Project Summary/Abstract
The past decade has seen outstanding advances in the genetics of autism spectrum disorder (ASD). Most of
this progress has occurred by the study of rare genetic variation, especially de novo variation, with the Autism
Sequencing Consortium (ASC) playing a central role. The ASC represents a coordinated international effort to
identify ASD risk genes. In our most recent, unpublished, analyses of 72,410 individuals from ASD families, we
identified 185 genes associated with risk (FDR < 0.05). Some of these genes have been linked to a broad
array of developmental disorders, while others have not. Based on these results, we posit that some risk genes
alter the core features of ASD, while creating fewer perturbations to other features of development: discovery
of such genes will provide deeper insights into pathways disrupted in ASD. We will build on this progress by
analysis of sequence data from three resources: ASD subjects and families; subjects with other developmental
and neuropsychiatric disorders; and subjects from population samples. We plan new research focusing on
interpretation of rare variation, including single nucleotide variation (SNV), indels, and copy number variation
(CNV). Our key targets are inherited variants, including X-linked inherited variants, which to date have shown
very little signal, and missense variants, for which signal has been confined to highly conserved substitutions.
We anticipate doubling the number of ASD genes discovered, ~ 400, by increasing the number of families
analyzed and by refined methods to interpret inherited and missense variation. And, in parallel, we expect to
resolve critical aspects of ASD genetic architecture and to unveil key aspects of what makes ASD and its core
features – social deficits and restrictive and repetitive behaviors – different from other neurodevelopmental
disorders. To discover ASD risk genes with a distinct effect on ASD, we have the following specific aims: 1) To
amalgamate existing and emerging whole exome and whole genome sequence data; 2) To develop new
analytical methods and analyze the accumulated sequence data; and, 3) To contrast ASD and other
neurodevelopmental disorder risk genes, examining developmental profiles, cell types implicated, and whether
variants in the same gene differ in how they affect risk for ASD and other neurodevelopmental and psychiatric
disorders. With this new research we will accelerate our overall objective, which is the identification of ASD
genes, thereby facilitating our long-term goal of building the foundation from which therapeutic targets for ASD
emerge. Our rationale is that the identification of genes conferring significant risk to ASD and associated
neurodevelopmental disorders can form the basis of studies to understand pathogenesis, as well as the basis
for novel therapies. Our central hypothesis – formulated based on results over the past decade – is that rare
and common variation contributes additively to risk for ASD, but only certain rare variants confer substantial
risk. The research proposed is innovative, in our opinion, because it uses groundbreaking and novel statistical
methods for identifying risk variants for ASD.
