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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 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? • How do we operationalize Gene X Environment Interactions? • Ethical implications of NCS Genomics Research • Summary & list of NCS Genomics Investigators
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
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
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
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
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
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
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?
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)
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
NCS Genomics Research THANK YOU!
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
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
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)
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
The National Children’s Study Data Collection related to Glucose Metabolism • HbA1C @ pre-pregnancy & 1st trimester • Glucose, insulin, IGF, & IGF-BP3 @ 3rd trimester