AI Article Synopsis

  • - The study highlights how the intra-uterine environment influences the genetic risk of schizophrenia, showing that early-life complications (ELCs) significantly increase the association between genomic risk scores and the disease.
  • - Research conducted in the U.S., Italy, Germany, and Japan found that individuals with ELC histories have much higher polygenic risk scores for schizophrenia compared to those without such histories.
  • - Genes linked to schizophrenia that interact with ELCs are highly expressed in the placenta, with changes noted between complicated and normal pregnancies, and between male and female offspring, suggesting a need to consider developmental responses to environmental stressors in understanding the disorder.

Article Abstract

Defining the environmental context in which genes enhance disease susceptibility can provide insight into the pathogenesis of complex disorders. We report that the intra-uterine environment modulates the association of schizophrenia with genomic risk (in this study, genome-wide association study-derived polygenic risk scores (PRSs)). In independent samples from the United States, Italy, and Germany, the liability of schizophrenia explained by PRS is more than five times greater in the presence of early-life complications (ELCs) compared with their absence. Patients with ELC histories have significantly higher PRS than patients without ELC histories, which is confirmed in additional samples from Germany and Japan. The gene set composed of schizophrenia loci that interact with ELCs is highly expressed in placenta, is differentially expressed in placentae from complicated in comparison with normal pregnancies, and is differentially upregulated in placentae from male compared with female offspring. Pathway analyses reveal that genes driving the PRS-ELC interaction are involved in cellular stress response; genes that do not drive such interaction implicate orthogonal biological processes (for example, synaptic function). We conclude that a subset of the most significant genetic variants associated with schizophrenia converge on a developmental trajectory sensitive to events that affect the placental response to stress, which may offer insights into sex biases and primary prevention.

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Source
http://dx.doi.org/10.1038/s41591-018-0021-yDOI Listing

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