Variants in several genomic regions associated with asperger disorder

Salyakina, Daria; Ma, Deqiong; Jaworski, James; Konidari, Ioanna; Whitehead, Patrice L.; Henson, Robin K.; Martinez, Diane; Robinson, Joycelyn L.; Sacharow, Stephanie; Wright, Harry H.; Abramson, Ruth K.; Gilbert, John R.; Cuccaro, Michael L.; Pericak‐Vance, Margaret A.

doi:10.1002/aur.158

Cited by 38 publications

(32 citation statements)

References 48 publications

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“…The lack of positive findings for both XPO1 and OTX1 in genomewide association studies (GWAS) by others [46][47][48][49][50][51][52][53][54] may reflect the greater genetic heterogeneity in these larger data sets, as we found a clear association with specific core ASD phenotypes. Re-analysis of GWAS separating those with more severe and milder ADI-R symptom scores should be done to test this possibility.…”

Section: Discussioncontrasting

confidence: 60%

2p15–p16.1 microdeletion syndrome: molecular characterization and association of the OTX1 and XPO1 genes with autism spectrum disorders

Malenfant

Reesor

et al. 2011

Eur J Hum Genet

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Reports of unrelated individuals with autism spectrum disorder (ASD) and similar clinical features having overlapping de novo interstitial deletions at 2p15-p16.1 suggest that this region harbors a gene(s) important to the development of autism. We molecularly characterized two such deletions, selecting two genes in this region, exportin 1 (XPO1) and orthodenticle homolog 1 (OTX1) for association studies in three North American cohorts (Autism Spectrum Disorder -Canadian American Research Consortium (ASD-CARC), New York, and Autism Genetic Resource Exchange (AGRE)) and one Italian cohort (Società Italiana per la Ricerca e la Formazione sull'Autismo (SIRFA)) of families with ASD. In XPO1, rs6735330 was associated with autism in all four cohorts (Po0.05), being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing (P FDR )¼1.29Â10 À5 ), the AGRE cohort (P FDR ¼0.0011) and the combined families (P FDR ¼2.34Â10 À9 ). Similarly, in OTX1, rs2018650 and rs13000344 were associated with autism in ASD-CARC cohorts (P FDR ¼8.65Â10 À7 and 6.07Â10 5 , respectively), AGRE cohort (P FDR ¼0.0034 and 0.015, respectively) and the combined families (P FDR ¼2.34Â10 À9 and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts. A significant association (P FDR ¼2.63Â10 À11 ) was found for the rs2018650G-rs13000344C haplotype. The above three SNPs were associated with severity of social interaction and verbal communication deficits and repetitive behaviors (P-values o0.01). No additional deletions were identified following screening of 798 ASD individuals. Our results indicate that deletion 2p15-p16.1 is not commonly associated with idiopathic ASD, but represents a novel contiguous gene syndrome associated with a constellation of phenotypic features (autism, intellectual disability, craniofacial/CNS dysmorphology), and that XPO1 and OXT1 may contribute to ASD in 2p15-p16.1 deletion cases and non-deletion cases of ASD mapping to this chromosome region.

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Section: Discussioncontrasting

confidence: 60%

2p15–p16.1 microdeletion syndrome: molecular characterization and association of the OTX1 and XPO1 genes with autism spectrum disorders

Malenfant

Reesor

et al. 2011

Eur J Hum Genet

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“…Nevertheless, a number of genetic risk factors have been associated with Asperger's syndrome (Salyakina et al 2010), whereas the yield of genetic testing in children with ASD other than autism has been reported at 8.3% (Abdul-Rahman and Hudgins 2006). In addition, EEG and BAEPs abnormalities have been recorded in 36 and 18% respectively in a group of adults with Asperger's syndrome (Cederlund and Gillberg 2004).…”

Section: Discussionmentioning

confidence: 99%

Clinical and Laboratory Data in a Sample of Greek Children with Autism Spectrum Disorders

Ververi

Vargiami

Papadopoulou

et al. 2011

J Autism Dev Disord

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The purpose of this study is to describe clinical and laboratory data, as well as comorbid disorders in Greek children with autism spectrum disorders (ASD). Data were retrospectively collected for 222 children aged 1.5-9 years. The mean age at diagnosis was 43.7 ± 17.6 months. Significantly earlier diagnoses were noted in children with comorbid disorders (epilepsy, hearing deficits, genetic/metabolic disorders), mental retardation and a large head circumference (HC). Macrocephaly (HC ≥ 97th percentile) was found in 21.2% of children, genetic and metabolic disorders in 11.7% and 2.7% respectively and mental retardation in 23%. Patients with certain clinical features (i.e. syndromic) are earlier diagnosed. It is of ultimate importance to promptly identify all children with ASD, probably through the appliance of screening and surveillance programs in the Greek population.

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“…Georgiades et al (2), using a mixture model, find distinct profiles of relative severity of social-communicative impairment and repetitive behaviors. Finally, while not beyond reasonable doubt (29, 30), some studies suggest that DSM-IV categorical diagnosis could relate to more specific genetic liability (23, 31). …”

Section: Introductionmentioning

confidence: 99%

A Genome-wide Association Study of Autism Using the Simons Simplex Collection: Does Reducing Phenotypic Heterogeneity in Autism Increase Genetic Homogeneity?

Chaste

Klei

Sanders

et al. 2015

Biological Psychiatry

136

111

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Background Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of sub-phenotyping of a well-characterized ASD sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. Methods Genome-wide genotypic data of 2576 families from the Simons Simplex Collection (SSC) were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. Results Association analyses revealed no genome-wide significant association signal. Sub-phenotyping did not increase power substantially. Moreover, allele scores built from the most associated SNPs, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. Conclusions In genome-wide association analysis of the SSC sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of sub-phenotypes is not a productive path forward for discovering genetic risk variants in ASD.

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Variants in several genomic regions associated with asperger disorder

Cited by 38 publications

References 48 publications

2p15–p16.1 microdeletion syndrome: molecular characterization and association of the OTX1 and XPO1 genes with autism spectrum disorders

2p15–p16.1 microdeletion syndrome: molecular characterization and association of the OTX1 and XPO1 genes with autism spectrum disorders

Clinical and Laboratory Data in a Sample of Greek Children with Autism Spectrum Disorders

A Genome-wide Association Study of Autism Using the Simons Simplex Collection: Does Reducing Phenotypic Heterogeneity in Autism Increase Genetic Homogeneity?

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