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Contributions of rare variants to risk for mood disorders

Psychiatric disorders such as bipolar disorder are strongly familial, with 8-10-fold relative risk in the first-degree relatives of probands. In the last few years, genoome-wide association studies have revealed >100 well-supported risk loci for psychiatric disorders, but the mechanisms by which these risk loci influence disease remain elusive, for at least two reasons. First, the effects of individual loci on risk for disease are very small (<1% relative risk). Second, most of the causal variants are non-coding, making it more difficult to determine their target genes. Identifying rare risk variants can help characterize disease mechanisms, since these variants may have larger effects on disease risk and clearer effects on gene function than common variants discovered through GWAS. The Ament lab is affiliated with several consortia generating large exome and genome sequencing datasets related to psychiatric disorders, including the Bipolar Genome Study, the Bipolar Sequencing Consortium, and the Anabaptist Sequencing Consortiun. Locally, we collaborate with the Program in Personalized and Genomic Medicine on genetics studies involving the Old Order Amish. The goal of all these studies is to identify rare variants, genes, and gene networks that influence risk for psychiatric disorders, as well as neurocognitive and neuroimaging endophenotypes.

Gene regulatory networks in the mammalian brain

Interpreting genomic data in the context of biological networks is another powerful strategy to discover disease mechanisms. We use cutting-edge informatics tools to analyze high-throughput genomic data in order to develop hypotheses about mechanisms of brain diseases. Recently, we have developed methods to reconstruct gene regulatory networks in the human and mouse brain, leveraging sequence motifs, epigenomic and transcriptomic data to predict the tissue-specific binding sites and target genes for hundreds of transcription factors. We are applying these methods to predict identify master regulator TFs in psychiatric and neurodegenerative diseases. We have validated several of these hypotheses through ChIP-seq and lentiviral overexpression of TFs in animal and cellular models, and using CRISPR/Cas9 genome editing. We are eager to collaborate with experimental groups generating new trancsriptomics and epigenomic datasets. Current projects aim to elucidate gene regulatory networks in psychiatric disorders, Huntington’s disease, hearing loss, and brain development.

Stem Cell Models of Psychiatric Disorders

Pluripotent stem cells (PSCs) and PSC-derived neurons are a promising system in which to characterize phenotypes associated with the genetic variation underlying human disease. My lab is using stem cells to model neurodevelopmental mechanisms by which genetic variants influence psychiatric disorders. We are utilizing genome editing in isogenic stem cell lines as well as a unique resource of patient-derived lines from deeply phenotyped Amish pedigrees with mental illnesses to investigate functional consequences of genetic variants. We are using these cell lines to test two hypotheses emerging from psychiatric genetics and systems biology studies. First, we hypothesize that psychiatric disorders involve neurodevelopmental changes in gene regulation. Second, we hypothesize that psychiatric disorders involve synaptic changes inducing neuronal hyperexcitability. Both mechanisms are predicted to alter the structure and function of the adult brain, perhaps in subtle ways.

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