Abstract
Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by impaired social communication coupled with stereotyped behaviors and restricted interests. Despite the high concordance rate for diagnosis, there is little information on the magnitude of genetic contributions to specific ASD behaviors. Using behavioral/trait severity scores from the Autism Diagnostic Interview-Revised (ADI-R) diagnostic instrument, we compared the phenotypic profiles of mono- and dizygotic twins where both co-twins were diagnosed with ASD or only one twin had a diagnosis. The trait distribution profiles across the respective twin populations were first used for quantitative trait association analyses using publicly available genome-wide genotyping data. Trait-associated single nucleotide polymorphisms (SNPs) were then used for case-control association analyses, in which cases were defined as individuals in the lowest (Q1) and highest (Q4) quartiles of the severity distribution curves for each trait. While all of the ASD-diagnosed twins exhibited similar trait severity profiles, the non-autistic dizygotic twins exhibited significantly lower ADI-R item scores than the non-autistic monozygotic twins. Case-control association analyses of twins stratified by trait severity revealed statistically significant SNPs with odds ratios that clearly distinguished individuals in Q4 from those in Q1. While the level of shared genomic variation is a strong determinant of the severity of autistic traits in the discordant non-autistic twins, the similarity of trait profiles in the concordantly autistic dizygotic twins also suggests a role for environmental influences. Stratification of cases by trait severity resulted in the identification of statistically significant SNPs located near genes over-represented within autism gene datasets.
Highlights
Autism spectrum disorder (ASD) is a highly heritable and heterogeneous neurodevelopmental disorder which is characterized by deficits in social communication and reciprocal interactions as well as by stereotyped behavior and restricted interests, often accompanied by language difficulties, especially in the area of pragmatics [1]
The goals of this study were to: (1) investigate how genetics influences specific autism-associated behaviors and traits among monozygotic versus dizygotic twins, either concordant or discordant for autism diagnosis; (2) utilize ASD trait distribution profiles based on individual Autism Diagnostic Interview-Revised (ADI-R) scores in quantitative trait association analyses to identify single nucleotide polymorphisms (SNPs or quantitative trait nucleotides [QTNs]) that associate with specific traits; (3) determine whether the QTNs can differentiate cases from controls using individuals with ASD at the extremes of each trait distribution profile to reduce the phenotypic heterogeneity of cases for case-control association analyses; and (4) identify genes, pathways, and biological functions associated with specific traits
A total of 284 pairs of twins represented in the Autism Genetic Resource Exchange (AGRE) were included in this study
Summary
Autism spectrum disorder (ASD) is a highly heritable and heterogeneous neurodevelopmental disorder which is characterized by deficits in social communication and reciprocal interactions as well as by stereotyped behavior and restricted interests, often accompanied by language difficulties, especially in the area of pragmatics [1]. A review of twin studies conducted between 1977 and 2011 suggests that concordance rates for autism are quite variable ranging from 36% to 96% for MZ twins, depending in part on sex as well as whether or not the diagnosis was narrowly defined (i.e., strict autism) or more broadly defined as autism spectrum disorder (ASD) [4]. To tease out the contributions of genetics and environment, there have been increased efforts to assemble large twin cohorts for genetic analyses and for studies on the associated phenotypes of autism, including neurodevelopmental differences [5,6,7,8]. Heritability studies that included subclinical (i.e., broad autism phenotype) diagnoses indicate that heritability is determined by both genetics and non-shared environment, but that concordance rates are somewhat dependent on diagnostic method [12]. Few studies have used a broad range of specific phenotypic differences among clinically discordant non-autistic twins to determine how zygosity influences the severity of autistic traits
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
