Genome-Wide Association Study of Autistic-Like Traits in a General Population Study of Young Adults

Jones, Rachel; Cadby, Gemma; Melton, Phillip E.; Abraham, Lawrence J.; Whitehouse, Andrew J. O.; Moses, Eric K.

doi:10.3389/fnhum.2013.00658

Cited by 31 publications

(29 citation statements)

References 48 publications

(62 reference statements)

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“…While a loss-of-function mutation in UBE3A underlies Angelman's syndrome, gain-of-function mutations of UBE3A are also associated with autistic features. A central mechanism implicating the autism-liked gene, cerebellin1 (CBLN1), was recently proposed to underlie these UBE3Amediated social deficits [82,83]. Krishnan et al demonstrate that the increase in UBE3A induces a downregulation of CBLN1, and further, that behavioral changes following loss of CBLN1 specifically in ventral tegmental area (VTA) neurons mimic the UBE3A-mediated social deficits.…”

Section: Rodent Models Relevant To Syndromic Asd With a Somatosensorymentioning

confidence: 99%

Mechanisms of Tactile Sensory Phenotypes in Autism: Current Understanding and Future Directions for Research

Schaffler

Middleton

Abdus-Saboor

2019

Curr Psychiatry Rep

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Purpose of Review This review aims to summarize the current body of behavioral, physiological, and molecular knowledge concerning tactile sensitivity in autism spectrum disorder (ASD), with a focus on recent studies utilizing rodent models. Recent Findings Mice with mutations in the ASD-related genes, Shank3, Fmr1, UBE3A, and Mecp2, display tactile abnormalities. Some of these abnormalities appear to be caused by mutation-related changes in the PNS, as opposed to changes in the processing of touch stimuli in the CNS, as previously thought. There is also growing evidence suggesting that peripheral mechanisms may contribute to some of the core symptoms and common comorbidities of ASD. Researchers are therefore beginning to assess the therapeutic potential of targeting the PNS in treating some of the core symptoms of ASD. Summary Sensory abnormalities are common in rodent models of ASD. There is growing evidence that sensory hypersensitivity, especially tactile sensitivity, may contribute to social deficits and other autism-related behaviors.

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Section: Rodent Models Relevant To Syndromic Asd With a Somatosensorymentioning

confidence: 99%

Mechanisms of Tactile Sensory Phenotypes in Autism: Current Understanding and Future Directions for Research

Schaffler

Middleton

Abdus-Saboor

2019

Curr Psychiatry Rep

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“…CUEDC2 encodes the protein ‘CUE domain containing 2’, shown to be involved in the ubiquitination-proteasomal degradation pathway. Others have previously identified associations at this region with the social skills domain of the autism quotient in a population cohort (independent of the PGC ASD GWAS [50]); identifying an association with rs927821 ( P = 3.4 × 10 −6 ), a marker in strong linkage disequilibrium with rs1409313 (1000 genomes project all ancestries: r 2 = 0.82; D ’ = 0.91; European ancestries: r 2 = 0.68; D ’ = 0.85). Other genes in this region include PITX3 which encodes the transcription factor Pitx3 (paired-like homeodomain 3) which plays an important role in the differentiation and maintenance of midbrain dopaminergic neurons during development.…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia

Anney¹,

Ripke²,

Anttila³

et al. 2017

Molecular Autism

499

210

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BackgroundOver the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15).MethodsWe conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls).ResultsWe observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10−6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a ‘neurodevelopmental hub’ on chromosome 8p11.23.ConclusionsThis study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4. Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0137-9) contains supplementary material, which is available to authorized users.

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“…Candidate SNP data for this study were obtained from genomewide genotype data described previously (Jones et al , 2013). Briefly, genotyping was performed on the Illumina Human 660W Quad Array (Illumina, San Diego, California, USA) and individuals were excluded due to low genotyping success (>3% missing), excessive heterozygosity, relation with another sample (identity by descent > 0.1875), ambiguous sex, and mislabeling.…”

Section: Methodsmentioning

confidence: 99%

MACROD2 gene associated with autistic-like traits in a general population sample

Jones

Cadby

Blangero

et al. 2014

Psychiatric Genetics

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There is now substantial evidence that autistic-like traits in the general population lie on a continuum, with clinical autism spectrum disorders (ASD) representing the extreme end of this distribution. In this study, we sought to evaluate five independently identified genetic associations with ASD with autistic-like traits in the general population. In the study cohort, clinical phenotype and genomewide association genotype data were obtained from the Western Australian Pregnancy Cohort (Raine) Study. The outcome measure used was the Autism Spectrum Quotient (AQ), a quantitative measure of autistic-like traits of individuals in the cohort. Total AQ scores were calculated for each individual, as well as scores for three subscales. Five candidate single nucleotide polymorphism (SNP) associations with ASD, reported in previously published genomewide association studies, were selected using a nominal cutoff value of P less than 1.0 × 10−5. We tested whether these five SNPs were associated with total AQ and the subscales, after adjustment for possible confounders. SNP rs4141463 located in the macro domain containing 2 (MACROD2) gene was significantly associated with the Communication/Mindreading subscale. No other SNP was significantly associated with total AQ or the subscales. The MACROD2 gene is a strong positional candidate risk factor for autistic-like traits in the general population.

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Genome-Wide Association Study of Autistic-Like Traits in a General Population Study of Young Adults

Cited by 31 publications

References 48 publications

Mechanisms of Tactile Sensory Phenotypes in Autism: Current Understanding and Future Directions for Research

Mechanisms of Tactile Sensory Phenotypes in Autism: Current Understanding and Future Directions for Research

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia

MACROD2 gene associated with autistic-like traits in a general population sample

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