Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function

Skuse, David; James, Rowena S.; Bishop, Dorothy V. M.; Coppin, B; Dalton, Pamela; Aamodt-Leeper, G.; Bacarese-Hamilton, M.; Creswell, Cathy; McGurk, Rhona; Jacobs, Patricia A.

doi:10.1038/42706

Cited by 630 publications

(445 citation statements)

References 19 publications

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“…Females with the single X chromosome of maternal origin display more social difficulties than Turner females with the single X chromosome of paternal origin (Skuse et al 1997). Unfortunately, in the present study subgroups of XXY men with an extra X chromosome of maternal origin versus paternal origin were not of sufficient size for statistical analyses.…”

Section: Discussionmentioning

confidence: 61%

Social Behavior and Autism Traits in a Sex Chromosomal Disorder: Klinefelter (47XXY) Syndrome

Rijn

Swaab

Alemán

et al. 2008

J Autism Dev Disord

108

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Although Klinefelter syndrome (47,XXY) has been associated with psychosocial difficulties, knowledge of the social behavioral phenotype is limited. We examined specific social abilities and autism traits in Klinefelter syndrome. Scores of 31 XXY men on the Scale for Interpersonal Behavior and the Autism Spectrum Questionnaire were compared to 24 and 20 control men respectively. XXY men reported increased distress during social interactions and less engagement in specific social behaviors. In the XXY group, levels of autism traits were significantly higher across all dimensions of the autism phenotype. These findings call for a clinical investigation of vulnerability to autism in Klinefelter syndrome. Klinefelter syndrome might serve as a model for studying a role of the X chromosome in social behavioral dysfunction and autism-like behavior.

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Section: Discussionmentioning

confidence: 61%

Social Behavior and Autism Traits in a Sex Chromosomal Disorder: Klinefelter (47XXY) Syndrome

Rijn

Swaab

Alemán

et al. 2008

J Autism Dev Disord

108

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“…3 Despite the fact that human beings belong to a group of highly social mammals with a complex social structure, little is known regarding the underlying genetic architecture of 'the social brain' in man. One notable exception is a single study by Skuse et al 26 on Turner's syndrome that suggested that an imprinted gene on chromosome X may be coding for 'social adjustment' or social cognition. We have recently observed linkage between the AVPR1a RS1 and RS3 microsatellites and two complex social behaviors in humans, sibling relationships and self-presentation style, 8 and now three independent studies show a link between this receptor gene and autism, a disorder characterized by core deficits in social adaptation.…”

Section: Discussionmentioning

confidence: 99%

Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills

et al. 2006

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We examined three microsatellites in the arginine vasopressin 1a receptor gene (AVPR1a), two in the promoter region (RS1 and RS3) and an intronic microsatellite (AVR), for association with autism as well as scores on the Vineland Adaptive Behavior Scale (VABS), the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Scale-Generic (ADOS-G), measures that are widely used to diagnose autism spectrum disorders. We tested for association between the AVPR1a microsatellites and autism in 116 families (128 probands diagnosed with the ADI-R and ADOS-G using a family-based association test (UNPHASED)). Testing each individual microsatellite showed significant transmission disequilibrium in these families with the AVR intronic microsatellite (UNPHASED: LRS = 11.46, global P-value = 0.009, df = 3). Haplotype analysis of three microsatellites also showed significant association (LRS = 144.94, df = 103, global P = 0.004). Additionally, significant association is observed between these three microsatellite haplotypes and the VABS scores (P = 0.009), with the ADI-R (P = 0.009) and the ADOS-G (P = 0.0000765) diagnoses of autistic disorder versus pervasive developmental disorder-not otherwise specified (PDD-NOS) that were available for 47 of these probands. This is the third consecutive report of an association between the AVPR1a gene and autism spectrum disorders and in the current study a third microsatellite is shown to be associated with autism spectrum disorders as well as haplotypes consisting of all three markers. Importantly, the association appears to be mainly mediated by the role of the AVPR1a gene in shaping socialization skills, similar to its role in lower vertebrates.

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“…Imprinting on the X-chromosome has been shown to influence phenotype in the study of Turner's syndrome patients who inherit an XO karyotype. 41 Skuse et al 41 compared the levels of social cognition of women with Turner's syndrome who had inherited the maternal X-chromosome, compared to those who had inherited the paternal X-chromosome. Patients inheriting the maternal Xchromosome tended to show more social difficulties, including offensive and disruptive behaviour.…”

Section: Discussionmentioning

confidence: 99%

Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor

Thomson

Wray

Thomson³

et al. 2004

Mol Psychiatry

105

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GPR50 is an orphan G protein-coupled receptor (GPCR) located on Xq28, a region previously implicated in multiple genetic studies of bipolar affective disorder (BPAD). Allele frequencies of three polymorphisms in GPR50 were compared in case-control studies between subjects with BPAD (264), major depressive disorder (MDD) (226), or schizophrenia (SCZ) (263) and ethnically matched controls (562). Significant associations were found between an insertion/ deletion polymorphism in exon 2 and both BPAD (P ¼ 0.0070), and MDD (P ¼ 0.011) with increased risk associated with the deletion variant (GPR50 D502-505 ). When the analysis was restricted to female subjects, the associations with BPAD and MDD increased in significance (P ¼ 0.00023 and P ¼ 0.0064, respectively). Two other single-nucleotide polymorphisms (SNPs) tested within this gene showed associations between: the female MDD group and an SNP in exon 2 (P ¼ 0.0096); and female SCZ and an intronic SNP (P ¼ 0.0014). No association was detected in males with either MDD, BPAD or SCZ. These results suggest that GPR50 D502-505 , or a variant in tight linkage disequilibrium with this polymorphism, is a sex-specific risk factor for susceptibility to bipolar disorder, and that other variants in the gene may be sex-specific risk factors in the development of schizophrenia. Bipolar affective disorder (BPAD) is a severe psychiatric disorder affecting approximately 1% of the world's population, and shows no difference in lifetime prevalence between male and female subjects. Twin and adoption studies have demonstrated a strong genetic component, with a concordance in BPAD between monozygotic twins of 60%. 1 Major depressive disorder (MDD) has a lifetime prevalence of 17% with women twice as likely as men to develop the disorder. 2 Estimates of the heritability of MDD vary, but a meta-analysis of studies gives a point estimate of heritability of liability to MDD of 0.37. 3 Schizophrenia (SCZ), as with BPAD, has an estimated frequency of 1% in the population, but heritability estimates suggest that it has a larger genetic component than either BPAD or MDD, with monozygotic twins giving a point estimate of comorbidity of 0.81 in another recent meta-analysis. 4 Despite the strong genetic component in these major psychiatric disorders, there are also strong environmental influences.Linkage to Xq28 has been studied many times in BPAD. Two loci, colour-blindness (CB), and glucose-6-phosphate dehydrogenase (G6PD), have been detected through linkage and association in more than one population. 5 Most significant are LOD scores of 8.1 and 7.35 between CB and BPAD in the American and Belgian populations, respectively, although reanalysis of much of the data from positive linkage results on the X chromosome has resulted in much reduced evidence for linkage and suggestions of ascertainment bias. 6-9 Several more recent studies have again renewed interest in the distal end of Xq, although the region implicated in these studies (Xq24-28) is larger than that depicted in the earlier reports. 5,[...

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Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function

Cited by 630 publications

References 19 publications

Social Behavior and Autism Traits in a Sex Chromosomal Disorder: Klinefelter (47XXY) Syndrome

Social Behavior and Autism Traits in a Sex Chromosomal Disorder: Klinefelter (47XXY) Syndrome

Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills

Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor

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