Whole-Genome Analysis for Autism Risk Variants Request for Applications

SFARI mission

The Simons Foundation Autism Research Initiative (SFARI) seeks to improve the understanding, diagnosis and treatment of autism spectrum disorders by funding innovative research of the highest quality and relevance.

Objective and rationale

Grants awarded through this request for applications (RFA) are intended to advance our understanding of the genetic basis of autism, and in particular, to begin to assess genetic variants conferring risk in non-coding regions and in coding regions of the genome that may be less accessible to whole-exome sequencing (WES).

The Simons Simplex Collection (SSC) is a rigorously characterized collection optimized to support the discovery of genetic events that increase risk of developing autism. The collection consists of approximately 2,600 simplex families, all of which have one child with autism, unaffected parents, and in over 80 percent of families at least one unaffected sibling. Analyses based on WES data from the SSC have already identified at least 30 risk genes for autism and have nominated several hundred other genes as strong candidates^1,2.

Whole-genome sequencing (WGS) of the SSC is expected to increase the detection of rare variants of clinical importance. In addition to identifying variants in non-coding regions of the genome, WGS analyses are anticipated to identify novel copy number variants (CNVs) and single nucleotide variants (SNVs) in protein-coding regions that have not previously been detected with WES. Preliminary WGS analyses of a separate group of 40 families (160 genomes) from the SSC compared WGS results with WES data from the same 40 families and support the value of WGS in identifying additional variants of potential clinical significance for autism.

To this end, SFARI has partnered with the New York Genome Center (NYGC) to sequence whole-genomes from the whole blood DNA of 500 SSC quartet families (2,000 genomes at 30X sequence coverage).

SFARI plans to make the alignment and variant call data available to all eligible researchers (i.e., not contingent on funding through this RFA) without delay following standard quality control and data processing steps by the NYGC. The first batch of data will likely be available starting in October 2015, and it is anticipated that 90 percent of the WGS data will be available by January 2016. There will be a publication embargo on whole-genome analyses that prevents submission of manuscripts for publication until SFARI has announced that data generation for the full cohort is finished and has passed quality controls and that a first level due diligence on confirmation of calls is complete.

SFARI will work with successful applicants to make the WGS data (estimated to be about 400 TB) available to their academic or cloud-based computing resources. SFARI understands that validation of prioritized hits is a key part of this project and will coordinate some of this confirmation of de novo calls with awardees and the NYGC.

The current RFA seeks applications from investigators who plan to develop innovative and efficient ways to analyze WGS data from the 500 SSC families.

Proposals of particular relevance to this RFA include, but are not limited to:

• Analyses of de novo and inherited mutations in exomes to identify coding variants not originally identified by WES.
• Analyses of de novo and inherited CNVs that were not identified by WES.
• Identification of non-coding variants associated with autism risk, including the potential development of novel algorithms/tools to analyze intronic and regulatory regions of the genome.
• Comparison of the current dataset with sequencing data from other autism and other neurodevelopmental disorders cohorts (including comparisons with WES data from SSC).
• Analyses of mitochondrial DNA.

Recognizing that successful analyses of such large datasets are likely to require multidisciplinary approaches, we encourage collaborations between investigators with complementary expertise.

Investigators should also note that proposals submitted in response to the RFA are expected to include plans to analyze the entire 500 family sample (rather than a subset of individuals).

Eligibility and collaboration

All applicants and key collaborators must hold a Ph.D., M.D. or equivalent degree and have a faculty position or the equivalent at a college, university, medical school or other research facility. Applications may be submitted by domestic and foreign nonprofit organizations; public and private institutions, such as colleges, universities, hospitals, laboratories and units of state and local government; and eligible agencies of the federal government. Applications may also be submitted by for-profit companies, in which case the funds provided for the grant are to be used only for charitable purposes toward research related to autism spectrum disorders. There are no citizenship or national residence requirements.

If the proposal includes investigators at more than one site, all investigators should have demonstrated prior success in similar collaborations.

Funding period and budget

The grant period is eighteen months. The maximum budget is $250,000 including indirect costs. SFARI may fund a number of projects as a result of this RFA.

Application requirements

Applications should include the following:

1. Narrative, not to exceed six pages (excluding references, figures, and figure legends). Proposals should include specific aims, background relevant to the application, significance of the proposed studies, preliminary results, experimental design, pitfalls and alternative strategies, and a timeline with milestones.
2. Biosketches for Principal Investigator(s) and Key Collaborators.
3. Current and pending support for Principal Investigator(s) and Key Collaborators.
4. Budget. The maximum budget is $250,000, including indirect costs. Exceptions with good justification will be considered but are not encouraged. Proposals should include a realistic budget sufficiently detailed for evaluation of needed resources. SFARI will work closely with investigative teams with competitive applications to arrive at a suitable budget. Indirect costs are limited to 20 percent of the modified total direct costs (see SFARI policies).

Applicants should detail a strategy and estimate a budget for confirmation of prioritized hits. But note that SFARI will coordinate and fund directly some of the validation for SNPs in a centralized fashion at the NYGC.

Applicants should detail a strategy and estimate a budget for computing costs (either cloud or academic computing facility). SFARI will pay directly for cloud storage costs so these costs need not be included.

Applications with multiple Principal Investigators from different institutions that would like to be paid separately must include a signed budget template and budget justification for each Principal Investigator’s institution. Applications with subcontracts must include a budget and budget justification. The budget template and budget justification are available for download in the proposal attachments section of proposalCENTRAL’s full application.

1. Research environment and resources. Investigators should demonstrate access to appropriate resources for high-capacity data analysis and computation.
2. Data-sharing plan. The plan should include the sharing of all analyzed data in addition to sharing any new algorithms/data visualization tools that are a direct result of this award. SFARI will work closely with awarded investigative teams to ensure that the plan includes timely dissemination of data.

For more details, see the Instructions document, which is available for download in the “Proposal Attachments” section of proposalCENTRAL.

Application deadline

We request that investigators who intend to submit a proposal send an email by 28 July 2015 with the intended investigators’ names and affiliations and their intended proposal’s title to grants@simonsfoundation.org with the subject line: SFARI WGA RFA Notice of Intent.

The deadline for full proposal submission is 14 August 2015. No extensions will be given. If you have any difficulties, please contact grants@simonsfoundation.org.

Competitive applications will receive external peer review. SFARI will make final funding decisions; notification of award is anticipated by 15 October 2015, with funding expected to begin 1 November 2015.

Instructions for submission

Applications must be completed electronically and submitted using forms provided at proposalCENTRAL. Please log in as an applicant, scroll to “Simons Foundation” and click on the program.

Contacts

Scientific inquiries:
sciencerfa@simonsfoundation.org
646-654-0066

Administrative inquiries:
grants@simonsfoundation.org
646-654-0066

SSC collection inquiries:
collections@sfari.org
646-654-0066

proposalCENTRAL:
pcsupport@altum.com
800-875-2562