Genetic advances in autism: heterogeneity and convergence on shared pathways

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The autism spectrum disorders (ASD) are a heterogeneous set of developmental disorders characterized at their core by deficits in social interaction and communication. Current psychiatric nosology groups this broad set of disorders with strong genetic liability and multiple etiologies into the same diagnostic category. This heterogeneity has challenged genetic analyses. But shared patient resources, genomic technologies, more refined phenotypes, and novel computational approaches have begun to yield dividends in defining the genetic mechanisms at work. Over the last five years, a large number of autism susceptibility loci have emerged, redefining our notion of autism's etiologies, and reframing how we think about ASD.

Introduction

Autism is a neurodevelopmental disorder defined by three categories of deficits: firstly, abnormal development or impairment of social interaction; secondly, abnormal development or impairment of communication skills; and thirdly, stereotypic and repetitive behaviors [1]. Autism is part of a larger family of neurodevelopmental disorders categorized by the Diagnostic and Statistical Manual IV-R under the term pervasive developmental disorders (PDD) [1]. PDD includes Asperger Syndrome (AS), where language appears normal, and pervasive developmental disorder not otherwise specified (PDD-NOS) in which children meet some but not all criteria for autism. Collectively, these disorders are known as the autism spectrum disorders (ASD) [1]. Rett syndrome and Childhood Disintegrative Disorder are also classified as a PDD, but are exclusionary for a diagnosis of autism.

Hypothesized by Kanner to be an innate or inborn disorder in his original description, autism was not formally determined to be a genetic disorder until Folstein and Rutter demonstrated a greater than 50% concordance for monozygotic, versus 0% for dizygotic twins. More recent twin studies have observed as high as 90% trait concordance for monozygotic twins [2], and family studies suggest a 22-fold increased risk over the general population for first-degree relatives [3], although this does not use the current CDC prevalence estimate of 1/152 for ASD [4]. Taken together, these studies indicate a high genetic liability, while leaving some room for environmental factors that may influence the penetrance or expressivity of these disorders with respect to genetic risk factors.

Although ASD is highly heritable, the identification of candidate genes has been hindered by the heterogeneity of the syndrome and insufficient numbers of participants, as compared to whole genome association studies in other complex genetic disorders. The establishment of collaborative groups, such as the International Molecular Genetic Study of Autism Consortium (IMGSAC) and Autism Genome Project Consortium [5, 6•], and shared resources, such as the Autism Genetic Resource Exchange (AGRE) Consortium [7], were therefore important steps in facilitating the identification of candidate genes. Linkage peaks on chromosomes 7q22–32 [5, 8] and chromosome 17q21 [9, 10, 11] have been replicated. However most linkage signals have not been replicated, despite large increases in sample size, consistent with significant genetic heterogeneity [6•, 12]. Recently, a whole genome association study involving over 3000 cases and more controls combined from different cohorts has identified and replicated at least one locus at genome-wide significance [13••]. This demonstrates the promise of this approach, while at the same time, suggesting that very large sample sizes will be needed to identify additional genetic risk because of common alleles. Currently, there are over 25 different loci that may be considered autism susceptibility candidate genes (ASCG) and many more implicated loci are under investigation [12]. Most of these are rare Mendelian mutations, including copy number variation (CNV) or syndromic forms of autism, and only a few are due to common genetic variation. In this brief overview, we will try to highlight some of the major advances in the study of autism, as well as discuss what the known ASCG can tell us about the neurodevelopmental mechanisms that may be causative.

Section snippets

A phenotypic renaissance

During the 1970s, psychiatric disorders were defined as deviations from the normal spectrum of behavior, but owing to practical and economic factors, diagnostic schemes eventually became highly categorical. This categorization, while necessary from a clinical and educational standpoint, resulted in large groups of heterogeneous patients with diverse etiologies being defined by a single terminology. This clinical diagnostic schema based on the DSM was the primary means of phenotypic

The genomic revolution

Structural chromosomal variations, including CNVs, have been shown to play an important role in the etiology of ASD [24••]. De novo CNVs, hypothesized to be ASD-specific, have been identified in up to 7–10% of sporadic ASD [24••, 25]. De novo CNVs are less frequent in multiplex families, occurring only in about 2% of families screened [24••, 26•], possibly suggesting different genetic liabilities in simplex and multiplex ASD. Recurrent CNVs at 15q11–13 (1–3% of ASD patients), 16p11 (∼1% of ASD

Candidates and compatriots

Epistasis is a basic and ubiquitous genetic paradigm well known within the developmental biology community. With the advent of large protein–protein interaction maps, full genome expression profiles and large-scale computing resources, network and pathway analyses offer promise of dealing with autism's complexities. Iossifov et al. [33••] utilized the idea that interacting proteins involved in linear signaling pathways would have a similar chance of being involved in the etiology of ASD. By

Continuing quandaries

Despite great advances in the genetics of ASD, there are still many major unanswered quandaries two of particular interest are: the basis of the skewed sex ratio and the effect of the environment on ASD. Early studies demonstrated that males are diagnosed with ASD four times as often as females, and gender skewing becomes more pronounced in high-functioning autistic and Asperger's patients as the ratio approaches 10 males to every 1 female [38]. Some of the gender bias might be explained by a

Synthesis of an integrated model

We have recently discussed genetic models for the etiology of ASD [43] and provided a neurodevelopmental synthesis of autism that is based on altered connectivity between higher order cortical association areas (“Developmental Disconnection”), especially anterior frontal and temporal lobes [44]. Anatomical evidence suggests that during the first three years of life, the trajectory of brain growth is elevated in ASD, head circumference increasing from approximately normal to 10% larger than

Conclusion

In this brief overview, we have outlined how genetic advances have led to a new level in understanding ASD etiologies. Genomic tools allowing for the identification of de novo and heritable CNVs have so far contributed the most to our understanding of ASD, explaining about 10% of sporadic ASD. The analysis of comorbid phenotypes and endophenotypes also provides a promising avenue of investigation, as indicated by the association of common variants in CNTNAP2 with language endophenotypes in ASD

References and recommended reading

Papers of particular interest published within the period of review have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We sincerely apologize to our colleagues and scientists who have contributed greatly to the literature discussed here, but owing to space restrictions were not cited. We would like to thank Dr Brett Abrahams, Dr Brent Fogel, Dr Shaohong Cheng, Li Hong, and Dr Genevieve Konopka for the critical reading of this manuscript. This work is supported by the National Institute of Child Health and Human Development (BRB, NIH T-32 HD0703230), Autism Speaks, and the National Institute of Mental Health

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