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R K Abramson

Publications and source records attributed to R K Abramson.

At least 19 recordsLinked to original sources
PubMed2006

Dissecting the locus heterogeneity of autism: significant linkage to chromosome 12q14.

Autism is a common neurodevelopmental disorder with a significant genetic component and locus heterogeneity. To date, 12 microsatellite genome screens have been performed using various data sets of sib-pair families (parents and affected children) resulting in numerous regions of potential linkage across the genome. However, no universal region or consistent candidate gene from these regions has emerged. The use of large, extended pedigrees is a recognized powerful approach to identify significant linkage results, as these families potentially contain more potential linkage information than sib-pair families. A genome-wide linkage analysis was performed on 26 extended autism families (65 affected, 184 total individuals). Each family had two to four affected individuals comprised of either avuncular or cousin pairs. For analysis, we used a high-density single-nucleotide polymorphism genotyping assay, the Affymetrix GeneChip Human Mapping 10K array. Two-point analysis gave peak heterogeneity limit of detection (HLOD) of 2.82 at rs2877739 on chromosome 14q. Suggestive linkage evidence (HLOD>2) from a two-point analysis was also found on chromosomes 1q, 2q, 5q, 6p,11q and 12q. Chromosome 12q was the only region showing significant linkage evidence by multipoint analysis with a peak HLOD=3.02 at rs1445442. In addition, this linkage evidence was enhanced significantly in the families with only male affected (multipoint HLOD=4.51), suggesting a significant gender-specific effect in the etiology of autism. Chromosome-wide haplotype analyses on chromosome 12 localized the potential autism gene to a 4 cM region shared among the affected individuals across linked families. This novel linkage peak on chromosome 12q further supports the hypothesis of substantial locus heterogeneity in autism.

Autistic Disorder↗
PubMed2006

An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder.

Gene-gene interactions are likely involved in many complex genetic disorders and new statistical approaches for detecting such interactions are needed. We propose a multi-analytic paradigm, relying on convergence of evidence across multiple analysis tools. Our paradigm tests for main and interactive effects, through allele, genotype and haplotype association. We applied our paradigm to genotype data from three GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) on chromosome 15 in 470 Caucasian autism families. Previously implicated in autism, we hypothesized these genes interact to contribute to risk. We detected no evidence of main effects by allelic (PDT, FBAT) or genotypic (genotype-PDT) association at individual markers. However, three two-marker haplotypes in GABRG3 were significant (HBAT). We detected no significant multi-locus associations using genotype-PDT analysis or the EMDR data reduction program. However, consistent with the haplotype findings, the best single locus EMDR model selected a GABRG3 marker. Further, the best pairwise genotype-PDT result involved GABRB3 and GABRG3, and all multi-locus EMDR models also selected GABRB3 and GABRG3 markers. GABA receptor subunit genes do not significantly interact to contribute to autism risk in our overall data set. However, the consistency of results across analyses suggests that we have defined a useful framework for evaluating gene-gene interactions.

Autistic Disorder↗
PubMed2005

Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism.

Autism is a common neurodevelopmental disorder with a significant genetic component. Existing research suggests that multiple genes contribute to autism and that epigenetic effects or gene-gene interactions are likely contributors to autism risk. However, these effects have not yet been identified. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, has been implicated in autism etiology. Fourteen known autosomal GABA receptor subunit genes were studied to look for the genes associated with autism and their possible interactions. Single-nucleotide polymorphisms (SNPs) were screened in the following genes: GABRG1, GABRA2, GABRA4, and GABRB1 on chromosome 4p12; GABRB2, GABRA6, GABRA1, GABRG2, and GABRP on 5q34-q35.1; GABRR1 and GABRR2 on 6q15; and GABRA5, GABRB3, and GABRG3 on 15q12. Intronic and/or silent mutation SNPs within each gene were analyzed in 470 white families with autism. Initially, SNPs were used in a family-based study for allelic association analysis--with the pedigree disequilibrium test and the family-based association test--and for genotypic and haplotypic association analysis--with the genotype-pedigree disequilibrium test (geno-PDT), the association in the presence of linkage (APL) test, and the haplotype family-based association test. Next, with the use of five refined independent marker sets, extended multifactor-dimensionality reduction (EMDR) analysis was employed to identify the models with locus joint effects, and interaction was further verified by conditional logistic regression. Significant allelic association was found for markers RS1912960 (in GABRA4; P = .01) and HCV9866022 (in GABRR2; P = .04). The geno-PDT found significant genotypic association for HCV8262334 (in GABRA2), RS1912960 and RS2280073 (in GABRA4), and RS2617503 and RS12187676 (in GABRB2). Consistent with the allelic and genotypic association results, EMDR confirmed the main effect at RS1912960 (in GABRA4). EMDR also identified a significant two-locus gene-gene effect model involving RS1912960 in GABRA4 and RS2351299 in GABRB1. Further support for this two-locus model came from both the multilocus geno-PDT and the APL test, which indicated a common genotype and haplotype combination positively associated with disease. Finally, these results were also consistent with the results from the conditional logistic regression, which confirmed the interaction between GABRA4 and GABRB1 (odds ratio = 2.9 for interaction term; P = .002). Through the convergence of all analyses, we conclude that GABRA4 is involved in the etiology of autism and potentially increases autism risk through interaction with GABRB1. These results support the hypothesis that GABA receptor subunit genes are involved in autism, most likely via complex gene-gene interactions.

Autistic Disorder↗
PubMed2005

Ordered-subset analysis of savant skills in autism for 15q11-q13.

Autism is a complex disorder characterized by genetic and phenotypic heterogeneity. Analysis of phenotypically homogeneous subtypes has been used to both confirm and narrow potential autism linkage regions such as the chromosomal region 15q11-q13. Increased evidence for linkage in this region had been found in a subgroup of 21 autism families (total families = 94) stratified based on a savant skill factor (SSF) from the Autism Diagnostic Interview, Revised (ADI-R). We examined the savant phenotypic finding in our sample of 91 multiplex autism families. Using two-point parametric analysis in stratification with a cutoff point of a savant skill score of 0.16, our families failed to demonstrate linkage to 15q11-q13. In addition, ordered subset analysis (OSA) using SSF as a covariate also failed to show evidence for linkage. Our findings do not support savant skills as an informative phenotypic subset for linkage in our sample.

Adolescent↗
PubMed2005

The relationship between restrictive and repetitive behaviors in individuals with autism and obsessive compulsive symptoms in parents.

This study investigated the relationship between repetitive behaviors in individuals with autism and obsessive-compulsive behaviors in parents. We hypothesized that repetitive behaviors in probands with autism would be associated with increased obsessive-compulsive behaviors in parents in sporadic families (1 known case of autism per family and no known history of autism). Parents with clinically significant Y-BOCS scores were more likely to have a family history of obsessive-compulsive disorder. The empirically derived Autism Diagnostic Interview-R (ADI-R) factor, Insistence on Sameness, was positively correlated with obsessive-compulsive behaviors in parents. Further, when probands were grouped on the basis of parental Y-BOCS scores (clinically significant versus non-clinically significant), probands whose parents had clinically significant Y-BOCS scores had higher ADI-R Insistence on Sameness factor scores. The findings of the current study of sporadic families extend previous work that has shown an association between restrictive/repetitive behaviors in probands with autism and obsessive-compulsive features in parents.

Adult↗
PubMed2004

No association between the APOE gene and autism.

Autism is a neurodevelopmental disorder characterized by stereotypic and repetitive behavior and interests, together with social and communicative deficiencies. The results of several genomic screens suggest the presence of an autism susceptibility locus on chromosome 19p13.2-q13.4. The apolipoprotein E (APOE) gene on chromosome 19 encodes for a protein, apoE, whose different isoforms (E2, E3, E4) influence neuronal growth. APOE participates in lipid transport and metabolism, repair, growth, and maintenance of axons and myelin during neuronal development. The APOE protein competes with the Reelin protein for VLDL/APOER2 receptor binding. Several studies have reported evidence for an association between autism and the Reelin gene. Based on these data we tested for association between APOE and autism using family-based association methods in a data set of 322 autism families. Three promoter, one intronic, and one 3' UTR single nucleotide polymorphisms (SNPs) in the APOE gene (-491a/t, -427c/t, -219g/t, 113c/g, and 5361c/t) as well as the APOE functional polymorphism (E2, E3, E4) were examined and failed to reveal significant evidence that autism is associated with APOE.

Apolipoproteins E↗
PubMed2003

Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes.

Autistic disorder (AutD) is a complex genetic disease. Available evidence suggests that several genes contribute to the underlying genetic risk for the development of AutD. However, both etiologic heterogeneity and genetic heterogeneity confound the discovery of AutD-susceptibility genes. Chromosome 15q11-q13 has been identified as a strong candidate region on the basis of both the frequent occurrence of chromosomal abnormalities in that region and numerous suggestive linkage and association findings. Ordered-subset analysis (OSA) is a novel statistical method to identify a homogeneous subset of families that contribute to overall linkage at a given chromosomal location and thus to potentially help in the fine mapping and localization of the susceptibility gene within a chromosomal area. For the present analysis, a factor that represents insistence on sameness (IS)--derived from a principal-component factor analysis using data on 221 patients with AutD from the repetitive behaviors/stereotyped patterns domain in the Autism Diagnostic Interview-Revised--was used as a covariate in OSA. Analysis of families sharing high scores on the IS factor increased linkage evidence for the 15q11-q13 region, at the GABRB3 locus, from a LOD score of 1.45 to a LOD score of 4.71. These results narrow our region of interest on chromosome 15 to an area surrounding the gamma-aminobutyric acid-receptor subunit genes, in AutD, and support the hypothesis that the analysis of phenotypic homogeneous subtypes may be a powerful tool for the mapping of disease-susceptibility genes in complex traits.

Autistic Disorder↗
PubMed2001

Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting via the GABAA receptors. The GABAA receptors are comprised of several different homologous subunits, forming a group of receptors that are both structurally and functionally diverse. Three of the GABAA receptor subunit genes (GABRB3, GABRA5 and GABRG3) form a cluster on chromosome 15q11-q13, in a region that has been genetically associated with autistic disorder (AutD). Based on these data, we examined 16 single nucleotide polymorphisms (SNPs) located within GABRB3, GABRA5 and GABRG3 for linkage disequilibrium (LD) in 226 AutD families (AutD patients and parents). Genotyping was performed using either OLA (oligonucleotide ligation assay), or SSCP (single strand conformation polymorphism) followed by DNA sequencing. We tested for LD using the Pedigree Disequilibrium Test (PDT). PDT results gave significant evidence that AutD is associated with two SNPs located within the GABRG3 gene (exon5_539T/C, p=0.02 and intron5_687T/C, p=0.03), suggesting that the GABRG3 gene or a gene nearby contributes to genetic risk in AutD.

Autistic Disorder↗
PubMed2000

Three probands with autistic disorder and isodicentric chromosome 15.

We have identified three unrelated probands with autistic disorder (AD) and isodicentric chromosomes that encompass the proximal region of 15q11.2. All three probands met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [DSM-IV; American Psychiatric Association, 1994], and International Classification of Diseases ( ICD-10) diagnostic criteria for AD, confirmed with the Autism Diagnostic Interview -Revised (ADI-R). Chromosome analysis revealed the following karyotypes: 47,XX,+idic(15)(q11.2), 47,XX, +idic(15) (q11.2), and 47,XY,+idic(15)(q11.2). Haplotype analysis of genotypic maker data in the probands and their parents showed that marker chromosomes in all three instances were of maternal origin. Comparison of the clinical findings of the three AD probands with case reports in the published literature (N = 20) reveals a clustering of physical and developmental features. Specifically, these three probands and the majority of reported probands in the literature exhibited hypotonia (n = 13), seizures (n = 13), and delayed gross motor development (n = 13). In addition, clustering of the following clinical signs was seen with respect to exhibited speech delay (n = 13), lack of social reciprocity (n = 11), and stereotyped behaviors (n = 12). Collectively, these data provide further evidence for the involvement of chromosome 15 in AD as well as present preliminary data suggesting a clustering of clinical features in AD probands with proximal 15q anomalies.

Adolescent↗
PubMed2000

Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder.

Autistic disorder (AD) is a neurodevelopmental disorder characterized by abnormalities in behavior, communication, and social interactions and functioning. Recently, Cook et al. reported significant linkage disequilibrium with an AD susceptibility locus and a marker, GABRB3 155CA-2, in the gamma-aminobutyric acid(A) (GABA(A)) receptor beta3-subunit gene on chromosome 15q11-q13. This linkage disequilibrium was detected using a multiallelic version of the transmission/disequilibrium test (TDT) in a sample of nuclear families having at least one child with autistic disorder. In an attempt to replicate this finding we tested for linkage disequilibrium with this marker, as well as with three additional markers in and around the GABA(A) receptor beta3-subunit gene, in an independent, clinically comparable set of AD families. Unlike Cook et al., we failed to detect significant linkage disequilibrium between GABRB3 155CA-2 and AD in our sample. We did, however, find suggestive evidence for linkage disequilibrium with a marker, GABRB3, approximately 60 kb beyond the 3' end of beta3-subunit gene. This finding lends support for previous reports implicating the involvement of genes in this region with AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:43-48, 2000

Autistic Disorder↗
PubMed2000

Genetic studies in autistic disorder and chromosome 15.

Autistic disorder (AD) is a developmental disorder affecting social interactions, communication, and behavior. AD is a disease of complex genetic architecture. It is postulated that several genes contribute to the underlying etiology of AD. Chromosome 15 is of particular interest due to numerous reports of AD in the presence of chromosomal abnormalities, located mainly in the 15q11-q13 region. There are also a number of plausible candidate genes in this area, including the gamma-aminobutyric acidA (GABA(A)) receptor gene complex. We have undertaken a study of this region of chromosome 15 in a data set of 63 multiplex families (with 2 or more AD affected individuals per family). We found evidence in support of linkage to the 15q11-q13 region, as well as evidence of increased recombination in this region. These findings provide further support for the involvement of chromosome 15q11-q13 in the genetic etiology of AD.

Autistic Disorder↗
PubMed1999

Genetic studies of autistic disorder and chromosome 7.

Genome-wide scans have suggested that a locus on 7q is involved in the etiology of autistic disorder (AD). We have identified an AD family in which three sibs inherited from their mother a paracentric inversion in the chromosome 7 candidate region (inv(7)(q22-q31.2)). Clinically, the two male sibs have AD, while the female sib has expressive language disorder. The mother carries the inversion, but does not express AD. Haplotype data on the family suggest that the chromosomal origin of the inversion was from the children's maternal grandfather. Based on these data, we have genotyped 76 multiplex (>/=2 AD affecteds/family) families for markers in this region of 7q. Two-point linkage analysis yielded a maximum heterogeneity lod score of 1.47 and maximum lod score (MLS) of 1.03 at D7S495. Multipoint MLS and NPL analyses resulted in peak scores of 1.77 at D7S2527 and 2.01 at D7S640. Examination of affected sibpairs revealed significant paternal (P = 0.007), but not maternal (P = 0. 75), identity-by-descent sharing at D7S640. Significant linkage disequilibrium was detected with paternal (P = 0.02), but not maternal (P = 0.15), transmissions at D7S1824 in multiplex and singleton families. There was also evidence for an increase in recombination in the region (D7S1817 to D7S1824) in the AD families versus non-AD families (P = 0.03, sex-averaged; and P = 0.01, sex-specific). These results provide further evidence for the presence of an AD locus on chromosome 7q, as well as provide evidence suggesting that this locus may be paternally expressed.

Adult↗
PubMed1993

Whole-blood serotonin and cognitive functioning in autistic individuals and their first-degree relatives.

The relationship between cognitive-intellectual abilities and whole-blood serotonin (5-hydroxytryptamine; 5-HT) in 18 autistic probands and their first-degree relatives (n = 21 parents, n = 13 siblings) was investigated. Whole-blood 5-HT was significantly negatively associated with verbal-expressive/symbolic abilities for the entire sample. The proportion of variance in cognitive-intellectual performances attributable to whole-blood 5-HT was substantial in the context of variance attributable to familial classification. The relationship between verbal-expressive abilities and whole-blood 5-HT, adjusted for race and familial classification, was noteworthy. Simple correlations between 5-HT and cognitive-intellectual performances were conducted. However, bias related to covariance attributable to race seriously limits such findings. The issue of bias and its relevance to previous research is discussed further.

Adolescent↗