SFARI scientific perspectives

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Last modified: November 11, 2019

The landscape of autism research has changed dramatically since SFARI issued its first request for applications in 2007. It is now truly a multidisciplinary field, attracting top researchers from around the world. Since 2007, SFARI has committed more than $480 million in external research support to more than 550 investigators in the U.S. and abroad in service of our mission: to improve the understanding, diagnosis and treatment of autism spectrum disorders by funding innovative research of the highest quality and relevance.

The SFARI science team often gets asked some version of the question, “What kind of science is SFARI likely to support?” Unfortunately, this is an impossible question to answer given the complexities and multidisciplinary nature of the field and our inherent uncertainties about where the next major advance may come from. That said, we want to be as transparent as possible with researchers, whom we view as partners in this quickly moving and challenging field.

Below are our views on various scientific topics, many of which we’ve expressed in previous blog posts. Given the importance of these views in guiding our funding process, we feel these perspectives deserve a more lasting place on our website. We view this page as a living document, one that we plan to update as the science and our viewpoints evolve.

As an overarching principle, we are particularly interested in projects that try to bridge different levels of understanding, especially by connecting insights from genes to molecular mechanisms to neural circuits to behavior. The causes of autism are almost always multifactorial but given the recent advances in the understanding of genetic risk for autism, we feel that working within a “genes to biology to behavior to therapeutics” framework provides a rigorous and tractable way forward for now. For an overview of why the genetics is bedrock, see SFARI Investigator Matthew State discuss the current state of autism genetics.

As a first step, when preparing a proposal, we strongly recommend that applicants familiarize themselves with SFARI’s current and past grant portfolio, as well as SFARI-generated resources. We have put tremendous effort into the development of these resources, and we hope you will take full advantage of the knowledge gained in thinking about how your work might complement, but not duplicate, existing efforts.

Regardless of the exact science proposed, SFARI is deeply committed to producing rigorous, reproducible data that is readily shared with the scientific community. The supposed lack of reproducibility in biomedical science has become a widely discussed topic1, so in support of this important issue, SFARI has created a list of methodological and statistical considerations for potential SFARI grant applicants.

Genetics

The most current estimates of autism risk indicate that approximately 80 percent of the risk results from genetic alterations2. More than 100 genes now have strong evidence implicating them as risk factors for ASD3, and several hundred additional genes have been implicated with lower levels of confidence.

Applicants can find more information about autism candidate genes and evolving community-based gene scores at SFARI Gene, an online database providing a convenient and comprehensive way to become familiar with the genetic landscape of autism. SFARI Gene lists hundreds of genes that have been implicated in ASD by various means but, importantly, also provides a scoring system (with 1 being the highest confidence and 6 being lowest confidence) to rate the strength of the evidence based on a range of criteria. We generally consider strong candidate risk genes (i.e., a false discovery probability under 10 percent) to be those with scores of 1, 2 or S (genes underlying syndromes that are frequently accompanied by an autism diagnosis). You can also find a list of autism-associated genes that SPARK analyzes here, which are genes deemed sufficiently likely to be involved in autism risk that results are returned to the research participants. In the coming weeks, the scoring system of SFARI Gene will be simplified, and those genes with the strongest support (category 1) will be essentially identical to those on the SPARK gene list.

With such large numbers of candidate genes, the research community will need to replicate results from the Simons Simplex Collection (SSC) and other collections in larger populations. Toward this end, SFARI has sponsored SPARK, a program with the goal of recruiting and generating exome sequences for 50,000 families with autism4. We anticipate that SPARK will continue to drive risk gene discovery in autism5 and will also enable the development of robust polygenic risk scores for the first time. While an exhaustive characterization of the genetic landscape of autism is probably neither feasible nor necessary in the short term, a better understanding of each class of genetic risk variant — from small to large and from common to rare — is an important goal, keeping in mind that de novo and familial influences likely contribute to some extent in every case6.

Given SFARI’s extensive investments in the genetics of ASD to date, prospective applicants are strongly encouraged to familiarize themselves with the data available from SFARI-supported cohorts, past genomics-focused RFAs (here and here) and related informatic tools to think carefully about how their research would complement SFARI’s ongoing efforts. Genetic and phenotypic data collected for some of the SFARI-supported cohorts can be requested through SFARI’s central database system, SFARI Base. Researchers planning genetic studies should also be cognizant of other autism gene discovery efforts and be prepared to justify the uniqueness of their proposed studies. We welcome novel and complementary efforts to identify risk variants of any sort and are particularly interested in innovative applications that combine analyses of variants across the allele frequency spectrum.

From genes to biological mechanisms

Given that a clearer picture of the landscape of autism genetics is now emerging, we prioritize science that increases our understanding of how alterations in particular ASD risk genes cause changes in cells and circuits, especially pathways and circuits that are likely to be evolutionarily conserved in humans.

Published network analyses3,7 have reached a consensus that most (though certainly not all) ASD risk genes cluster broadly into the categories of regulators of gene expression (transcription factors, chromatin modulators, RNA-binding proteins, genes involved in protein modification) and regulators of synaptic function. Other, smaller clusters of genes seem to have important roles in cytoskeletal biology and cell migration. In addition, several groups have reported enrichment of ASD risk genes in particular intracellular signaling pathways8-10, including Wnt, Notch, PI3K/AKT, ERK and mTOR.

The first network analyses incorporating brain gene expression data11,12 suggested that many of these risk genes converge on mid-fetal glutamatergic neurons. It’s important to remember that these results were based on a fraction of the risk genes we now have in hand. Nonetheless, subsequent analyses based on larger datasets and orthogonal methods have confirmed and deepened this finding: specifically, that disruption of many ASD risk genes is likely to have very early developmental consequences for neurogenesis.

As it happens, studies of any number of mouse lines carrying mutations in ASD risk genes have likewise identified early disruption in the timing and execution of neuronal differentiation from the proliferating population of neural progenitors13-27. Moreover, there is at least some evidence that this is not likely to be a rodent-specific phenomenon. For example, human induced pluripotent stem cell (iPSC) lines derived from individuals with idiopathic ASD and macrocephaly have a common phenotype: the premature appearance of a gene expression program that promotes neuronal differentiation28.

Disruption of the orderly progression of neuronal differentiation therefore emerges as a potential point of convergence across multiple ASD risk genes as well as idiopathic ASD and deserves to be investigated into more detail. Of course, many questions remain: is it the same types of neurons that show changes in their proliferative progression? Which cellular mechanisms lead to those changes? And what are the consequences of early disruption of timing and execution of neuronal proliferation for neural circuits function later in life?

The range of other ASD risk genes with acute effects on synaptic biology, dendritic spine development, axon guidance29-31, or other core aspects of neuronal function are of equal interest to SFARI, and we also encourage applications that explore how mutations in this set of genes leads to changes in circuitry and behavior that are characteristic of ASD.

Given that many of these biological effects occur early in development, at prenatal or neonatal stages, when intervention options are limited, it will be important to determine whether there are downstream phenotypes that may be amenable for intervention. These potentially malleable phenotypes may come in the form of convergent molecular, circuit, and systems-level effects. We welcome applications that address potential therapeutic mechanisms and their developmental windows of opportunity.

Choosing an experimental system

Experimental systems, such as rodents, DrosophilaC. elegans, zebrafish, nonhuman primates, postmortem tissue and iPSCs — provide critical platforms to explore the molecular, cellular and circuit mechanisms underlying ASD. SFARI is open to using these and other compelling organisms/systems for autism-relevant studies.

SFARI emphasizes construct validity over face validity when choosing an experimental system; we prioritize proposals that start with an experimental system that recapitulates a mutation in a risk gene or an epidemiological factor that can be linked to ASD with high confidence. For rodent models in particular, behavioral resemblance to the human disorder (e.g., in the BTBR mouse strain) — such as social interaction deficits or repetitive behaviors — can be a useful functional readout of the function of the underlying circuits in that species, but such behavioral phenotypes on their own do not have sufficient etiological validity to constitute a strong autism model. As discussed in a recent NIMH Workgroup on Genomics Report, it may be superficial and misleading to accept phenocopies of human characteristics as predictive endpoints for translation.

SFARI is continuing its efforts to make mouse, rat and iPSC models of high-risk autism genes and copy number variants identified in human genetic studies available to researchers. For a list of mouse and rat models currently available because of SFARI efforts, please visit our autism mouse and rat model websites. For more information on available iPSC lines, how to request them and our perspectives on experimental considerations, please visit our iPSC models page.

In addition to rodent and cellular models, SFARI makes postmortem human tissue available through the SFARI-funded Autism BrainNet, a collaborative network for the acquisition of postmortem brain tissue for research.

Studies of human subjects

For work in the clinical realm, SFARI prioritizes research that is grounded in biology. Although we recognize the value of other types of research, such as optimizing behavioral interventions, we hope that, over the long term, focusing on biological mechanisms will lead to effective interventions.

We encourage the use of noninvasive methods, such as magnetic resonance imaging (MRI), electroencephalography (EEG), and magnetoencephalography (MEG), to interrogate the human biology of autism, rather than for merely descriptive purposes. Such approaches can help advance ‘forward’ translation to biomarkers and objective outcome measures as well as ‘back’ translation to studies of neural mechanisms in experimental systems.

It should be noted, however, that given the heterogeneity of ASD, we place a premium on the use of sufficiently powered and well-characterized cohorts. We’ve learned from our own efforts as well as the experiences of previous grantees that recruitment and retention is far more difficult, time-consuming and costly than many researchers anticipate. Therefore, we recommend that researchers should strongly consider collaborating with an existing team or teams (i.e., multi-site recruitment) that already have a study group(s) and pay careful attention to ascertainment biases that can influence the results.

We also believe that it is no longer sensible to study individuals with ASD without knowing something about their genetic background or, at a minimum, including a collection of biospecimens for future studies and analyses. We will work with investigators who need advice about such logistics while preparing their applications.

Examples of well-characterized cohorts include the SFARI-supported SSC, Simons Searchlight and SPARK; genetic data is available (or will be forthcoming) for all or many of these participants. In addition to genetic data, multiple other types of data and biospecimens are available for those cohorts (medical history, psychometric testing, brain imaging, cell lines, etc.). SPARK in particular has an active research match program, allowing researchers to apply to recruit its more than 85,000 participants with ASD. We encourage researchers interested in recruiting SFARI cohort participants for their own studies to familiarize themselves with the research match process and to contact collections@sfari.org to learn about the availability of individuals suitable for the proposed study.

We hope this webpage provides the community with some insight on our evolving scientific perspectives and priorities. We welcome constructive feedback (sciencerfa@simonsfoundation.org) and we will continue to update this page as new information and additional resources become available.

References

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