variation. En ligne : http://dx.doi.org/10.1017/s0954579420000930 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Look duration at the face as a developmental endophenotype: elucidating pathways to autism and ADHD [texte imprimé] / Anna GUI, Auteur ; Luke MASON, Auteur ; Teodora GLIGA, Auteur ; Alexandra HENDRY, Auteur ; Jannath BEGUM-ALI, Auteur ; Greg PASCO, Auteur ; Elizabeth SHEPHARD, Auteur ; Charles CURTIS, Auteur ; Tony CHARMAN, Auteur ; Mark H. JOHNSON, Auteur ; Emma MEABURN, Auteur ; Emily J.H. JONES, Auteur . - p.1303-1322. Langues : Anglais (eng) in Development and Psychopathology > 32-4 (October 2020) . - p.1303-1322 Mots-clés : attention  endophenotypes  eye-tracking  infant siblings  polygenic score Index. décimale : PER Périodiques Résumé : Identifying developmental endophenotypes on the pathway between genetics and behavior is critical to uncovering the mechanisms underlying neurodevelopmental conditions. In this proof-of-principle study, we explored whether early disruptions in visual attention are a unique or shared candidate endophenotype of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We calculated the duration of the longest look (i.e., peak look) to faces in an array-based eye-tracking task for 335 14-month-old infants with and without first-degree relatives with ASD and/or ADHD. We leveraged parent-report and genotype data available for a proportion of these infants to evaluate the relation of looking behavior to familial (n = 285) and genetic liability (using polygenic scores, n = 185) as well as ASD and ADHD-relevant temperament traits at 2 years of age (shyness and inhibitory control, respectively, n = 272) and ASD and ADHD clinical traits at 6 years of age (n = 94).Results showed that longer peak looks at the face were associated with elevated polygenic scores for ADHD (β = 0.078, p = .023), but not ASD (β = 0.002, p = .944), and with elevated ADHD traits in mid-childhood (F(1,88) = 6.401, p = .013, $\eta _p^2$=0.068; ASD: F (1,88) = 3.218, p = .076), but not in toddlerhood (ps > 0.2). This pattern of results did not emerge when considering mean peak look duration across face and nonface stimuli. Thus, alterations in attention to faces during spontaneous visual exploration may be more consistent with a developmental endophenotype of ADHD than ASD. Our work shows that dissecting paths to neurodevelopmental conditions requires longitudinal data incorporating polygenic contribution, early neurocognitive function, and clinical phenotypic variation. En ligne : http://dx.doi.org/10.1017/s0954579420000930 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation / Ayden SAFFARI in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 38 p. Titre : RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation Type de document : texte imprimé Auteurs : Ayden SAFFARI, Auteur ; Matt ARNO, Auteur ; Eric NASSER, Auteur ; Angelica RONALD, Auteur ; Chloe C.Y. WONG, Auteur ; Leonard C. SCHALKWYK, Auteur ; Jonathan MILL, Auteur ; Frank DUDBRIDGE, Auteur ; Emma MEABURN, Auteur Article en page(s) : 38 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  DNA methylation  Discordance  Epigenomics  Gene expression  Immune  MZ twins  RNA-seq  Transcriptomics Index. décimale : PER Périodiques Résumé : Background: A gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC. Methods: Genome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (N = 36) and (b) within discordant ASC MZ twin pairs (total N = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in cis. Results: In the discordant twin analysis, three genes showed evidence for DE at FDR < 10%: IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR < 10% including IGHG4, PRR13P5, DEPDC1B, and ZNF501. We find enrichment for DE of genes curated in the SFARI human gene database. Pathways showing evidence of enrichment included those related to immune cell signalling and immune response, transcriptional control and cell cycle/proliferation. Integrative methylomic and transcriptomic analysis identified a number of genes showing suggestive evidence for cis dysregulation. Limitations: Identical twins stably discordant for ASC are rare, and as such the sample size was limited and constrained to the use of peripheral blood tissue for transcriptomic and methylomic profiling. Given these primary limitations, we focused on transcript-level analysis. Conclusions: Using a cohort of ASC discordant and concordant MZ twins, we add to the growing body of transcriptomic-based evidence for an immune-based component in the molecular aetiology of ASC. Whilst the sample size was limited, the study demonstrates the utility of the discordant MZ twin design combined with multi-omics integration for maximising the potential to identify disease-associated molecular signals. En ligne : http://dx.doi.org/10.1186/s13229-019-0285-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414 [article] RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation [texte imprimé] / Ayden SAFFARI, Auteur ; Matt ARNO, Auteur ; Eric NASSER, Auteur ; Angelica RONALD, Auteur ; Chloe C.Y. WONG, Auteur ; Leonard C. SCHALKWYK, Auteur ; Jonathan MILL, Auteur ; Frank DUDBRIDGE, Auteur ; Emma MEABURN, Auteur . - 38 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 38 p. Mots-clés : Autism spectrum disorder  DNA methylation  Discordance  Epigenomics  Gene expression  Immune  MZ twins  RNA-seq  Transcriptomics Index. décimale : PER Périodiques Résumé : Background: A gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC. Methods: Genome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (N = 36) and (b) within discordant ASC MZ twin pairs (total N = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in cis. Results: In the discordant twin analysis, three genes showed evidence for DE at FDR < 10%: IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR < 10% including IGHG4, PRR13P5, DEPDC1B, and ZNF501. We find enrichment for DE of genes curated in the SFARI human gene database. Pathways showing evidence of enrichment included those related to immune cell signalling and immune response, transcriptional control and cell cycle/proliferation. Integrative methylomic and transcriptomic analysis identified a number of genes showing suggestive evidence for cis dysregulation. Limitations: Identical twins stably discordant for ASC are rare, and as such the sample size was limited and constrained to the use of peripheral blood tissue for transcriptomic and methylomic profiling. Given these primary limitations, we focused on transcript-level analysis. Conclusions: Using a cohort of ASC discordant and concordant MZ twins, we add to the growing body of transcriptomic-based evidence for an immune-based component in the molecular aetiology of ASC. Whilst the sample size was limited, the study demonstrates the utility of the discordant MZ twin design combined with multi-omics integration for maximising the potential to identify disease-associated molecular signals. En ligne : http://dx.doi.org/10.1186/s13229-019-0285-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414

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