A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet

Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland.
Human Molecular Genetics (Impact Factor: 6.39). 10/2010; 19(20):4072-82. DOI: 10.1093/hmg/ddq307
Source: PubMed


Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

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    • "Despite the high heritability of ASD (approximately 90%), its basis remains poorly explained by common genetic risk variants [3]. Genome-wide association studies (GWAS) have so far provided only tenuous evidence for individual common variants that affect risk of ASD [3-6], drawing attention to the contribution of rare variants to ASD pathophysiology. Indeed, recent studies have shown that rare genomic variation, both copy number variants (CNVs) and point mutations, may account for a significant proportion of cases of idiopathic autism [7]. "
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    ABSTRACT: Background Autism spectrum disorder (ASD) is a highly heritable, neurodevelopmental condition showing extreme genetic heterogeneity. While it is well established that rare genetic variation, both de novo and inherited, plays an important role in ASD risk, recent studies also support a rare recessive contribution. Methods We identified a compound heterozygous deletion intersecting the CTNNA3 gene, encoding αT-catenin, in a proband with ASD and moderate intellectual disability. The deletion breakpoints were mapped at base-pair resolution, and segregation analysis was performed. We compared the frequency of CTNNA3 exonic deletions in 2,147 ASD cases from the Autism Genome Project (AGP) study versus the frequency in 6,639 controls. Western blot analysis was performed to get a quantitative characterisation of Ctnna3 expression during early brain development in mouse. Results The CTNNA3 compound heterozygous deletion includes a coding exon, leading to a putative frameshift and premature stop codon. Segregation analysis in the family showed that the unaffected sister is heterozygote for the deletion, having only inherited the paternal deletion. While the frequency of CTNNA3 exonic deletions is not significantly different between ASD cases and controls, no homozygous or compound heterozygous exonic deletions were found in a sample of over 6,000 controls. Expression analysis of Ctnna3 in the mouse cortex and hippocampus (P0-P90) provided support for its role in the early stage of brain development. Conclusion The finding of a rare compound heterozygous CTNNA3 exonic deletion segregating with ASD, the absence of CTNNA3 homozygous exonic deletions in controls and the high expression of Ctnna3 in both brain areas analysed implicate CTNNA3 in ASD susceptibility.
    Journal of Neurodevelopmental Disorders 07/2014; 6(1):17. DOI:10.1186/1866-1955-6-17 · 3.27 Impact Factor
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    • "Here, we focus on the molecular evolution of protein-coding genes associated with schizophrenia, autism, and other neuropsychiatric diseases compared across mammalian species and among disease classes, with a focus on the primate (chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, baboon, marmoset, and squirrel monkey) and human lineages. Recent genome wide association studies (GWAS) have identified multiple genomic loci associated with autism (Ma et al., 2009; Wang et al., 2009; Weiss et al., 2009; Anney et al., 2010, 2012; Tsang et al., 2013) and Asperger syndrome (Salyakina et al., 2010), and schizophrenia (Fanous et al., 2012; Levinson et al., 2012; Aberg et al., 2013; Ripke et al., 2013). Using these datasets and similar meta-analyses in the literature that have identified genes implicated in neuropsychiatric disease it is possible to test whether mutations have occurred recently and uniquely in the evolution of humans, or whether similar changes are seen in other mammals. "
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    ABSTRACT: Many psychiatric diseases observed in humans have tenuous or absent analogs in other species. Most notable among these are schizophrenia and autism. One hypothesis has posited that these diseases have arisen as a consequence of human brain evolution, for example, that the same processes that led to advances in cognition, language, and executive function also resulted in novel diseases in humans when dysfunctional. Here, the molecular evolution of the protein-coding regions of genes associated with these and other psychiatric disorders are compared among species. Genes associated with psychiatric disorders are drawn from the literature and orthologous sequences are collected from eleven primate species (human, chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, baboon, marmoset, squirrel monkey, and galago) and 34 non-primate mammalian species. Evolutionary parameters, including dN/dS, are calculated for each gene and compared between disease classes and among species, focusing on humans and primates compared to other mammals, and on large-brained taxa (cetaceans, rhinoceros, walrus, bear, and elephant) compared to their small-brained sister species. Evidence of differential selection in humans to the exclusion of non-human primates was absent, however elevated dN/dS was detected in catarrhines as a whole, as well as in cetaceans, possibly as part of a more general trend. Although this may suggest that protein changes associated with schizophrenia and autism are not a cost of the higher brain function found in humans, it may also point to insufficiencies in the study of these diseases including incomplete or inaccurate gene association lists and/or a greater role of regulatory changes or copy number variation. Through this work a better understanding of the molecular evolution of the human brain, the pathophysiology of disease, and the genetic basis of human psychiatric disease is gained.
    Frontiers in Human Neuroscience 05/2014; 8:283. DOI:10.3389/fnhum.2014.00283 · 3.63 Impact Factor
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    • "CNV data were available for 2,147 ASD patients of European ancestry that passed all quality control filters. These subjects were recruited at centres in North America and Europe and assessed using the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule, as previously described [20]. The Autism Simplex Collection database, established in a parallel project, is available for part of the study dataset and includes comprehensive clinical information with detailed diagnostic evaluation and neuropsychological profiling of patients and relatives. "
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    ABSTRACT: Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study. From the AGP CNV genomic screen in 2,147 ASD individuals, we selected for characterization an ANXA1 gene duplication that was absent in 4,964 population-based controls. We further screened the duplication in a follow-up sample including 1,496 patients and 410 controls, and evaluated clinical correlations and family segregation. Sequencing of exonic/downstream ANXA1 regions was performed in 490 ASD patients for identification of additional variants. The ANXA1 duplication, overlapping the last four exons and 3'UTR region, had an overall prevalence of 11/3,643 (0.30%) in unrelated ASD patients but was not identified in 5,374 controls. Duplication carriers presented no distinctive clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD traits in multiple relatives carrying the duplication, suggestive of a complex genetic inheritance. Sequencing of exonic regions and the 3'UTR identified 11 novel changes, but no obvious variants with clinical significance. We provide multilevel evidence for a role of ANXA1 in ASD etiology. Given its important role as mediator of glucocorticoid function in a wide variety of brain processes, including neuroprotection, apoptosis, and control of the neuroendocrine system, the results add ANXA1 to the growing list of rare candidate genetic etiological factors for ASD.
    Molecular Autism 04/2014; 5(1):28. DOI:10.1186/2040-2392-5-28 · 5.41 Impact Factor
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