Slide 1

Genes, Environments and Human Development, Health and Disease (GEHDHD) Geneticists are interested in the NCS We invited 25 scientists & almost all decided to participate Geneticists are excited by potential of NCS With prospective, repeated measures from before birth and large sample critical GxE by Time issues can be evaluated Geneticists can advance new areas by using NCS Ideas generated from developing areas (complexity of genome, systems biology, epigenetics, mtDNA, evolutionary biology, and others now emerging) can be evaluated Slide 2 Organization of GEHDHD Meeting Additional group of eminent scientists Many eminent scientists already participated and we wanted new expertise at this point to build upon what had already been established Topics defined by participants expertise Presentations were on scientific topics rather than about existing set of NSC hypotheses Discussion of basic concepts & development Discussion encouraged focus on GxE interactions with processes of development Slide 3 2-Day GEHDHD Meeting: Participants and Topics Day 1: Hood (Systems Biology) Wadhwa (Fetal Adaptation) Sing (Analysis of Complexity) Cox (Genetic Epidemiology) Kramer (Cohort Design) Simhan (Fetal Medicine) Ayala (Evolutionary Biology) Wallace (Mitochondria) Feinberg (Epigenetics) Haig (Conflict in Evolution) Moyzis (Positive Selection) Day 2: Hartwell (Biotechnology) Gillman (Fetal Origins) Meaney (Maternal Nurturing) Jirtle (Imprinting) Cooper (Exercise) Murray (Clefting & Preterm Birth) Lanphear (Biomarkers) Posner (Attention & Development) Cheverud (Parent of Origin) Templeton (Ancestry) Procaccio (Positive Selection) Slide 4 National Childrens Study Sample All Births in the Nation Sample of Study Locations Sample of Study Segments Sample of Study Households Sample of Study Women 105 Locations (counties) Selection of neighborhoods All or a sample of households within neighborhoods All eligible women in the households - ~1.5 million ~4 million births in 3,141 counties Sample of Study Children 105,000 births Slide 5 NCS Schedule of Contacts or Visits 16 face-to-face contacts over 21 year study period Contacts most frequent early in the study Between visits: ongoing data collection by phone, PDA, etc. Enrollment 18 months 1 st Trimester 3 years 2 nd Trimester 5 years 3 rd Trimester 7 years Delivery 9 years 1 month 12 years 6 months 16 years 12 months 20 years Slide 6 Group Recognized Strengths of NCS Representative & large sample Provides power to assess GxE & GxG interactions in complex disorders Prospective assessment starting early Assess adaptation of structures that have long-lasting effects Repeated observations over time Phenotypes defined by trajectories over time and individual as control Reciprocal relationship based on feedback Observe environmental effects that then affect environment Comprehensive exposure measures in all participants In separate cohorts chance to evaluate interactions is lost Comprehensive outcome measures in all participants Assess risks, precursors, & origins of later disease and GxE interaction Slide 7 Group Recognized Opportunities Genetics should be part of every hypothesis In example 29 only two were genetic but all are GxE Great repository of stored samples for future use GxE & GxG models using appropriate complex assumptions Considering genetics in two entities & genomes that interact Adding genetics to developmental origin hypothesis Providing evolutionary context for gene sequence Set of genes based on concepts as well as pathways Opportunity to test proof of principle studies Use of molecules in blood to evaluate body & brain Epigenetic & mitochondrial genetic change over time Slide 8 Impact of public policy and programs on child health Impact of media exposure on child health and development Social institutions and child health and development Impact of neighborhood and communities on child health Family influences on child health and development Psychosocial Exposure Genetics, environmental exposures, and Type I Diabetes Gene Environment Interactions and Behavior Genetics Chemical environmental agents and the endocrine system and age at puberty Impact of neighborhood environment on risk of obesity and insulin resistance Fiber, whole grains, high glycemic index and obesity, insulin Breastfeeding associated with lower rates of obesity and lower risk of insulin resistance Obesity and insulin resistance from intrauterine growth restriction Obesity and insulin resistance from impaired maternal glucose metabolism Obesity & Growth Early exposure to bacterial and microbial product decreases risk of asthma Disparities in asthma and physical environmental risk factors, psychosocial stress, and HRBs Dietary antioxidants and asthma risk Indoor, outdoor air pollution and asthma risk Infection expos early in life and increased risk of asthma Environmental exposures and genetic variation interactions and asthma Impact of maternal stress during pregnancy and risk of asthma Asthma Behavioral exposures and adolescent-onset physical aggression Behavioral exposures, genetics, and early onset physical aggression Repeated head trauma and neurocognitive development Injury Prenatal and perinatal infection and schizophrenia Prenatal infection and neurodevelopmental disabilities Non-persistent pesticides and poor neurobehavioral and cognitive skills Neuro- development & Behavior Increased risk of birth defects and developmental disabilities in children born through ART Increased risk of preterm birth from intrauterine exposure to mediators of inflammation Birth defects from impaired glucose metabolism Pregnancy Outcomes http://nationalchildrensstudy.gov/research/hypotheses/hypotheses_list.cfm Class Plus GxE Slide 9 Use of molecules in blood to evaluate body & brain: Hood and Hartwell Assume & anticipate technological developments Efficient sequencing of each persons genome will avoid reliance on current sets of markers (SNPs) Efficient measurement of all molecules in a blood sample will provide information on gene products from most organs of body Store & annotate repeated samples over time Use nested case-control design and repeated samples to allow efficient backtracking of changes from healthy to diseased state Use change over time to reduce dimensionality of the data due to individual differences in genotype and phenotype Use databases & multivariate analyses Evaluate sets of genes in networks by using large databases of accumulated information on gene pathways Evaluate change over time in complex networks that may be different across individuals Slide 10 Slide 11 Dynamics of a Brain Perturbed Network: Prion Disease in Mice Slide 12 Disease Arises from Disease Perturbed Networks Non-Diseased Diseased Hood and Hartwell emphasized the importance of within- individual change over time for the reduction of the dimensionality of data and characterization of the fundamental network properties that are similar across individuals but may be the result of different interactions and combinations of factors in different individuals. Slide 13 Epigenetic & mitochondrial genetic change Feinberg, Meaney, Jirtle, Cheverud, Wallace Epigenetics marks and mtDNA are not fixed for lifetime Methylation & chromatin structure affect what DNA does by imprinting and other mechanisms Over the course of development, epigenetic change and mtDNA change can occur and have large effects Environmental effects are documented Maternal diet affects imprinting of agouti gene and appearance & size of Agouti mouse (Jirtle) Maternal-infant interaction affects imprinting of genes and affects stress response (Meaney) Conditions at conception (in ART), during pregnancy, and in infant development may affect epigenetic status (Feinberg) Germ mutations associated with diseases and accumulation of somatic mutations affects energy utilization (Wallace) Multiple measures over time should be taken Maternal and paternal epigenotype and mtDNA genotype should be used to evaluate parent of origin effects (Cheverud) Multiple measures over time should be obtained to document if & when change (methylation) or mutations (mtDNA) occur Slide 14 DNA methylation serves as an interface between the dynamic environment and the fixed genome C - methylation 5' CpG region of NGFI-A/RE High Low Days of Age Licking/grooming C T A C G T A C T C G G A A T C T C G CH 3 3 3 Meaney: DNA methylation serves to imprint social factors, such as maternal behavior, upon the offsprings genome Slide 15 Jirtle: Methyl Donor Supplementation Viable yellow Agouti (A vy ) Locus Waterland et al. Mol. Cell Biol. 23: 5293-5300, 2003 Pseudo- agouti Heavily Mottled Slightly Mottled Yellow 50 40 30 20 10 0 A vy Offspring (% of Total) Control Diet Supplemented Diet (Folic acid, Vitamin B 12, Choline chloride and Betaine) p = 0.008 Pseudo- agouti Heavily Mottled Slightly Mottled Yellow 3 4.1 Kb 5 1APS1A2 ~100 Kb A vy A, a IAP 5 ~15 Kb 3 Slide 16 BWS is linked to an imprinted gene domain on 11p15 LOI of LIT1 (40%) and IGF2 (15%), Paternal UPD (10%) Mutation of p57 KIP2 (5%). Chromosomal rearrangement (1%) Beckwith-Wiedemann Syndrome (BWS) as a Model Disorder for Cancer Epigenetics Prenatal overgrowth, Macrosomia, organomegaly, Pancreatic islet cell hyperplasia, Neonatal hypoglycemia, Macroglossia, Abdominal wall defects, Dysmorphic, Embryonal tumors (Wilms) IGF2 K V LQT1 p57 TSSC5H19ASCL2NAP2 TSSC3 TSSC4 TSSC6 LIT1 Slide 17 Threshold Expression (CNS, heart, etc.) High Mutation Rate (germ line & somatic) Principles of Mitochondrial Genetics Maternal Inheritance Replicative segregation & heteroplasmy Slide 18 Considerations for Design and Analysis Sing, Cox, Murray, Kramer, Wadhwa, Gillman, Lanphear Genetic heterogeneity will be great Genotypes with large effects are rare & with small effects are common Genetic epidemiology and reciprocity Environmental effects feedback & affect gene-environment interaction Phenotype is defined over time as a trajectory Developmental origins and fetal adaptive response initiates journey Optimal cohort design includes relatives Information on relatives allow for additional analyses of affected relatives & evaluation of parent of origin effect (maternal G & E) Size of cohort depends on burden & resources Large/thick & small/thin cohorts have been established to address different questions about change over time Slide 19 Developmental Origins & Fetal Adaptation Wadhwa, Gillman, Lanphear, Sing, Cox, Templeton GENOTYPE (Conception) HEALTHY DISEASED Potential to react DISEASED PHENOTYPE (Age 63) Nested Case-Control Comparisons Early environment Later outcome Asthma & GSTMI ADHD & DAT Birth Weight & GSTTI Bhargava, et al., NEJM 2004 thrifty genotype & thrifty phenotype Barker Hypothesis Slide 20 Genes, Environments and Human Development, Health and Disease: Issues and Challenges Which genetic factors should be evaluated? Which environments should be targeted? Which developmental processes are most critical? at what periods of time? in which tissues? Slide 21 Theme 1: Technology and Biology Hood and Hartwell Assume & anticipate technological developments Store & annotate repeated samples over time Use databases & multivariate analyses Slide 22 Theme 2: Epigenetics & mtDNA Feinberg, Meaney, Jirtle, Cheverud, Wallace Epigenetics marks are not fixed for lifetime Environmental effects are documented Multiple measures over time should be taken Slide 23 Theme 3: Maternal-Fetal Environment Gillman, Wadhwa, Simhan, Cheverud Developmental origins of health and disease Fetal adaptive response and environment Fetal environment and timing of events Parent of origin effects Slide 24 Theme 4: Evolutionary Biology Ayala, Moyzis, Haig, Procaccio, Templeton Positive Selection and set of gene Evolutionary Conflict Ancestry and Thrifty Genes Geographical Variation in mtDNA Evolutionary Biology and Social Behavior Slide 25 Theme 5: Design and Analysis Sing, Cox, Murray, and Kramer Genetic heterogeneity will be great Genetic epidemiology and reciprocity Optimal cohort design includes relatives Size of cohort depends on burden & resources Slide 26 Theme 6: Infant & Child Development Cooper, Lanphear, and Posner Exercise and growth The new morbidities and low exposures Development of brain networks and attention