How rare and common risk variation jointly affect liability for autism spectrum disorder / L. KLEI in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 66 p. Titre : How rare and common risk variation jointly affect liability for autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : L. KLEI, Auteur ; L. L. MCCLAIN, Auteur ; B. MAHJANI, Auteur ; K. PANAYIDOU, Auteur ; S. DE RUBEIS, Auteur ; A. S. GRAHNAT, Auteur ; G. KARLSSON, Auteur ; Y. LU, Auteur ; N. MELHEM, Auteur ; X. XU, Auteur ; A. REICHENBERG, Auteur ; S. SANDIN, Auteur ; C. M. HULTMAN, Auteur ; Joseph D. BUXBAUM, Auteur ; K. ROEDER, Auteur ; B. DEVLIN, Auteur Article en page(s) : 66 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  De novo mutation  Genomic-Best Linear Unbiased Prediction (G-BLUP)  Liability  Polygenic risk score Index. décimale : PER Périodiques Résumé : BACKGROUND: Genetic studies have implicated rare and common variations in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study. METHODS: To explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variations (Simons Simplex Collection and Population-Based Autism Genetics and Environment Study). We analyzed data from 3011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3011 subjects matched for ancestry to ASD subjects and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk of ASD (henceforth "burden"), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a potentially damaging variant implicated in risk of ASD ("PDV carriers"); ASD subjects who do not ("non-carriers"); and unaffected subjects who are assumed to be non-carriers. RESULTS: Burden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For PDV carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability. LIMITATIONS: Only 305 ASD subjects were known PDV carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific PDVs or genes. Also, a small fraction of subjects that are categorized as non-carriers could be PDV carriers. CONCLUSIONS: Liability arising from common and rare risk variations likely combines additively to determine risk of any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare PDV affecting risk. En ligne : http://dx.doi.org/10.1186/s13229-021-00466-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] How rare and common risk variation jointly affect liability for autism spectrum disorder [Texte imprimé et/ou numérique] / L. KLEI, Auteur ; L. L. MCCLAIN, Auteur ; B. MAHJANI, Auteur ; K. PANAYIDOU, Auteur ; S. DE RUBEIS, Auteur ; A. S. GRAHNAT, Auteur ; G. KARLSSON, Auteur ; Y. LU, Auteur ; N. MELHEM, Auteur ; X. XU, Auteur ; A. REICHENBERG, Auteur ; S. SANDIN, Auteur ; C. M. HULTMAN, Auteur ; Joseph D. BUXBAUM, Auteur ; K. ROEDER, Auteur ; B. DEVLIN, Auteur . - 66 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 66 p. Mots-clés : Autism spectrum disorder  De novo mutation  Genomic-Best Linear Unbiased Prediction (G-BLUP)  Liability  Polygenic risk score Index. décimale : PER Périodiques Résumé : BACKGROUND: Genetic studies have implicated rare and common variations in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study. METHODS: To explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variations (Simons Simplex Collection and Population-Based Autism Genetics and Environment Study). We analyzed data from 3011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3011 subjects matched for ancestry to ASD subjects and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk of ASD (henceforth "burden"), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a potentially damaging variant implicated in risk of ASD ("PDV carriers"); ASD subjects who do not ("non-carriers"); and unaffected subjects who are assumed to be non-carriers. RESULTS: Burden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For PDV carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability. LIMITATIONS: Only 305 ASD subjects were known PDV carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific PDVs or genes. Also, a small fraction of subjects that are categorized as non-carriers could be PDV carriers. CONCLUSIONS: Liability arising from common and rare risk variations likely combines additively to determine risk of any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare PDV affecting risk. En ligne : http://dx.doi.org/10.1186/s13229-021-00466-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder / B. MAHJANI in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 65 p. Titre : Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : B. MAHJANI, Auteur ; S. DE RUBEIS, Auteur ; C. GUSTAVSSON MAHJANI, Auteur ; M. MULHERN, Auteur ; X. XU, Auteur ; L. KLEI, Auteur ; F. K. SATTERSTROM, Auteur ; J. FU, Auteur ; Michael E. TALKOWSKI, Auteur ; A. REICHENBERG, Auteur ; S. SANDIN, Auteur ; C. M. HULTMAN, Auteur ; D. E. GRICE, Auteur ; K. ROEDER, Auteur ; B. DEVLIN, Auteur ; Joseph D. BUXBAUM, Auteur Article en page(s) : 65 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Copy number variant  Intellectual disability  Pages  Single nucleotide variant  Whole exome sequencing  that they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV). METHODS: SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes. RESULTS: Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy. LIMITATIONS: The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification. CONCLUSIONS: In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD. En ligne : http://dx.doi.org/10.1186/s13229-021-00465-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder [Texte imprimé et/ou numérique] / B. MAHJANI, Auteur ; S. DE RUBEIS, Auteur ; C. GUSTAVSSON MAHJANI, Auteur ; M. MULHERN, Auteur ; X. XU, Auteur ; L. KLEI, Auteur ; F. K. SATTERSTROM, Auteur ; J. FU, Auteur ; Michael E. TALKOWSKI, Auteur ; A. REICHENBERG, Auteur ; S. SANDIN, Auteur ; C. M. HULTMAN, Auteur ; D. E. GRICE, Auteur ; K. ROEDER, Auteur ; B. DEVLIN, Auteur ; Joseph D. BUXBAUM, Auteur . - 65 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 65 p. Mots-clés : Autism spectrum disorder  Copy number variant  Intellectual disability  Pages  Single nucleotide variant  Whole exome sequencing  that they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV). METHODS: SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes. RESULTS: Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy. LIMITATIONS: The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification. CONCLUSIONS: In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD. En ligne : http://dx.doi.org/10.1186/s13229-021-00465-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

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