Genetic Liability For Autism Research Articles

The genetics of autism and steroid-related traits in prenatal and postnatal life.

Autism likelihood is a largely heritable trait. Autism prevalence has a skewed sex ratio, with males being diagnosed more often than females. Steroid hormones play a mediating role in this, as indicated by studies of both prenatal biology and postnatal medical conditions in autistic men and women. It is currently unclear if the genetics of steroid regulation or production interact with the genetic liability for autism. To address this, two studies were conducted using publicly available datasets, which focused respectively on rare genetic variants linked to autism and neurodevelopmental conditions (study 1) and common genetic variants (study 2) for autism. In Study 1 an enrichment analysis was conducted, between autism-related genes (SFARI database) and genes that are differentially expressed (FDR<0.1) between male and female placentas, in 1st trimester chorionic villi samples of viable pregnancies (n=39). In Study 2 summary statistics of genome wide association studies (GWAS) were used to investigate the genetic correlation between autism and bioactive testosterone, estradiol and postnatal PlGF levels, as well as steroid-related conditions such as polycystic ovaries syndrome (PCOS), age of menarche, and androgenic alopecia. Genetic correlation was calculated based on LD Score regression and results were corrected for multiple testing with FDR. In Study 1, there was significant enrichment of X-linked autism genes in male-biased placental genes, independently of gene length (n=5 genes, p<0.001). In Study 2, common genetic variance associated with autism did not correlate to the genetics for the postnatal levels of testosterone, estradiol or PlGF, but was associated with the genotypes associated with early age of menarche in females (b=-0.109, FDR-q=0.004) and protection from androgenic alopecia for males (b=-0.135, FDR-q=0.007). The rare genetic variants associated with autism appear to interact with placental sex differences, while the common genetic variants associated with autism appear to be involved in the regulation of steroid-related traits. These lines of evidence indicate that the likelihood for autism is partly linked to factors mediating physiological sex differences throughout development.

On the Misapplication of the Broad Autism Phenotype Questionnaire in a Study of Autism

Nishiyama et al. (2013) recently examined the reliability and construct validity of the Broad Autism Phenotype Questionnaire (BAPQ) and three other instruments with the goal of measuring quantitative autistic traits in 64 individuals with autism spectrum disorder (ASD) and two population samples. As the authors of the BAPQ (Hurley et al. 2007; Sasson et al. 2013),we write to point out that although the study appeared to be carefully and thoughtfully conducted in almost every way, the BAPQ was not designed to be administered to individuals with ASD, nor measure the defining characteristics of autism. Thus, we question the appropriateness of the validation process employed by the authors as well as their interpretation of the study’s results. In contrast to the other questionnaires examined in Nishiyama et al. (2013), the BAPQ does not measure autistic traits but rather is, to our knowledge, the only instrument currently available in the field that was specifically designed to measure the broad autism phenotype. As described in our two papers that detail the development of the instrument, examine its psychometric properties and discuss its extensive validation (Hurley et al. 2007; Sasson et al. 2013), the BAPQ was designed on the basis of the senior author’s experience conducting direct assessments of the parents of autistic individuals, who themselves specifically did not have an ASD (Piven et al. 1997). This distinction is important, and results in three primary ways in which the constructs underlying the BAP and ASD differ. First, while the BAP is often referred to as representing characteristics that are milder but qualitatively similar to ASD, there are also areas in which the two differ qualitatively. For instance, the BAPQ purports to measure the personality construct ‘rigidity’, defined primarily as a preference for routine. An example might include a father who prefers to go to the same restaurant every Saturday night or gets uncomfortable when asked to vary his route to work by two blocks in order to mail a letter for his wife. This differs vastly from characteristics like immediate and delayed echolalia, which is an example of a repetitive and stereotyped characteristic specific to ASD that is not addressed in the BAPQ. Second, there is a difference between the level of severity in the construct of the BAP as assessed by the BAPQ and the level of severity inherent in a diagnosis of ASD. Specifically the BAP is not associated with clinical impairment in our studies (Piven 2002), whereas impairment is an implicit aspect of the diagnosis of ASD. Finally, while the BAPQ is both a selfand informant-report questionnaire, the validity of its use as a self-report questionnaire in individuals with ASD, who by definition have impairments in language and appreciation of social nuances, is suspect. In summary, we believe that Nishiyama et al. (2013) inappropriately evaluated the BAPQ by assessing its ability to differentiate adults with ASD from a population sample, a task it was not designed to address. Although the BAPQ performed well in this context and we applaud the conceptualization of the characteristics inherent in the genetic liability for autism as quantitative traits, it is critical to keep in mind that the measurement of constructs at different ends of such a dimension are not equivalent. To us, this invalidates the results of this paper with respect to analyses involving the BAPQ. J. Piven (&) University of North Carolina, Chapel Hill, NC, USA e-mail: joe_piven@med.unc.edu

Cognitive and Verbal Abilities of 24- to 36-month-old Siblings of Children with Autism

The cognitive and language skills of 30 siblings of children with autism (SIBS-A) and 30 siblings of typically developing children (SIBS-TD) were compared. Non-significant group differences emerged for cognition at both ages. At 24 months, significantly more SIBS-A demonstrated language scores one or two standard deviations below the mean compared to SIBS-TD. At 36 months, the groups differed significantly in receptive language, and more SIBS-A displayed receptive and expressive difficulties compared to SIBS-TD. Six SIBS-A (including one diagnosed with autism) revealed language scores more than two standard deviations below the mean at both ages, a pattern not seen in the SIBS-TD. Results are discussed in reference to language difficulties in autism spectrum disorders and the genetic liability for autism.

The broad autism phenotype: A complementary strategy for molecular genetic studies of autism

The genetic liability for autism appears to be expressed not only as the full syndrome of autism, but in milder, qualitatively similar characteristics that collectively have been referred to as constituting the broad autism phenotype. Identification of components of the broad autism phenotype that segregate independently in relatives of autistic individuals may provide an index of genes that, when present together, may interact to produce autism. Inclusion of information on the broad autism phenotype in relatives, in linkage studies of autism, may provide a potentially important, complementary approach for detecting the genes causing this condition. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 105:34–35, 2001. © 2001 Wiley-Liss, Inc.

The broad autism phenotype: A complementary strategy for molecular genetic studies of autism

The genetic liability for autism appears to be expressed not only as the full syndrome of autism, but in milder, qualitatively similar characteristics that collectively have been referred to as constituting the broad autism phenotype. Identification of components of the broad autism phenotype that segregate independently in relatives of autistic individuals may provide an index of genes that, when present together, may interact to produce autism. Inclusion of information on the broad autism phenotype in relatives, in linkage studies of autism, may provide a potentially important, complementary approach for detecting the genes causing this condition.

Genetic liability for autism: the behavioural expression in relatives

Twin and family studies have suggested that, in addition to causing the full syndrome of autism, the genetic liability for autism may also cause milder, but qualitatively similar behavioural characteristics in non-autistic relatives. Together these characteristics have been referred to as constituting a broad autism phenotype and include such phenomena as rigid and aloof personality and language abnormalities. Clarification of the type and range of characteristics that make up the broad autism phenotype are important for studies aimed at elucidating the biological basis of autism. In particular further defining the full phenotypic expression of the genes that cause autism may aid in teasing apart gene-behaviour relationships as well as brain-behaviour relationships. In this paper the pattern of behaviours which define the broad autism phenotype is reviewed, as well as the potential importance of further characterizing this phenotype for future studies of the biological basis of this disorder.

Personality and language characteristics in parents from multiple-incidence autism families

Several studies have suggested that the genetic liability for autism may be expressed in non-autistic relatives of autistic probands, in behavioral characteristics that are milder but qualitatively similar to the defining features of autism. We employ a variety of direct assessment approaches to examine both personality and language in parents ascertained through having two autistic children (multiple-incidence autism parents) and parents of Down syndrome probands. Multiple-incidence autism parents had higher rates of particular personality characteristics (rigidity, aloofness, hypersensitivity to criticism, and anxiousness), speech and pragmatic language deficits, and more limited friendships than parents in the comparison group. The implications of these findings for future genetic studies of autism are discussed.

Personality and language characteristics in parents from multiple‐incidence autism families

Several studies have suggested that the genetic liability for autism may be expressed in non-autistic relatives of autistic probands, in behavioral characteristics that are milder but qualitatively similar to the defining features of autism. We employ a variety of direct assessment approaches to examine both personality and language in parents ascertained through having two autistic children (multiple-incidence autism parents) and parents of Down syndrome probands. Multiple-incidence autism parents had higher rates of particular personality characteristics (rigidity, aloofness, hypersensitivity to criticism, and anxiousness), speech and pragmatic language deficits, and more limited friendships than parents in the comparison group. The implications of these findings for future genetic studies of autism are discussed. Am. J. Med. Genet. 74:398–411, 1997. © 1997 Wiley-Liss, Inc.

Cognitive deficits in parents from multiple-incidence autism families

This study compares parents of two autistic children with parents of a Down syndrome (DS) proband, on tests of intelligence, reading and spelling, and executive function. Autism parents performed significantly worse than DS parents on performance IQ, a test of executive function, and some reading measures (e.g. passage comprehension and rapid automatized naming). These results suggest that cognitive deficits may be an expression of the underlying genetic liability for autism and that these characteristics may contribute to a more broadly defined autism phenotype.