AutDB: A Modular Database for Accelerating Autism Genetic Research

Background:  A major focus of research in the post-genomic era is to decipher the heterogeneous genetic landscape underlying the pathogenesis of complex human diseases such as Autism Spectrum Disorders (ASD). A number of genes in which rare and/or common genetic variants thought to potentially play a role in ASD onset and pathogenesis have been identified. The advent of new techniques such as next generation sequencing (NGS) has resulted in a significant increase in the number of ASD genes with rare genetic variants. With the accelerated growth of genetic data obtained from ASD individuals adding to the already complex genetic landscape of this disease, there is a critical need for databases specialized in the storage and assessment of this data.

Objectives:  The autism genetic database AutDB (http://autism.mindspec.org/autdb/Welcome.do) was developed to serve as a publically available web-based modular database for the on-going curation and visualization of ASD candidate genes. Since its release in 2007, AutDB has been become widely used by individual laboratories in the ASD research community, as well as by consortiums such as the Simons Foundation, which licenses it as SFARI Gene.  AutDB has been designed using a systems biology approach, integrating genetic information within the original Human Gene module to corresponding data in subsequent Animal Model, Protein Interaction (PIN) and Copy Number Variant (CNV) modules.  We had previously performed functional profiling of a reference dataset of ASD-associated genes (Kumar et al., PLoS One 2011) and decided to utilize an updated reference dataset of candidate genes to identify potentially novel enriched molecular functions and pathways.

Methods:  ASD candidate genes are systemically extracted from peer-reviewed primary scientific literature and manually curated for inclusion in AutDB.  A subset of annotated genes with at least suggestive evidence for a role in ASD was selected for further use in functional profiling analyses.

Results:  The number of ASD susceptibility genes in the Human Gene Module of AutDB has increased from 304 genes in December 2011 to 573 genes in September 2013, which demonstrates both the continued discovery of ASD candidate genes and the ongoing curation of these genes into AutDB. In addition, the usage of NGS techniques has contributed to a dramatic increase in the number of rare variants identified in ASD candidate genes (from 1202 in Dec 2011 to 3399 in September 2013) compared to common variants (from 534 to 812 over the same period). Functional profiling using a subset of annotated ASD-linked genes provides insight into the enriched molecular functions of these genes, including gated ion channel activity, synaptic transmission, axon guidance, and chromatin binding.

Conclusions:  AutDB serves as a valuable resource for understanding the ever-evolving genetic landscape of ASD and provides researchers with information useful in bioinformatics analyses such as those described above that will aid in unraveling the molecular mechanisms underlying the disease.