Showing papers by "Sarah Curran published in 2005"

Prader-Willi syndrome: intellectual abilities and behavioural features by genetic subtype.

Abstract: Background: Studies of chromosome 15 abnormality have implicated over-expression of paternally imprinted genes in the 15q11–13 region in the aetiology of autism. To test this hypothesis we compared individuals with Prader-Willi syndrome (PWS) due to uniparental disomy (UPD – where paternally imprinted genes are over-expressed) to individuals with the 15q11–13 deletion form of the syndrome (where paternally imprinted genes are not over-expressed). We also tested reports that PWS cases due to the larger type I (TI) form of deletion show differences to cases with the smaller type II (TII) deletion. Method: Ninety-six individuals with PWS were recruited from genetic centres and the PWS association. Forty-nine individuals were confirmed as having maternal UPD of chromosome 15 and were age and sex matched to 47 individuals with a deletion involving 15q11–13 (32 had the shorter (T II) deletion, and 14 had the longer (TI) deletion). Behavioural assessments were carried out blind to genetic status, using the Autism Diagnostic Observation Schedule (ADOS), the Autism Diagnostic Interview (ADI), the Autism Screening Questionnaire (ASQ), the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), the Vineland Adaptive Behaviour Scales (VABS), and measurements of intellectual ability, including the Wechsler and Mullen Scales and Raven's Matrices. Results: UPD cases exhibited significantly more autistic-like impairments in reciprocal social interaction on questionnaire, interview and standardised observational measures. Comparison of TI and TII deletion cases revealed few differences, but ability levels tended to be lower in the TI deletion cases. Conclusions: Findings from a large study comparing deletion and UPD forms of Prader-Willi syndrome were consistent with other evidence in indicating that paternally imprinted genes in the 15q11–13 region constitute a genetic risk factor for aspects of autistic symptomatology. These genes may therefore play a role in the aetiology of autism. By contrast with another report, there was no clear-cut relationship between the size of the deletion and the form of cognitive and behavioural phenotype.

Quantitative trait locus analysis of candidate gene alleles associated with attention deficit hyperactivity disorder (ADHD) in five genes: DRD4, DAT1, DRD5, SNAP-25, and 5HT1B.

Abstract: It has been widely postulated that the categorical diagnosis of attention deficit hyperactivity disorder (ADHD) should be seen as the extreme end of a set of traits quantitatively distributed in the general population. A consequence of this is that the genes associated with DSM-IV ADHD should also influence these underlying traits in non-affected individuals. The aim of this study was to examine if specific candidate loci previously shown to be associated with DSM-IV ADHD, also act as quantitative trait loci (QTLs) for ADHD-symptoms in the general population. We have genotyped five candidate markers in a population-based sample of male dizygous twin-pairs (n = 329 pairs). We found little evidence to support a role for the previously-nominated alleles of a DRD4 VNTR, a 5HT1B SNP, or a microsatellite marker near to DRD5, in the distribution of ADHD-symptoms scores; however, we found some evidence to suggest that the DAT1 3'UTR VNTR and weak evidence that a microsatellite in SNAP-25 may have a role in continuous measures of ADHD-symptoms hyperactivity above and beyond their role in clinical ADHD.

Molecular and phenotypic characterization of ring chromosome 22.

Abstract: We performed a phenotype study of 35 individuals (19 males, 16 females) with ring chromosome 22 or r(22) with a mean age of 10 years. In common with other studies, a phenotype of moderate-to-profound learning difficulties and delay or absence of speech affected all individuals with the exception of the case with the smallest deletion. Autistic traits were significantly associated with r(22), as shown by an autism screening questionnaire. Mild and variable dysmorphic features, predominantly craniofacial and distal limb, were observed. Internal organ involvement was uncommon. Even though ring chromosomes are reportedly associated with growth abnormalities, only 2 out of 24 individuals showed evidence of growth failure, while 2 showed accelerated growth. Chromosome 22 long arm deletions, as determined by hemizygosity for informative microsatellite markers, varied from <67 kb to 10.2 Mb in size (or <0.15 to 21% of total chromosome length), with no significant differences in the parental origin of the ring chromosome. Few phenotypic features correlated with deletion size suggesting a critical gene, or genes, of major effect lies close to the telomere. Loss of the SHANK3/PROSAP2 gene has been proposed to be responsible for the main neurological developmental deficits observed in 22q13 monosomies. This study supports this candidate gene by identifying a phenotypically normal r(22) individual whose ring chromosome does not disrupt SHANK3. All other r(22) individuals were hemizygous for SHANK3, and we propose it to be a candidate gene for autism or abnormal brain development.

The serotonin transporter gene as a QTL for ADHD

Abstract: Molecular studies of attention deficit hyperactivity disorder (ADHD) have identified susceptibility genes for the categorically diagnosed disorder using operational diagnostic criteria. Here, we take a QTL approach to mapping genes for ADHD using a composite continuous index of ADHD behavior in a large epidemiological sample. Previous studies of clinical ADHD suggest that two functional polymorphisms in the serotonin transporter gene (SLC6A4), one in the 5'-regulatory region of the gene (5-HTTLPR) and the other a VNTR (5-HTTVNTR) in the second intron, as well as a single nucleotide polymorphism in the 3'-untranslated region (3'-UTR SNP), may be associated with the disorder. Here, we investigate these polymorphisms as well as an additional ten SNPs spread across the gene. We found significant association with the long (L) allele of the 5-HTTLPR; P = 0.019, but neither the 5-HTTVNTR nor the 3'-UTR SNP were significantly associated. Significant associations (P < 0.05) were found for a further 5 the 10 other markers tested. We found evidence for two haplotype blocks spanning the region. We found strong evidence for association with the first haplotype block (comprised of four markers), with the significance of a combined primary and secondary test of association reaching an empirical P value = 0.0054 for the global test and an empirical P value = 0.00081 for the largest local test. Thus, we show here that SLC6A4, which has a major influence on brain serotonin availability, may be a QTL for ADHD.

Continuity and change in preschool ADHD symptoms: longitudinal genetic analysis with contrast effects.

Abstract: The genetic and environmental mediation of continuity and change in parent-reported ADHD symptoms were investigated in a cohort of over 6000 twin pairs at 2, 3 and 4 years of age. Genetic analyses of the cross-sectional data yielded heritability estimates of 0.78–0.81 at each age, with contrast effects. A common pathway model provided the best fit to the longitudinal data, indicating that genetic influences underlie 91% of the stable variance in ADHD symptomatology. In other words, what is stable for ADHD symptoms is largely genetic. Contrast effects acting in the same direction at different ages contributed to the observed continuity:longitudinal correlations were greater for dizygotic than monozygotic twins.

An association analysis of microsatellite markers across the Prader–Willi/Angelman critical region on chromosome 15 (q11‐13) and autism spectrum disorder

Abstract: Autism (OMIM 209850) is a neurodevelopmental disorder with a significant genetic component of a complex nature. Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome critical region (PWACR) on chromosome 15 (q11-13) have been described in several individuals with autism. We have examined five microsatellite markers spread across the 4 Mb PWACR for linkage disequilibrium (LD) in 148 families with autism spectrum disorder (ASD) and a subset of 82 families with autism using the extended transmission disequilibrium test (ETDT). The markers examined were D15S11, D15S128, D15S1506, GABRB3, and D15S1002. In addition we have examined the microsatellite D15S822 for hemizygous deletion status in our sample as it had been previously reported to be increased in autism. We found no significant LD with any of the markers tested either in the ASD or autism families when looking at paternal and maternal meioses combined. However, as there are known imprinted genes in the region, including possibly GABRB3, we also examined for LD in paternal and maternal meioses separately. Examining paternal transmissions only, we found marginal evidence for LD with a protective allele at marker D15S11 in the ASD families (Chi-sq 7 df, P = 0.05) and marginal evidence for risk alleles at markers D15S1506 (Chi-sq 13.7, 6 df, P = 0.06), GABRB3 (Chi-sq 15.9, 8 df, P = 0.11) and D15S1002 (Chi-sq 17.7, 9 df, P = 0.08) in the autism only families. The allele responsible for the association with GABRB3 is the 191 allele which was previously reported to be overtransmitted. Hemizygous deletion of the microsatellite D15S822 was found in 3 out of 340 independent chromosomes in our sample; a rate of 0.8%. This is not significantly different to the frequency in the general population. In conclusion, our results did not rule out the involvement of this chromosomal region, but provided further evidence, albeit very limited, to implicate GABRB3. Further more systematic work in larger samples is required and confirmation that GABRB3 is imprinted is desirable.

Chromosome 15 abnormalities and autistic symptomatology. Case - Control investigations

Abstract: Introduction: Case reports and uncontrolled studies of small case series have suggested that abnormalities of chromosome 15 that involve the Prader-Willi/Angelman Syndrome critical region (PWACR) are associated with an increased risk for autism spectrum disorders. We have investigated this issue in a large number of individuals with various forms of chromosome 15 abnormality, comparing the frequency of autistic symptomatology in these cases with the frequency in various control samples. Methods: Individuals with duplications (n¼30), supernumery marker chromosome 15’s (n¼32), Prader-Willi Syndrome (disomy cases¼49 deletion cases¼47) were assessed using questionnaire (SCQ), innterview (ADI-R) and observational (ADOS-G) measures of autistic symptomatology and the frequency of symptoms compared to the that found in unaffected relative and Down syndrome controls. Results: Autisitc symptomatalogy was strongly associated with the presence and number of extra copies of the PWACR. Within and between group contrasts suggested that the increased risk for autistic symptomatology was related to over expression of maternally expressed genes. Conclusions: Genes within the Prader-Willi/Angelman syndrome critical region are candidate genes in the aetiology of autism spectrum disorders. Dysregulation of maternally expressed genes is a potential candidate mechanism. However, molecular genetic organisation in this region is complex with methylation and chromatin structure change and epistatic interactions with genes in other regions being possible.

Chromosome 15 abnormalities and autistic symptomatology: case—control investigations

Abstract: Introduction: Case reports and uncontrolled studies of small case series have suggested that abnormalities of chromosome 15 that involve the Prader-Willi/Angelman Syndrome critical region (PWACR) are associated with an increased risk for autism spectrum disorders. We have investigated this issue in a large number of individuals with various forms of chromosome 15 abnormality, comparing the frequency of autistic symptomatology in these cases with the frequency in various control samples. Methods: Individuals with duplications (n¼30), supernumery marker chromosome 15’s (n¼32), Prader-Willi Syndrome (disomy cases¼49 deletion cases¼47) were assessed using questionnaire (SCQ), innterview (ADI-R) and observational (ADOS-G) measures of autistic symptomatology and the frequency of symptoms compared to the that found in unaffected relative and Down syndrome controls. Results: Autisitc symptomatalogy was strongly associated with the presence and number of extra copies of the PWACR. Within and between group contrasts suggested that the increased risk for autistic symptomatology was related to over expression of maternally expressed genes. Conclusions: Genes within the Prader-Willi/Angelman syndrome critical region are candidate genes in the aetiology of autism spectrum disorders. Dysregulation of maternally expressed genes is a potential candidate mechanism. However, molecular genetic organisation in this region is complex with methylation and chromatin structure change and epistatic interactions with genes in other regions being possible.