Genetic Heterogeneity Between the Three Components of the Autism Spectrum: A Twin Study

Ronald, Angelica; Happé, Francesca; Bolton, Patrick; Butcher, Lee M.; Price, Thomas S.; Wheelwright, Sally; Baron‐Cohen, Simon; Plomin, Robert

doi:10.1097/01.chi.0000215325.13058.9d

Cited by 430 publications

(457 citation statements)

References 25 publications

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“…16,61 However, what is interesting is that we observed genetic heterogeneity within a single large pedigree. While it is possible that more than a single autism predisposition gene may lie in one of the identified regions, our findings suggest that the number of potential genes and various combinations of genes that may be involved in autism within our pedigree are limited, and we have identified a relatively small number of regions to follow-up.…”

Section: Discussionmentioning

confidence: 79%

A high-density SNP genome-wide linkage scan in a large autism extended pedigree

et al. 2008

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We performed a high-density, single nucleotide polymorphism (SNP), genome-wide scan on a six-generation pedigree from Utah with seven affected males, diagnosed with autism spectrum disorder. Using a two-stage linkage design, we first performed a nonparametric analysis on the entire genome using a 10K SNP chip to identify potential regions of interest. To confirm potentially interesting regions, we eliminated SNPs in high linkage disequilibrium (LD) using a principal components analysis (PCA) method and repeated the linkage results. Three regions met genome-wide significance criteria after controlling for LD: 3q13.2-q13.31 (nonparametric linkage (NPL), 5.58), 3q26.31-q27.3 (NPL, 4.85) and 20q11.21-q13.12 (NPL, 5.56). Two regions met suggestive criteria for significance 7p14.1-p11.22 (NPL, 3.18) and 9p24.3 (NPL, 3.44). All five chromosomal regions are consistent with other published findings. Haplotype sharing results showed that five of the affected subjects shared more than a single chromosomal region of interest with other affected subjects. Although no common autism susceptibility genes were found for all seven autism cases, these results suggest that multiple genetic loci within these regions may contribute to the autism phenotype in this family, and further followup of these chromosomal regions is warranted.

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Section: Discussionmentioning

confidence: 79%

A high-density SNP genome-wide linkage scan in a large autism extended pedigree

et al. 2008

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“…23,[25][26][27] A recent study examining the relationship between core symptoms of autism in twins provided evidence that, while highly heritable, the domains of social impairment and repetitive behavior were genetically heterogeneous. 28,29 These findings raise the intriguing possibility that mouse models reflecting different components of the autism behavioral phenotype might be used to distinguish the specific genetic pathways that mediate stereotypy and cognitive inflexibility from those underlying deficiencies in social interaction or communication. Lewis et al 13 provide a comprehensive overview of animal models for repetitive behavior, including both the lower-order and higher-order response clusters.…”

Section: Behavioral Phenotyping Of Mouse Modelsmentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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“…5 Family studies indicate that the prevalence of ASD in siblings of the affected individuals is 50-100 times higher than the general population. 6 Lines of compelling evidence have firmly established that ASD has a strong genetic component; however, the underlying mechanism remains elusive, which might be due to the genetic heterogeneity and complexity.…”

Section: Introductionmentioning

confidence: 99%

Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population

et al. 2010

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The oxytocin receptor (OXTR) gene, which is located on chromosome 3p25.3, has been implicated as a candidate gene for susceptibility of autism spectrum disorder (ASD). Positive associations between OXTR and ASD have been reported in earlier studies. However, the results were inconsistent and demand further studies. In this study, we investigated the associations between OXTR and ASD in a Japanese population by analyzing 11 single-nucleotide polymorphisms (SNPs) using both familybased association test (FBAT) and population-based case-control test. No significant signal was detected in the FBAT test. However, significant differences were observed in allelic frequencies of four SNPs, including rs2254298 between patients and controls. The risk allele of rs2254298 was 'A', which was consistent with the previous study in Chinese, and not with the observations in Caucasian. The difference in the risk allele of this SNP in previous studies might be attributable to an ethnic difference in the linkage disequilibrium structure between the Asians and Caucasians. In addition, haplotype analysis exhibits a significant association between a five-SNP haplotype and ASD, including rs22542898. In conclusion, our study might support that OXTR has a significant role in conferring the risk of ASD in the Japanese population.

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Genetic Heterogeneity Between the Three Components of the Autism Spectrum: A Twin Study

Cited by 430 publications

References 25 publications

A high-density SNP genome-wide linkage scan in a large autism extended pedigree

A high-density SNP genome-wide linkage scan in a large autism extended pedigree

Advances in behavioral genetics: mouse models of autism

Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population

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