I have three major foci of research in my laboratory. The first focus is molecular gene-environment (GxE) studies of large longitudinal cohorts. The second focus is centered on my work with MED12 in human health and behavior. The third area is the development of transcriptional profiling techniques in behavioral health.
Molecular Studies of GxE Effects in Behavioral Illness. The importance of GxE effects in complex behavior illnesses has become increasingly appreciated over the past several years. In order to study these interactions, I have assembled one of the largest collections of biomaterial from longitudinal cohorts in the United States. From these individual, my group has prepared DNA, RNA and cell lines for each of the individuals in the study. Using these materials, we are taking a radical approach by using our lymphoblast cell models to construct an integrated view of gene variation, methylation, mRNA expression and clinical phenotype for each individual study. For example, in a direct follow-up to our earlier study that described and characterized the role of a CpG island that regulates mRNA transcription from the serotonin transporter (5HTT, SLC6A4; U.S. Patent pending) locus we have submitted a manuscript which will detail the relationship of each SNP, haplotype, CpG residue methylation status at this locus with mRNA expression and clinical phenotype at this locus.
The Role of MED12 (HOPA) In Human Health and Behavior MED12 regulates monoaminergic neurodifferentiation. Our group has identified and patented a protein variant which alters dopaminergic cell fate and increases risk for psychosis. In the past several years, my laboratory has gained increasing traction on the understanding of the differential biology associated by coupling our clinical studies this gene variant with more basic approaches using stable, doubly transfected, inducible PC63 cell lines and our newly developed transcriptional profiling techniques. This approach has been extremely productive with nduction of constructs antagonizing Opa domain function alters PC63 morphology. Most excitingly, transcriptional profiling of lymphoblast cell lines derived from psychotic subjects with the HOPA12bp demonstrates a differential expression profile that implicates Wnt dysfunction. This fall we have begun direct translation of these finding into humans and have begun construction of transgenic human embryonic stems, a first here at the University of Iowa. Transcriptional Profiling in Neuropsychiatric Syndromes. The Holy Grail in most medical disciplines is to define the biological diatheses for illness. Psychiatry is no exception. As we have demonstrated in several high profile studies, by conducting genome wide transcriptional profiling studies coupled with a systems biology analytic paradigm, is possible to identify not only genes, but gene pathways involved in the etiology of many common mental disorders. Furthermore, in collaboration with private companies, we are developing specific transcriptional approaches for use as diagnostic tools in the clinic.