AB040. Biomarkers for Autism: where are we now and what will the future bring?

Abstract: Autism spectrum disorders (ASD) is a complex disorder in which both genes and environmental factors play important roles. ASD is characterized by a high concordance rate in monozygotic twins pointing to high heritability for this disorder. Notably, the sibling recurrence risk ratio (λs) is 22 for autism. Despite the high heritability clinical symptoms are markedly variable and multiple genetic factors including Mendelian mutations, copy number variations and common polymorphisms all contribute to the genetic load towards passing the clinical threshold to ASD. Indeed, multiple genetic loci have been with various degrees of certainty associated with this disorder. In addition to genetic factors environmental variables and epigenetic signatures are also important modifiers of susceptibility to ASD. For example, studies show that DNA methylation differences can occur in many loci across the genome of ASD subjects. Among biomarkers that have been examined in ASD are metabolic, oxidative stress, mitochondrial dysfunction, methylation, immune dysregulation, amino acids and neuropeptides, peripheral blood gene expression, digit ratio and dysbiosis (gut inflammation) among others. In my talk today after giving an overview (see above) of biomarkers in ASD, I will discuss my own group’s approach that includes both gene markers (serotonin transporter, OXTR and AVPR1a) as well as an innovative endophenotype biomarker approach to better understanding ASD. In a recent study we found that 2D:4D digit ratio (also a proposed marker for ASD) relationship to cognitive empathy (a core deficit in ASD) is dependent in normal subjects on an OXTR SNP linked to ASD in some studies. We have also shown that OXTR and AVPR1a gene polymorphisms are associated in normal subjects with cognitive and emotional empathy respectively. Notably, common polymorphisms in both genes are also associated with ASD. Similarly, the DRD4 gene shows a gender-sensitive association with cognitive empathy. In a parallel talk at this meeting I discuss in some detail how gene expression studies in lymphoblastoid cells may be a marker for ASD as well as personality traits. I will also discuss a finding with a colleague identifying a functional rare variant in autism using genome-wide screen for monoallelic expression. Altogether, our studies have revealed genetic and other biomarkers that jointly contribute to the social cognitive deficits that represent core diagnostic features of ASD. The biomarkers are not specific to ASD but nevertheless shed considerable light on the underlying common polymorphisms and multiple etiologies of this highly heritable disorder characterized by intellectual and social dysfunctions. One promising area of future studies of biomarkers in ASD is prenatal diagnosis using ultrasound.

Keywords: Autism spectrum disorders (ASD); biomarkers; serotonin transporter; OXTR; AVPR1a