Gene x Gene Interaction in Shared Etiology of Autism and Specific Language Impairment

Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio. Electronic address: .
Biological psychiatry (Impact Factor: 9.47). 06/2012; 72(8):692-9. DOI: 10.1016/j.biopsych.2012.05.019
Source: PubMed

ABSTRACT To examine the relationship between autism spectrum disorders (ASD) and specific language impairment (SLI), family studies typically take a comparative approach where families with one disease are examined for traits of the other disease. In contrast, the present report is the first study with both disorders required to be present in each family to provide a more direct test of the hypothesis of shared genetic etiology.
We behaviorally assessed 51 families including at least one person with ASD and at least one person with SLI (without ASD). Pedigree members were tested with 22 standardized measures of language and intelligence. Because these extended families include a nonshared environmental contrast, we calculated heritability, not just familiality, for each measure twice: 1) baseline heritability analysis, compared with; 2) heritability estimates after statistically removing ASD subjects from pedigrees.
Significant increases in heritability on four supra-linguistic measures (including Pragmatic Judgment) and a composite language score but not on any other measures were observed when removing ASD subjects from the analysis, indicating differential genetic effects that are unique to ASD. Nongenetic explanations such as effects of ASD severity or measurement error or low score variability in ASD subjects were systematically ruled out, leaving the hypothesis of nonadditive genetics effects as the potential source of the heritability change caused by ASD.
Although the data suggest genetic risk factors common to both SLI and ASD, there are effects that seem unique to ASD, possibly caused by nonadditive gene-gene interactions of shared risk loci.


Available from: Chris Bartlett, May 10, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Language and communication development is a complex process influenced by numerous environmental and genetic factors. Many neurodevelopment disorders include deficits in language and communication skills in their diagnostic criteria, including autism spectrum disorders (ASD), language impairment (LI), and dyslexia. These disorders are polygenic and complex with a significant genetic component contributing to each. The similarity of language phenotypes and comorbidity of these disorders suggest that they may share genetic contributors. To test this, we examined the association of genes previously implicated in dyslexia, LI, and/or language-related traits with language skills in children with ASD. We used genetic and language data collected in the Autism Genome Research Exchange (AGRE) and Simons Simplex Collection (SSC) cohorts to perform a meta-analysis on performance on a receptive vocabulary task. There were associations with LI risk gene ATP2C2 and dyslexia risk gene MRPL19. Additionally, we found suggestive evidence of association with CMIP, GCFC2, KIAA0319L, the DYX2 locus (ACOT13, GPLD1, and FAM65B), and DRD2. Our results show that LI and dyslexia genes also contribute to language traits in children with ASD. These associations add to the growing literature of generalist genes that contribute to multiple related neurobehavioral traits. Future studies should examine whether other genetic contributors may be shared among these disorders and how risk variants interact with each other and the environment to modify clinical presentations. Autism Res 2014, ●●; ●●-●●. © 2014 International Society for Autism Research, Wiley Periodicals, Inc. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
    Autism Research 12/2014; DOI:10.1002/aur.1436 · 4.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Social (pragmatic) communication disorder (SCD) is a new diagnostic category in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). The purpose of this review is to describe and synthesize the relevant literature from language and autism spectrum disorder (ASD) research relating to pragmatic language impairment and other previously used terms that relate to SCD. The long-standing debate regarding how social communication/pragmatic impairments overlap and/or differ from language impairments, ASD, and other neurodevelopmental disorders is examined. The possible impact of the addition of SCD diagnostic category and directions for future research are also discussed.
    Journal of Neurodevelopmental Disorders 11/2014; 6(1):41. DOI:10.1186/1866-1955-6-41 · 3.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: The PTPRA gene, which encodes the protein RPTP-alpha, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks. Methods: We sequenced the protein-encoding areas of the PTPRA gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 382 schizophrenia patients. To validate their association with the disorders, rare (minor allele frequency, <1%), missense mutations as well as one InDel in the 39UTR region were then genotyped in another independent sample set comprising 944 schizophrenia patients, 336 autism spectrum disorders patients, and 912 healthy controls. Results: Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase. In the following association analysis, L59P, one of the two missense mutations, was only observed among patients of schizophrenia. Additionally, a novel duplication in the 3'UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element. Major Conclusions: No evidence was seen for the association of rare, missense mutations in the PTPRA gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.
    PLoS ONE 11/2014; 9(11):e112531. DOI:10.1371/journal.pone.0112531 · 3.53 Impact Factor