Autism as a Strongly Genetic Disorder: Evidence from a British Twin Study

ArticleinPsychological Medicine 25(1):63-77 · February 1995with820 Reads
DOI: 10.1017/S0033291700028099 · Source: PubMed
Abstract
Two previous epidemiological studies of autistic twins suggested that autism was predominantly genetically determined, although the findings with regard to a broader phenotype of cognitive, and possibly social, abnormalities were contradictory. Obstetric and perinatal hazards were also invoked as environmentally determined aetiological factors. The first British twin sample has been re-examined and a second total population sample of autistic twins recruited. In the combined sample 60% of monozygotic (MZ) pairs were concordant for autism versus no dizygotic (DZ) pairs; 92% of MZ pairs were concordant for a broader spectrum of related cognitive or social abnormalities versus 10% of DZ pairs. The findings indicate that autism is under a high degree of genetic control and suggest the involvement of multiple genetic loci. Obstetric hazards usually appear to be consequences of genetically influenced abnormal development, rather than independent aetiological factors. Few new cases had possible medical aetiologies, refuting claims that recognized disorders are common aetiological influences.
    • "In ASD, some evidence supports the theory that the brain is excessively masculinized [62, 63]. Genetic vulnerability also impacts risk for highly heritable neurodevelopmental disorders such as schizophre- nia [52][53][54]and ASD [64, 65], likely via the combined influence of multiple risk variants. Among the genes which may increase the susceptibility to schizophrenia and ASD is DTNBP1 (dysbindin). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia differentially impact males and females and are highly heritable. The ways in which sex and genetic vulnerability influence the pathogenesis of these disorders are not clearly understood. The n-methyl-d-aspartate (NMDA) receptor pathway has been implicated in schizophrenia and autism spectrum disorders and changes dramatically across postnatal development at the level of the GluN2B-GluN2A subunit "switch" (a shift from reliance on GluN2B-containing receptors to reliance on GluN2A-containing receptors). We investigated whether sex and genetic vulnerability (specifically, null mutation of DTNBP1 [dysbindin; a possible susceptibility gene for schizophrenia]) influence the developmental GluN2B-GluN2A switch. Methods: Subcellular fractionation to enrich for postsynaptic density (PSD), together with Western blotting and kinase assay, were used to investigate the GluN2B-GluN2A switch in the cortex and hippocampus of male and female DTNBP1 null mutant mice and their wild-type littermates. Main effects of sex and DTNBP1 genotype, and interactions with age, were assessed using factorial ANOVA. Results: Sex differences in the GluN2B-GluN2A switch emerged across development at the frontal cortical synapse, in parameters related to GluN2B. Males across genotypes displayed higher GluN2B:GluN2A and GluN2B:GluN1 ratios (p < 0.05 and p < 0.01, respectively), higher GluN2B phosphorylation at Y1472 (p < 0.01), and greater abundance of PLCγ (p < 0.01) and Fyn (p = 0.055) relative to females. In contrast, effects of DTNBP1 were evident exclusively in the hippocampus. The developmental trajectory of GluN2B was disrupted in DTNBP1 null mice (genotype × age interaction p < 0.05), which also displayed an increased synaptic GluN2A:GluN1 ratio (p < 0.05) and decreased PLCγ (p < 0.05) and Fyn (only in females; p < 0.0005) compared to wild-types. Conclusions: Sex and DTNBP1 mutation influence the GluN2B-GluN2A switch at the synapse in a brain-region-specific fashion involving pY1472-GluN2B, Fyn, and PLCγ. This highlights the possible mechanisms through which risk factors may mediate their effects on vulnerability to disorders of NMDA receptor dysfunction.
    Full-text · Article · Dec 2016
    • "This has been termed the ''broader autism phenotype'' (Piven et al. 1997). In support of the dimensional hypothesis, family members of people with ASD show higher levels of autistic-like traits than comparison groups drawn from families without a history of ASD (Bailey et al. 1995; Bishop et al. 2004; Constantino and Todd 2003; Lainhart et al. 2002; Piven et al. 1997). Additionally, autistic-like traits below the threshold for clinical diagnosis also appear to be heritable (Constantino and Todd 2005). "
    [Show abstract] [Hide abstract] ABSTRACT: People with autism show superior performance to controls on the Embedded Figures Test (EFT). However, studies examining the relationship between autistic-like traits and EFT performance in neurotypical individuals have yielded inconsistent findings. To examine the inconsistency, a meta-analysis was conducted of studies that (a) compared high and low Autism-Spectrum Quotient (AQ) groups, and (b) treated AQ as a continuous variable. Outcomes are consistent with superior visual search forming part of the broader autism phenotype, but in existing literature, this is evident only when comparing extreme groups. Reanalysis of data from previous studies suggests findings are unlikely to be driven by a small number of high scorers. Monte Carlo simulations are used to illustrate the effect of methodological differences on results.
    Full-text · Article · Jun 2016
    • "(1977) seminal paper reporting higher concordance rates for ASD in monozygotic compared to same-sex dizygotic twins, a pattern that has been replicated in a number of subsequent twin studies (Bailey et al., 1995; Hallmayer et al., 2011; Le Couteur et al., 1996; Ritvo, Freeman, Mason-Brothers, Mo, & Ritvo, 1985). In addition, siblings have been found to have both an increased risk of ASD and elevated rates of autistic-like idiosyncrasies and communication disorders. "
    [Show abstract] [Hide abstract] ABSTRACT: The Broader Autism Phenotype (BAP) is a term applied to individuals with personality and cognitive traits that are similar to but milder than those observed in Autism Spectrum Disorder (ASD). Subtle autistic traits in the core diagnostic domains of social communication and rigid behavior were described in family members of people with an ASD even in the initial reports of ASD. In this paper, we discuss the benefits and limitations of researching the BAP in typically developing individuals for understanding autism and development.
    Article · Jun 2016
Show more