This new FOA requests submission of applications for the National Institute on Aging (NIA) Late Onset of Alzheimer’s Disease (LOAD) Family Based Study (FBS). Analysis of families that are multiply affected with Alzheimer’s disease (AD) provides distinct advantages for characterizing the impact of genetic variants on disease risk. First, multiplex families are likely to be enriched for genetic variants associated with increased risk, providing increased statistical power to estimate the effects. Second, analysis of multiply affected families provides insight into the remaining unknown genetic influences (i.e., the “residual heritability”) as well as antecedent modifying factors that interact with identified genetic variants to influence disease risk. Third, family members at risk are followed at regular intervals, facilitating prospective investigation of the effects of the genetic variants on age-at-onset as well as the modifying effects of antecedent risk and protective factors. Finally, family data can provide information regarding the influence of known variants on the rate of disease progression and the residual heritability of disease progression.
The NIA LOAD FBS began in 2003 with the collection and longitudinal follow up of large multiply affected families under individual NIA investigator awards. Funded investigators developed, refined, and circulated a procedure manual for the collection and follow up of families with AD that is still in use. In this initial phase 1,885 samples from 422 families were collected. A cooperative agreement to continue this collection was funded in 2005 to complete the collection of 1,000 new families, recruit appropriate members in existing families, and initiate and complete follow-up in all participating families. The Center for Inherited Disease Research (CIDR) genotyped the first 500 families; data were deposited into the Database of Genotypes and Phenotypes (dbGaP) for broad sharing with the genetics community. At the conclusion of the cooperative agreement, investigators had created a resource of 1,000 well-characterized families with LOAD. Sample acquisition and longitudinal follow up has continued under an R01 that was funded simultaneous with the launch (2012) of the Alzheimer’s Disease Sequencing Project (ADSP).
The ADSP Discovery Phase included the sequencing of 583 subjects from 111 multiply affected families (three or more) drawn largely from the NIA LOAD FBS. The criteria and standards employed by the NIA LOAD FBS were adopted by the ADSP. The ADSP Discovery Extension Study (2015-2016) includes whole genome sequencing (WGS) on up to 500 individuals from multiply affected families. The ADSP Follow-Up Phase (2016-2021) will heavily engage resources provided by the NIA LOAD FBS and will depend upon the longitudinal follow-up of families and the collection of additional families, in particular those from diverse populations. The characterization of additional relatives with ascertainment of antecedent risk factors, and recruitment for autopsy will benefit the field by expanding the scientific value of the NIA-LOAD FBS. Numerous investigators outside of the ADSP are also using DNA from the NIA LOAD FBS.
NIA LOAD FBS DNA samples are provided to the National Cell Repository for Alzheimer’s Disease (NCRAD) at Indiana University, which makes the samples and phenotypic data broadly available to the research community. Clinical data are collected in a uniform fashion as the NIA-LOAD FBS developed specific criteria for the inclusion of families with LOAD and has used standardized methods to identify affected and unaffected individuals across the NIA-funded Alzheimer’s Disease Centers (ADCs).
As an essential research resource, the NIA LOAD FBS acts as the key provider of the DNA and clinical data on large multiplex families for the ADSP, the Alzheimer Disease Genetics Consortium (ADGC), the Consortium for Alzheimer’s Sequence Analysis (CASA), and the network of NIA sponsored Alzheimer’s Disease Centers (ADCs). Other ongoing collaborations include the NIA Cell Repository for Alzheimer’s Disease (NCRAD), the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), and the National Alzheimer’s Coordinating Center (NACC). The NIA LOAD FBS works closely with the NHGRI- funded Large Scale Sequencing and Analysis Centers (LSAC), the Data Base for Genotypes and Phenotypes (dbGaP), the National Human Genome Research Institute (NHGRI) and other NIH Institutes and Centers (ICs). The NIA LOAD FBS has developed working relationships with all of these entities. Future success depends on keeping the relationships together. Thus, an important aspect of the function of the NIA LOAD FBS is to continue to coordinate with NCRAD, NACC, NIAGADS and dbGaP and to provide infrastructural support in the form of DNA and clinical data for the ADGC, CASA, ADSP, and other NIA-funded genetic studies such as the ADSP Discovery Phase, the ADSP Follow-Up Phase Analysis Studies, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), and other multiple- and single-site studies that involve the collection and storage of DNA and phenotypic data for genetic research on AD.
The NIA LOAD FBS should continue providing overall support for the ADSP family based studies and analysis and for investigators outside of the ADSP. The NIA LOAD FBS should have the ability to assess subjects for AD status at sites inside and outside of the United States in diverse populations; to acquire new DNA from large multiply affected families and provide these samples to NCRAD; to coordinate DNA receipt, processing, and storage; to share data related to families in keeping with appropriate informed consent; and to analyze genetic, genomic, and phenotypic data. It should devise plans for working with a range of stakeholders including government, academic scientists, industry, and data-management experts including but not exclusive to NACC; NCRAD; the Alzheimer’s Disease Neuroimaging Initiative (ADNI); the Accelerating Medicines Partnership-Alzheimer’s Disease (AMP)and AMP-AD Sage Bionetworks (SAGE).
It is expected in the coming five-year funding period that the NIA LOAD FBS will expand its scope to ensure that up to ~2,000 families (~8,000 subjects) are available to the AD genetics community for analysis to meet the needs of genetic/genomic research on AD with an emphasis on deep endophenotypes. The NIA LOAD FBS will act as a comprehensive resource to enhance the scientific community’s ability to better understand how the Alzheimer’s genome can affect risk for and protection against disease. Community outreach is an important aspect of the overall activity of the NIA LOAD FBS. Sample and data sharing, effective work flow management, and protocol standardization are expected to play a significant role in the success of these activities as an Alzheimer’s community research resource to enhance rapid discovery of therapeutic approaches for AD. The rationale for continued study of multiply AD affected families should be clear. Families selected for further study should be carefully chosen and selection criteria well defined.
Under this funding opportunity announcement, in the next five years the NIA LOAD FBS should:
- Follow-up existing families to confirm current or past diagnoses, documenting any changes in diagnoses and recruiting new family members within these families;
- Phenotype and genotype (GWAS and/or exon chip) all new family members;
- Recruit offspring of the proband generation for each of the existing families, and phenotype and genotype (GWAS, exon chip, or a related approach) offspring;
- Recruit new families from other ethnic groups (3 or more affected per family) including but not exclusively African American, Afro-Caribbean, Mexican American, Central and South American, and Asian populations;
- Create a repository of biological resources for follow-up of genetic studies in order to develop biomarkers and induced pluripotent stem (iPS) cells: peripheral blood mononuclear cells, plasma and serum, and cerebrospinal fluid (CSF);
- Augment the repository of autopsy material for diagnostic accuracy and for follow-up of genetic variants, coordinate the deposition of samples from new individuals and their phenotype and any genotype data to NIAGADS;
- Facilitate the disposition of DNA and other biological material to NCRAD for use by the greater scientific community;
- Facilitate the discovery of genetic factors that may lead to the development of new therapies to prevent and treat the disease.
- Engage in community outreach to help bring new subjects into the NIA LOAD FBS.
In summary, this FOA addresses NIA’s vital need for well-coordinated acquisition and handling of DNA and related clinical data from large multiply affected AD families. The NIA is committed to facilitating the collection, storage, and sharing of DNA and related data from large multiplex AD families for research in the area of the genetics of AD. The NIA LOAD FBS is a critical facet of the NIA Alzheimer’s Disease Genetics Initiative that effectively leverages the investments already made related to the etiology of AD. Applications considered for funding should effectively leverage the investments already made related to investigation of the core causes of the disease. The research resource should provide a large sample set of DNA and related phenotypic data for broad use by the research community. The research resource of families forms the core of the Family Based Study for the ADSP and is a central component of NIA funded infrastructure that supports the project to inform investigators about the genetic penetrance and heritability of the disease based on the genetic variants already discovered in families multiply affected with AD.
Deadlines: standard dates apply
Filed Under: Funding Opportunities