Abstract
BackgroundAutism spectrum conditions (ASC) are a group of neurodevelopmental conditions characterized by difficulties in social interaction and communication alongside repetitive and stereotyped behaviours. ASC are heritable, and common genetic variants contribute substantial phenotypic variability. More than 600 genes have been implicated in ASC to date. However, a comprehensive investigation of candidate gene association studies in ASC is lacking.MethodsIn this study, we systematically reviewed the literature for association studies for 552 genes associated with ASC. We identified 58 common genetic variants in 27 genes that have been investigated in three or more independent cohorts and conducted a meta-analysis for 55 of these variants. We investigated publication bias and sensitivity and performed stratified analyses for a subset of these variants.ResultsWe identified 15 variants nominally significant for the mean effect size, 8 of which had P values below a threshold of significance of 0.01. Of these 15 variants, 11 were re-investigated for effect sizes and significance in the larger Psychiatric Genomics Consortium dataset, and none of them were significant. Effect direction for 8 of the 11 variants were concordant between both the datasets, although the correlation between the effect sizes from the two datasets was poor and non-significant.ConclusionsThis is the first study to comprehensively examine common variants in candidate genes for ASC through meta-analysis. While for majority of the variants, the total sample size was above 500 cases and 500 controls, the total sample size was not large enough to accurately identify common variants that contribute to the aetiology of ASC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-015-0041-0) contains supplementary material, which is available to authorized users.
Highlights
Autism spectrum conditions (ASC) are a group of neurodevelopmental conditions characterized by difficulties in social interaction and communication alongside repetitive and stereotyped behaviours
Studies were included in the meta-analysis if: (1) they reported effect sizes or statistics to measure effect sizes and confidence intervals; (2) the studies were either a case-control association study or a transmission disequilibrium study of autism; (3) the variants did not deviate from Hardy-Weinberg Equilibrium (HWE) in the control group or if the sample size was too small to effectively calculate HWE due to sampling effect
Though we checked for HWE in family-based studies, this was not a requirement for including these studies as the study design overcomes the issue of population stratification; (4) cases had a diagnosis of an autism spectrum condition (Autism, PDDNOS, Asperger Syndrome) according to DSM-IV, DSM-5 or ICD-10 criteria; (5) the global minor allele frequency (MAF) of the variant investigated was greater than 0.01; (6) the studies were reported in English and (7) the common variants were investigated in independent cohorts
Summary
Autism spectrum conditions (ASC) are a group of neurodevelopmental conditions characterized by difficulties in social interaction and communication alongside repetitive and stereotyped behaviours. Strategies to identify common variants through genome-wide association studies have failed to produce consistent, replicable results across cohorts [5]. Over the last 15 years, a large number of studies have investigated common variants in candidate genes for ASC [6] typically investigating variants in a small number of genes using a relatively small sample size. These studies have provided some evidence of the association of a few genes with ASC, though they are not rigorous enough to definitively identify variants and results vary based on ethnicity, sample size, study methodology and clinical ascertainment [6]
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