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A genome-wide association study of social and non-social autistic-like traits in the general population using pooled DNA, 500 K SNP microarrays and both community and diagnosed autism replication samples.

ABSTRACT: Two separate genome-wide association studies were conducted to identify single nucleotide polymorphisms (SNPs) associated with social and nonsocial autistic-like traits. We predicted that we would find SNPs associated with social and non-social autistic-like traits and that different SNPs would be associated with social and nonsocial. In Stage 1, each study screened for allele frequency differences in approximately 430,000 autosomal SNPs using pooled DNA on microarrays in high-scoring versus low-scoring boys from a general population sample (N = approximately 400/group). In Stage 2, 22 and 20 SNPs in the social and non-social studies, respectively, were tested for QTL association by individually genotyping an independent community sample of 1,400 boys. One SNP (rs11894053) was nominally associated (P < .05, uncorrected for multiple testing) with social autistic-like traits. When the sample was increased by adding females, 2 additional SNPs were nominally significant (P < .05). These 3 SNPs, however, showed no significant association in transmission disequilibrium analyses of diagnosed ASD families.

SUBMITTER: Ronald A

PROVIDER: S-EPMC2797846 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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A genome-wide association study of social and non-social autistic-like traits in the general population using pooled DNA, 500 K SNP microarrays and both community and diagnosed autism replication samples.

Ronald Angelica A Butcher Lee M LM Docherty Sophia S Davis Oliver S P OS Schalkwyk Leonard C LC Craig Ian W IW Plomin Robert R

Behavior genetics 20091213 1

Two separate genome-wide association studies were conducted to identify single nucleotide polymorphisms (SNPs) associated with social and nonsocial autistic-like traits. We predicted that we would find SNPs associated with social and non-social autistic-like traits and that different SNPs would be associated with social and nonsocial. In Stage 1, each study screened for allele frequency differences in approximately 430,000 autosomal SNPs using pooled DNA on microarrays in high-scoring versus low ...[more]

PMID: 20012890

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Project description:BackgroundThe social domain of autism has been studied in depth, but the relationship between the non-social traits of autism has received less attention. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) outlines four criteria that make up the non-social domain including repetitive motor movements, insistence on sameness, restricted interests and sensory sensitivity. There is a lack of research into the relationship between these four criteria. This study aimed to evaluate the relationship between the non-social traits of autism in a large sample of autistic adults. It explored whether these traits are best conceptualised as four distinct factors, or exist along a single dimension.MethodsParticipants included autistic adults from the Netherlands Autism Register. The four components identified within the DSM-5 non-social domain were measured by items from the Adult Routines Inventory, the Autism Spectrum Quotient short and the Sensory Perception Quotient short. Confirmatory factor analysis, as well as exploratory factor analysis and exploratory structural equation modelling, was implemented to examine the relationship between these four criteria.ResultsResults indicated that a four-factor model provided the best fit, mapping onto the DSM-5 criteria. These four factors were moderately correlated, suggesting that four distinct, yet related factors best describe the non-social domain of autism. The one-factor model did not provide a good fit, highlighting that the non-social domain of autism is not a unitary construct.LimitationsThe study included autistic adults who were cognitively able to complete the self-report measures. This may limit the generalisability of the findings to those who are less able to do so.ConclusionsThis study provided evidence for the multidimensional nature of the non-social domain of autism. Given only two of the four criteria within the non-social domain need to be endorsed for a diagnosis of autism, there is room for substantial variation across individuals, who will have a unique profile within the non-social domain. The results have implications for our understanding of the heterogeneous nature of autistic traits, as well as for how we conceptualise autism as a diagnostic category. This is important for the provision of diagnosis and support within research and clinical practice.

Project description:BackgroundGene expression microarrays measure the levels of messenger ribonucleic acid (mRNA) in a sample using probe sequences that hybridize with transcribed regions. These probe sequences are designed using a reference genome for the relevant species. However, most model organisms and all humans have genomes that deviate from their reference. These variations, which include single nucleotide polymorphisms, insertions of additional nucleotides, and nucleotide deletions, can affect the microarray's performance. Genetic experiments comparing individuals bearing different population-associated single nucleotide polymorphisms that intersect microarray probes are therefore subject to systemic bias, as the reduction in binding efficiency due to a technical artifact is confounded with genetic differences between parental strains. This problem has been recognized for some time, and earlier methods of compensation have attempted to identify probes affected by genome variants using statistical models. These methods may require replicate microarray measurement of gene expression in the relevant tissue in inbred parental samples, which are not always available in model organisms and are never available in humans.ResultsBy using sequence information for the genomes of organisms under investigation, potentially problematic probes can now be identified a priori. However, there is no published software tool that makes it easy to eliminate these probes from an annotation. I present equalizer, a software package that uses genome variant data to modify annotation files for the commonly used Affymetrix IVT and Gene/Exon platforms. These files can be used by any microarray normalization method for subsequent analysis. I demonstrate how use of equalizer on experiments mapping germline influence on gene expression in a genetic cross between two divergent mouse species and in human samples significantly reduces probe hybridization-induced bias, reducing false positive and false negative findings.ConclusionsThe equalizer package reduces probe hybridization bias from experiments performed on the Affymetrix microarray platform, allowing accurate assessment of germline influence on gene expression.

Project description:BackgroundDNA extracted from historical samples is an important resource for understanding genetic consequences of anthropogenic influences and long-term environmental change. However, such samples generally yield DNA of a lower amount and quality, and the extent to which DNA degradation affects SNP genotyping success and allele frequency estimation is not well understood. We conducted high density SNP genotyping and allele frequency estimation in both individual DNA samples and pooled DNA samples extracted from dried Atlantic salmon (Salmo salar) scales stored at room temperature for up to 35 years, and assessed genotyping success, repeatability and accuracy of allele frequency estimation using a high density SNP genotyping array.ResultsIn individual DNA samples, genotyping success and repeatability was very high (> 0.973 and > 0.998, respectively) in samples stored for up to 35 years; both increased with the proportion of DNA of fragment size > 1000 bp. In pooled DNA samples, allele frequency estimation was highly repeatable (Repeatability = 0.986) and highly correlated with empirical allele frequency measures (Mean Adjusted R2 = 0.991); allele frequency could be accurately estimated in > 95% of pooled DNA samples with a reference group of at least 30 individuals. SNPs located in polyploid regions of the genome were more sensitive to DNA degradation: older samples had lower genotyping success at these loci, and a larger reference panel of individuals was required to accurately estimate allele frequencies.ConclusionsSNP genotyping was highly successful in degraded DNA samples, paving the way for the use of degraded samples in SNP genotyping projects. DNA pooling provides the potential for large scale population genetic studies with fewer assays, provided enough reference individuals are also genotyped and DNA quality is properly assessed beforehand. We provide recommendations for future studies intending to conduct high-throughput SNP genotyping and allele frequency estimation in historical samples.

Dataset Information

A genome-wide association study of social and non-social autistic-like traits in the general population using pooled DNA, 500 K SNP microarrays and both community and diagnosed autism replication samples.

Publications

A genome-wide association study of social and non-social autistic-like traits in the general population using pooled DNA, 500 K SNP microarrays and both community and diagnosed autism replication samples.

Similar Datasets

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