While human behavioral phenotypes are invariably heterogeneous, an emerging literature supports the supposition that both genetic heritability and environmental influences contribute to behavioral conditions and disorders commonly diagnosed in children. Nevertheless, the pathways by which genetics, as well as maternal stress, depression and anxiety influence childhood behavior remain obscure. Utilizing a publically available, unbiased genome-wide association study (GWAS), we identified polymorphisms in genes associated with measures of childhood conduct problems, inattention, hyperactivity emotional symptoms, peer problems and prosocial behavior in children with ADHD. We hypothesize that maternal mental illness during pregnancy, or its pharmacological treatment, may alter the offspring's vulnerability to later psychopathology and that genetic variation will increase the offspring's risk developing childhood psychopathology. This hypothesis will be tested by examining associations of 1) polymorphisms in evidence-based candidate genes with phenotypes prospectively-evaluated, high-risk children born to women who were mentally ill during pregnancy 2) methylation patterns of those candidate genes in placental tissue with traits and behaviors measured in these children, and 3) the expression of mRNA encoded by those genes in placental tissue. This research proposal along with the didactic coursework and interaction with the multidisciplinary mentoring team provides a training platform designed to accomplish the following training goals: acquiring proficiency with 1) phenotypic characterization and the biological underpinnings of childhood psychopathology 2) the principles of bioinformatics and biostatistics as they apply to the design, conduct, and analysis of family-based association studies and 3) the technical and methodological issues related to methylation and gene expression analysis as they apply to psychiatric genetic research. Upon completion of the proposed project and the formal training described in the education plan, the candidate will have made significant progress towards initiating an independent academic career.

Public Health Relevance

The children of women with mood or anxiety disorders ate at increased risk for the development of psychopathology. The examination of environmental and genetic predictors in prospectively- evaluated children will provide insight into the development of mental illness and will help to identify those requiring intervention.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research & Training (K01)
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Genetics of Health and Disease Study Section (GHD)
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Zehr, Julia L
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Emory University
Schools of Medicine
United States
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Smith, Alicia K; Kilaru, Varun; Kocak, Mehmet et al. (2014) Methylation quantitative trait loci (meQTLs) are consistently detected across ancestry, developmental stage, and tissue type. BMC Genomics 15:145
Almli, Lynn M; Fani, Negar; Smith, Alicia K et al. (2014) Genetic approaches to understanding post-traumatic stress disorder. Int J Neuropsychopharmacol 17:355-70
Barfield, Richard T; Almli, Lynn M; Kilaru, Varun et al. (2014) Accounting for population stratification in DNA methylation studies. Genet Epidemiol 38:231-41
Mehta, Divya; Klengel, Torsten; Conneely, Karen N et al. (2013) Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder. Proc Natl Acad Sci U S A 110:8302-7
Schroeder, James W; Smith, Alicia K; Brennan, Patricia A et al. (2012) DNA methylation in neonates born to women receiving psychiatric care. Epigenetics 7:409-14
Smith, Alicia K; Conneely, Karen N; Newport, D Jeffrey et al. (2012) Prenatal antiepileptic exposure associates with neonatal DNA methylation differences. Epigenetics 7:458-63
Kilaru, Varun; Barfield, Richard T; Schroeder, James W et al. (2012) MethLAB: a graphical user interface package for the analysis of array-based DNA methylation data. Epigenetics 7:225-9
Schroeder, James W; Conneely, Karen N; Cubells, Joseph C et al. (2011) Neonatal DNA methylation patterns associate with gestational age. Epigenetics 6:1498-504
Smith, Alicia K; Conneely, Karen N; Kilaru, Varun et al. (2011) Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet 156B:700-8
Brand, Sarah R; Brennan, Patricia A; Newport, D Jeffrey et al. (2010) The impact of maternal childhood abuse on maternal and infant HPA axis function in the postpartum period. Psychoneuroendocrinology 35:686-93

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