Examples of ADSP Collaboration with AMP-AD Investigators

• GCAD has processed AMP-AD whole-genome sequence data as part of its joint calling efforts. Processed data have been returned to AMP-AD investigators to be posted on the SAGE Bionetworks website. These data will also be part of a joint-called dataset with ADSP data, which will be released through NIAGADS.
• AMP-AD data were used in Kunkle BW, et al. "Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing." Nat Genet. 2019 https://www.nature.com/articles/s41588-019-0358-2
• ADSP investigators Will Bush and Badri Vardarajan are members of the AMP-AD variant calling working group. The working group is running the existing AMP-AD genomic data through the GCAD pipeline to call variants and working toward developing a TWAS imputation panel for application to ADSP and ADGC datasets.
• The CADRE target prioritization group includes representation from the AMP-AD coordinating center (Ben Logdson). CADRE also has accessed a variety of data from the AMP-AD consortium, which will be integrated into Aim 3 of the CADRE grant (Prioritize Variants and Genes by Integrating Statistical and Biological Information) in consultation with AMP-AD.
• ADSP investigator Lindsay Farrer and Boston University colleague Rhoda Au have been collaborating for 1-2 years with the Duke University AMP-AD project led by Rima Kaddurah-Daouk. Specifically, the BU team is curating existing Framingham Heart Study metabolomics data to replicate AMP-AD findings in other samples. This work is funded through a small sub-K award from Kaddurah-Daouk to BU (Farrer is the sub-K PI). Farrer and Au also have an FHS-approved protocol to perform metabolomic assays in collaboration with Kaddurah-Daouk. This work is partially funded, and additional funding pending.
• Current ADSP investigator Kim Worley(5U01AG058589-02: “Therapeutic target discovery in ADSP data via comprehensive whole-genome analysis incorporating ethnic diversity and systems approaches”) is part of an application with AMP-AD investigator Josh Shulman and NIA funded AD investigator Olivier Lichtarge (5R01AG061105-02: “A knowledge map to find Alzheimer’s Disease Drugs) entitled “Cognitive computing of Alzheimer’s disease genes and risk" in response to NIA PAR-19-269. The team seeks apply novel methods to improve the interpretation of the functional impact of genetic variants associated with Alzheimer’s disease risks.
• Baylor College of Medicine investigator Joshua Shulman (AMP-AD) and investigators at the Human Genome Sequencing Center (ADSP) are working with four other major clinical care institutions in the Texas Medical Center to develop the Houston AD Research Center Consortium to unite clinical, basic, and translational research programs and advance precision neurological care for Houston’s diverse population with dementia. An initial grant application submitted from this group integrates comprehensive neurological evaluation, biomarker-based characterization and molecular omics profiling.
• ADSP investigators at the University of Miami submitted an ADC application with University of Florida AMP-AD investigator Todd Golde. The application scored well. If funded, this would enable closer interactions between the Florida groups.
• AMP-AD investigator Phil De Jager is an MPI on the CHARGE ADSP FUS Analysis U01.
• ADSP investigators at the University of Washington meet regularly with the University of Washington AMP-AD group.
• ADSP investigator Richard Mayeux has collaborated with AMP-AD investigators Phil De Jager and David Bennet. Examples in which the genetic work took advantage of the accumulated resources and data from the AMP-AD work in the ROS/MAP study are provided in the following papers:
  1. Ma Y, et al. "CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease." Aging Cell. 2019 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612647/pdf/ACEL-18-e12964.pdf
  2. Tosto G, et al. "Association of Variants in PINX1 and TREM2 With Late-Onset Alzheimer Disease." JAMA Neurol. 2019 https://jamanetwork.com/journals/jamaneurology/article-abstract/2732175
  3. Zhang X, et al. "A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease." Alzheimers Dement. 2019 https://www.sciencedirect.com/science/article/pii/S1552526018335799?via%3Dihub
  4. Lee S, et al. "Episodic memory performance in a multi-ethnic longitudinal study of 13,037 elderly." PLoS One. 2018 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248922/pdf/pone.0206803.pdf
  5. Vardarajan BN, et al. "Ultra-rare mutations in SRCAP segregate in Caribbean Hispanic families with Alzheimer disease." Neurol Genet. 2017 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570674/pdf/NG2017004986.pdf

  Additional papers are in preparation:

  1. Raghavan NS, et al. Common Variants in RBFOX1 are associated with Brain Amyloidosis (submitted).
  2. Ma Y, Evidence of CpG-related SNPs on loci on chromosome 10 and in the APOE region among Caribbean Hispanics with Alzheimer’s disease (in preparation).
  3. Tang M, et al. Synonymous variants associated with Alzheimer’s disease in multiplex families (in review).
  4. Kunkle BW, et al. Meta-analysis employing the African Genome Resources panel identifies novel Alzheimer disease risk loci and pathways in African Americans (submitted).

  Additional planned collaborative work includes:

  • Transcriptomic analysis—Brain samples from EFIGA, WHICAP, and NIA LOAD are now being analyzed at the New York Genome Center and will be compared with ROS/MAP.
  • Metabolomic analyses—Plasma from EFIGA, WHICAP and NIA LOAD are being collected now and will be compared to ROS/MAP.
  • GWAS of episodic memory performance in a multiethnic longitudinal study of the elderly.