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Genetics, Genomics, Epigenomics in the NCS

Genetics, Genomics, Epigenomics in the NCS. Carol H. Kasten, MD Geneticist. NCS Genomics Research Overview. Data driven study assessments for Main Study Analysis of Legacy questionnaire and biospecimens Formative Research Projects - what is possible?

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Genetics, Genomics, Epigenomics in the NCS

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  1. Genetics, Genomics, Epigenomics in the NCS Carol H. Kasten, MD Geneticist

  2. NCS Genomics Research Overview • Data driven study assessments for Main Study • Analysis of Legacy questionnaire and biospecimens • Formative Research Projects - what is possible? • How do we operationalize Gene X Environment Interactions? • Ethical implications of NCS Genomics Research • Summary & list of NCS Genomics Investigators

  3. Legacy Data • Integrity and utility of aliquotted DNA, RNA, proteins, tissues • Placental studies including toxicant content • Family History • Current instrument works well • However, Surgeon General’s Office has online tool • Fetal Ultrasound data • Writing group has just formed to analyze data

  4. Formative Research Projects • Dysmorphology Screening Tool • Goal to develop protocol which can be used at the bed or cribside by minimally trained data collectors • Digital photos of face, hands, feet collected • Time to complete will be ~ 30 minutes • Analysis by non-geneticist physician using Dysmorphology Screening Tool software will identify birth defects

  5. Formative Research Projects • Fetal Cells, DNA in blood from Pregnant Moms A new window on human development • Goals • Study changes in fetal epi/genome expression • What cells/DNA/RNA can be recovered currently? • Link with Environmental Exposure data (ultimately) • OMB just approved • Protocol ready

  6. Formative Research Feasibility Projects • Whole Genome Sequencing of 3 NCS family trios completed at University of Washington • First scan (12 genes) – reportable mutations found in all 3 families • Issues with mixed red cell aliquots resolved • Telomere sequencing of same NCS family trios by Elizabeth Blackburn (Nobel Laureate) pending • While waiting for OMB approval • WGS will be done on non-NCS family trios with Autism, ADHD, Prematurity, Bone Density

  7. Formative Research Feasibility Projects • Epigenome, Methylation, ASM, ASE-B Tycko • Placental Epigenome, Histone Modifications-K Aagaard-Tillery • Premature Birth Genomics- J Murray • Pharmacogenomics & Molecular Ancestry • Many more

  8. Operationalizing‘Gene X Environment Interactions’ • Investigate alternative approaches to measure toxicant concentrations • Placenta projects • “Exposome” project with E Faustman • Collect all RNA (including microRNAs) from many sources & times • NCS Protocol modified to make RNA collection frequent & from more than one source if possible • In queue for Vanguard phase-in • Pharmacogenomic data integration with NCS environmental exposures estimates

  9. Ethical implications of NCS Research • Return of Results one of key ethical issues • Formative Research projects underway at U Wash, UCI, & CWRU • How will these influence recruitment/retention? • Depositing WGS in public database • Offering to return ancestry data • How/Do we return results of Genomics of Fertility? • Should we return Incidental Findings?

  10. NCS Research - First Ever Anywhere • Largest number of family trios with complete WGS, 40X coverage • WGS + Complete Telomere sequencing in a family trio (we will have several) • Direct calculation of μ – spontaneous mutation rate (replaces estimate)

  11. NCS Genomics Investigators Incomplete List • U Wash • Debbie Nickerson • Mike Bamshad • Jay Shendure • Evan Eichler • Elaine Faustman • Wylie Burke • Holly Tabor • UCI • Jim Swanson • Pathik Wadhwa • U Iowa • Jeff Murray • UCSF (pending) • Elizabeth Blackburn • Stanford (pending) • Carlos Bustamente • Columbia • Ben Tycko • Baylor • Kjersti Aagaard-Tillery • Pittsburgh • Hy Simhan

  12. NCS Genomics Research THANK YOU!

  13. The National Children’s Study Biospecimen Collections • Mother – blood, urine, hair, nails, saliva, vaginal swab, breast milk • Father – blood, urine, hair, nails, saliva • Child – placenta (sections), cord blood, cord (section), meconium, blood, urine, hair, nails, saliva • All biospecimens are aliquotted and stored • There is no ‘real-time’ analysis of biospecimens

  14. The National Children’s Study • Chemical Exposures classified by “Domain of Exposure,” sub-classified by “Specific Measure” • Allergens (pets, dust, mold) • Carbonyls (formaldehyde, acrolein) • Metals (Pb, Hg, Cd, Mn, Uranium, As) • Gaseous Air Pollutants (ozone, SO2) • Pesticides (carbamates, pyrethroids, atrazine) • VOCs (benzene, chloroform) • ETS • Nitrates • Halogenated Phenols, & more

  15. The National Children’s Study Chemical Exposure Measures divided into • Household & Community samples • Related Data Collection • Biological (blood, hair, nails, urine, breast milk) • Questionnaires • Observation (home, yard, neighborhood, agricultural area)

  16. The National Children’s Study How will Birth Defects be identified? • 1st Trimester U/S • Placenta photos, wt & dimensions, blocks &/or specimens • Dysmorphology Assessment Instrument exam after birth while still in hospital • PE at 6 & 12 months • NUMEROUS physical measurements of pregnant Mo & child throughout

  17. The National Children’s Study Data Collection related to Glucose Metabolism • HbA1C @ pre-pregnancy & 1st trimester • Glucose, insulin, IGF, & IGF-BP3 @ 3rd trimester

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