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SUMMARY:Genomic insights about the prenatal origins of behavioral disorder
 s - Prof Daniel Weinberger
DTSTART:20220217T150000Z
DTEND:20220217T160000Z
UID:TALK169097@talks.cam.ac.uk
CONTACT:Sarah Morgan
DESCRIPTION:Compelling evidence from various approaches to identifying ris
 k for behavioral disorders\, such as autism\, \nschizophrenia\, ADHD and i
 ntellectual deficiency\, implicates early development as playing a critica
 l role. \nEpidemiological studies have long suggested that diverse complic
 ations during pregnancy increase risk upwards of \ntwo-fold. Pathway and g
 ene ontology analyses of sets of genes in recent risk loci identified from
  large scale case \ncontrol GWAS studies implicate neuronal differentiatio
 n and early processes in brain development. Studies of gene \nexpression a
 cross the human lifespan have shown that genes in GWAS risk associated loc
 i are as a group more \nlikely to be expressed during fetal life than duri
 ng postnatal life\, suggesting that they are dynamically regulated during 
 fetal brain development (Birnbaum et al AJP 2012\, Jaffee et al Nature Neu
 rosci 2018). Moreover\, studies of DNA methylation and of the 3D chromatin
  state\, as epigenetic marks of environmental experience\, have further \n
 shown that schizophrenia risk associated loci from recent GWAS studies imp
 licate epigenetic variation that \ndistinguishes fetal from postnatal deve
 lopment (Jaffe et al Nat Neurosci 2016\, de la Torre-Ubieta et al Cell 201
 8). \nThese data argue that both genetic and epigenetic risk for these dis
 orders involve early brain development\, and \nsurprisingly\, not the peri
 od of time when the clinical diagnosis is first made. These data\, however
 \, are \ncircumstantial and not definitive. Accordingly\, we have recently
  shown that genetic risk for schizophrenia\, as \nmeasured with polygene r
 isk scores calculated from the most GWAS-significant loci\, interact with 
 serious prenatal \nand perinatal complications in affecting risk for schiz
 ophrenia\, 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 a
 nd differentially expressed in placentae from complicated in comparison wi
 th normal pregnancies\; moreover\, they are differentially up-regulated in
  placentae from male compared with female offspring. Genetic risk scores b
 ased on schizophrenia GWAS and \nplacental gene expression predict brain s
 ize at birth and cognitive development during the first postnatal year \n(
 Ursini et al PNAS 2021). Such finding suggests a link between genetic risk
  for schizophrenia and placenta \npathophysiology\, together with a sex-bi
 ased role for the placenta in expressing genetic risk for schizophrenia. T
 hese \ndata establish a time window of fetal life as a major component of 
 the risk architecture of schizophrenia and \nsuggest potentially new avenu
 es for prevention based on placental health and high placental genetic ris
 k. These \nstudies and their implications are the subject of this lecture.
LOCATION:Online
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