Novel Autism Subtype-Dependent Genetic Variants Are Revealed by Quantitative Trait and Subphenotype Association Analyses of Published GWAS Data

Abstract

The heterogeneity of symptoms associated with autism spectrum disorders (ASDs) has presented a significant challenge to genetic analyses. Even when associations with genetic variants have been identified, it has been difficult to associate them with a specific trait or characteristic of autism. Here, we report that quantitative trait analyses of ASD symptoms combined with case-control association analyses using distinct ASD subphenotypes identified on the basis of symptomatic profiles result in the identification of highly significant associations with 18 novel single nucleotide polymorphisms (SNPs). The symptom categories included deficits in language usage, non-verbal communication, social development, and play skills, as well as insistence on sameness or ritualistic behaviors. Ten of the trait-associated SNPs, or quantitative trait loci (QTL), were associated with more than one subtype, providing partial replication of the identified QTL. Notably, none of the novel SNPs is located within an exonic region, suggesting that these hereditary components of ASDs are more likely related to gene regulatory processes (or gene expression) than to structural or functional changes in gene products. Seven of the QTL reside within intergenic chromosomal regions associated with rare copy number variants that have been previously reported in autistic samples. Pathway analyses of the genes associated with the QTL identified in this study implicate neurological functions and disorders associated with autism pathophysiology. This study underscores the advantage of incorporating both quantitative traits as well as subphenotypes into large-scale genome-wide analyses of complex disorders.

Genetic Variation in Melatonin Pathway Enzymes in Children with Autism Spectrum Disorder and Comorbid Sleep Onset Delay

“…However, due to the diverse symptomatology among individuals with ASD, it is difficult to replicate genetic effects across datasets or identify clinically useful information related to outcomes from symptom treatment. It is possible that expression of various medical comorbidities in individuals with ASD can be explained by distinct underlying genetic effects (Alarcon et al 2005, 2008; Bruining et al 2010; Geschwind 2011; Hu et al 2011; Peter et al 2011; Whitehouse et al 2011; Talebizadeh et al 2013). By focusing on individuals with ASD also expressing a specific comorbidity, we may increase our ability to detect replicable genetic effects and identify clinically useful genetic information.…”

Genetic pathways to autism spectrum disorders

“…Although it has been estimated that 85% of disease-causing mutations are in exons [85], this estimate stems from known Mendelian genetic disorders; there are multiple lines of evidence ruling out a Mendelian mode of inheritance for the vast majority of ASD. It is interesting to note that SNPs associated with ASD primarily localize to intergenic regions [45,72,86], reminiscent of the pattern seen with many risk alleles influencing nonpsychiatric complex disease.…”

Subphenotype-Dependent Disease Markers for Diagnosis and Personalized Treatment of Autism Spectrum Disorders

“…Although all 18 of the ASD-associated SNPs are located in noncoding regions (that is, promoter, intronic and intergenic regions), some of the genes associated with the identified SNPs offer new insight into the pathobiology of ASD as well as novel therapeutic tar- [36]. One of these genes, 5-hydroxytryptamine receptor 4 (HTR4), is a serotonin receptor subtype that is present not only in the central nervous system, but also in the gastrointestinal (GI) system, where it has been associated with irritable bowel disease and other GI disorders [37].…”

“…To test the hypothesis that division of ASD cases into more homogeneous subtypes might also aid in the identification of significant SNPs in genome-wide association (GWA) analyses, we undertook a meta-analysis of published GWA data in which individuals with ASD were subgrouped according to ADI-R symptom severity profiles [36]. GWA data was derived from the study of Wang et al [30] and ADI-R scoresheets for a subset of the genotyped individuals were obtained through the Autism Genetic Resource Exchange (courtesy of Dr. Vlad Kustanovich).…”