Our main objective is to find the factors mediating the relationship between genetic risk factors, complications in early life (ELCs, i.e. pre-, and perinatal) and altered neuro- development (ND) in humans, so that, in high-risk individuals, disorders of ND such as schizophrenia (SZ), can be prevented or rescued in early stages. Epidemiological findings show that ELCs increase the risk for ND disorders including SZ; preclinical models show that ELCs alter ND, an effect partially mediated by gene expression in placenta, with males more vulnerable than females. However, the mechanism linking ELCs with SZ are still elusive. Our recent human work found that genetic factors converge with placenta biology in affecting risk for SZ. Here, we focus on detecting the molecular mediators involved: that is, the molecules that, by regulating placenta's physiology, regulate ND, drive susceptibility to SZ, and may mediate the interaction between genetic factors and ELCs on the risk for the disorder. We propose a multi-step strategy, which leverages our strengths in analyzing transcriptomic and genetic data, using well-established and innovative methodologies to explore a novel area of research: the relationship between genomic risk factors, placenta and SZ. We will first investigate the transcriptomic correlates of genetic risk factors for SZ in the placenta, and we will analyze whether gene isoforms associated with risk for SZ are co-expressed in placenta, as part of specific biological processes. Using genotype-based prediction of gene expression in large cohorts, we will identify the specific placental isoforms associated with SZ case-control status. We will then generate placental genomic predictors of SZ risk, and we will test their relationship with ND outcomes. To investigate sex-specific placental processes relevant for SZ, we will stratify each analysis by sex. We expect our data to converge in identifying placental molecules and pathways that are relevant for SZ. The detection of such molecules may be translated into the development of novel prenatal prevention of SZ, aimed at preserving / optimizing the important placental support to ND, and the development of novel postnatal prevention, based on the identification of high-risk individuals ? through placental and genetic biomarkers.

Public Health Relevance

In the US 46% of newborns have a least one pre-, or perinatal complication (ELC), increasing relative risk of altered neuro-development and ultimate potential outcomes, i.e. brain disorders such as schizophrenia. However, the mechanisms linking ELCs with schizophrenia are still elusive. The objective of this project is to identify non-invasive placental factors of risk, that will inform precision medicine approaches of prenatal prevention of schizophrenia, and potential rescue of high-risk individuals via early postnatal prevention.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Meinecke, Douglas L
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Lieber Institute, Inc.
United States
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