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 In our most recent, unpublished, analyses of 72,410 individuals from ASD families, we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 neuro-
psychiatric 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 as-
pects 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.
