A systematic variant annotation approach for ranking genes associated with autism spectrum disorders.

Eric Larsen,Alan Packer,Idan Menashe,Mark N Ziats,Sharmila Banerjee-Basu,Wayne Pereanu

doi:10.1186/s13229-016-0103-y

Abstract

BackgroundThe search for genetic factors underlying autism spectrum disorders (ASD) has led to the identification of hundreds of genes containing thousands of variants that differ in mode of inheritance, effect size, frequency, and function. A major challenge involves assessing the collective evidence in an unbiased, systematic manner for their functional relevance.MethodsHere, we describe a scoring algorithm for prioritization of candidate genes based on the cumulative strength of evidence for each ASD-associated variant cataloged in AutDB (also known as SFARI Gene). We retrieved data from 889 publications to generate a dataset of 2187 rare and 711 common variants distributed across 461 genes implicated in ASD. Each individual variant was manually annotated with multiple attributes extracted from the original report, followed by score assignment using a set of standardized parameters yielding a single score for each gene.ResultsThere was a wide variation in scores; SHANK3, CHD8, and ADNP had distinctly higher scores than all other genes in the dataset. Our gene scores were significantly correlated with other recently published rankings of ASD genes (R Spearman = 0.40–0.63; p< 0.0001), providing support for our scoring algorithm.ConclusionsThis new resource, which is freely available, for the first time aggregates on one-platform variants identified from various study types (simplex, multiplex, multigenerational, and consanguineous families), from both common and rare variants, and also incorporates their putative functional consequences to arrive at a genetically and biologically driven ranking scheme. This work represents a major step in moving from simply cataloging autism variants to using data-driven approaches to gain insight into their significance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0103-y) contains supplementary material, which is available to authorized users.

Highlights

The search for genetic factors underlying autism spectrum disorders (ASD) has led to the identification of hundreds of genes containing thousands of variants that differ in mode of inheritance, effect size, frequency, and function
There were 2187 rare variants and 711 common variants in our dataset. These data were retrieved from 889 scientific publications of which 584 (65.7 %) reported only on rare variants, 266 (29.9 %) reported only on common variants, and only 39 (4.4 %) reported on both rare and common variants associated with ASD (Fig. 1a)
Examination of the spectrum of variants in our database revealed that the majority of rare variants associated with ASD are nonsynonymous in the coding region (71.2 %), whereas most common variants are non-coding (88.9 %) (Fig. 1c)

Summary

Introduction

The search for genetic factors underlying autism spectrum disorders (ASD) has led to the identification of hundreds of genes containing thousands of variants that differ in mode of inheritance, effect size, frequency, and function. Autism spectrum disorder (ASD) is a clinical diagnosis defined by neurodevelopmental impairments in two domains: persistent deficits in social reciprocity and communication across multiple contexts, together with restricted, repetitive patterns of behavior [1]. Individuals with ASD can display a broad clinical profile with varying severity in the core symptoms and often accompanied by medical comorbidities. Several epidemiological studies have firmly established a genetic component underlying ASD with heritability estimates ranging from 50–90 % depending on the study parameters [4,5,6]. The ability to screen large cohorts using high-throughput genomic technologies has led to the discovery of hundreds of candidate genes

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Discussion

Conclusion