Over the course of a year, the SFARI Gene scoring advisory panel carefully reviewed published literature on the genetics of autism in an effort to establish criteria for assessing the strength of the evidence linking candidate genes to ASD. Given the complex and wide-ranging nature of the data, which encompasses both rare and common variant approaches, there are many different ways researchers could have chosen to grade these genes. Our goal was to come up with a sensible set of rules to assess the relative value of sample size, statistical significance, replication, functional evidence, and other kinds of data that exist for each gene.
We set out with three guiding principles. First, our emphasis would be on evidence from human genetics. While functional studies will eventually be of great importance, and knockout mice will be of great value, we considered the gold standard for relevance to autism to be the study of genotypes in human cohorts. Second, we started with no assumptions about individual genes, finding, in fact, that the evidence for many “high profile” genes is surprisingly weak. Finally, we emphasized the importance of community feedback as a way to improve the scoring criteria and the scores themselves.
Although the annotation criteria may seem complex at first glance, they can be usefully summarized as follows:
We recognized that genes predisposing to autism in the context of a syndromic disorder (e.g., fragile X syndrome) should be placed in a separate category (S). Any such genes that also have evidence implicating them in idiopathic autism will have a number in front of the S indicating the strength of that evidence (e.g., 3S, which would be listed both in the S category and in category 3).
Category 1(High confidence)
Category 2(Strong candidate)
We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.
Category 3(Suggestive evidence)
Category 4(Minimal evidence)
The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of “accessory evidence” (indicated as “acc” in the score cards) could also boost a gene from category 4 to 3.
Category 5(Hypothesized but untested)
Category 6(Evidence does not support a role)
The list of genes in SFARI Gene is inclusive, and as such there are genes that have been implicated solely by evidence in model organisms or other evidence of a marginal nature. These genes were placed in category 5, as they have not yet been rigorously tested in a human cohort. Category 6 is for those genes that have been tested in a human cohort, but the weight of the evidence argues against a role in autism.
Users will note that less than 10% of the genes fall into categories 1 and 2. For both common and rare variants, with a relatively modest but growing number of exceptions, sample sizes are currently too small to reliably detect true associations. Over the next few years, we expect the combination of larger collections, deep resequencing efforts, and relatively inexpensive genotyping platforms to help change this.
Finally, it's important to note that there is much still to be done. Additional genes and multi-genic copy number variants will be continuously curated, scored, and added to the database in an effort to constantly improve this resource for the autism research community.