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Genomic insights about the prenatal origins of behavioral disorders

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  • UserProf Daniel Weinberger
  • ClockThursday 17 February 2022, 15:00-16:00
  • HouseOnline.

If you have a question about this talk, please contact Sarah Morgan.

Compelling evidence from various approaches to identifying risk for behavioral disorders, such as autism, schizophrenia, ADHD and intellectual deficiency, implicates early development as playing a critical role. Epidemiological studies have long suggested that diverse complications during pregnancy increase risk upwards of two-fold. Pathway and gene ontology analyses of sets of genes in recent risk loci identified from large scale case control GWAS studies implicate neuronal differentiation and early processes in brain development. Studies of gene expression across the human lifespan have shown that genes in GWAS risk associated loci are as a group more likely to be expressed during fetal life than during postnatal life, suggesting that they are dynamically regulated during fetal brain development (Birnbaum et al AJP 2012 , Jaffee et al Nature Neurosci 2018). Moreover, studies of DNA methylation and of the 3D chromatin state, as epigenetic marks of environmental experience, have further shown that schizophrenia risk associated loci from recent GWAS studies implicate epigenetic variation that distinguishes fetal from postnatal development (Jaffe et al Nat Neurosci 2016, de la Torre-Ubieta et al Cell 2018). These data argue that both genetic and epigenetic risk for these disorders involve early brain development, and surprisingly, not the period of time when the clinical diagnosis is first made. These data, however, are circumstantial and not definitive. Accordingly, we have recently shown that genetic risk for schizophrenia, as measured with polygene risk scores calculated from the most GWAS -significant loci, interact with serious prenatal and perinatal complications in affecting risk for schizophrenia, so that the liability of schizophrenia of genetic risk is more than six times higher in individuals with a history of such complications compared with its absence (Ursini et al Nat Medicine 2018). Consistently, we have found that the genes mapping to the schizophrenia risk loci, and interacting with those complications, are highly expressed in placenta and differentially expressed in placentae from complicated in comparison with normal pregnancies; moreover, they are differentially up-regulated in placentae from male compared with female offspring. Genetic risk scores based on schizophrenia GWAS and placental gene expression predict brain size at birth and cognitive development during the first postnatal year (Ursini et al PNAS 2021 ). Such finding suggests a link between genetic risk for schizophrenia and placenta pathophysiology, together with a sex-biased role for the placenta in expressing genetic risk for schizophrenia. These data establish a time window of fetal life as a major component of the risk architecture of schizophrenia and suggest potentially new avenues for prevention based on placental health and high placental genetic risk. These studies and their implications are the subject of this lecture.

This talk is part of the Making connections- brains and other complex systems series.

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