Convergence of placenta biology and genetic risk for schizophrenia

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.

Distinct molecular processes in placentae involved in two major subtypes of preeclampsia

“…Accumulating evidences point to association of preeclampsia with brain developmental disorders, including intellectual disability, 15 epilepsy, 16 autism [17][18][19] and schizophrenia. 20,21 It might be partially due to the placenta-derived factors that affects the development of the brain and thus leads to complex brain disorders. 21,74 Ursini et al found that, for some loci of schizophrenia, the association between genetic risk and schizophrenia is affected by complicated pregnancies, and the gene set within these loci are differentially expressed in placentae from complicated in comparison with normal pregnancies 21 .…”

“…Recently, a meta-analysis reported that hypertensive disorders of pregnancy may be associated with an increase in the risk of ASD (autism spectrum disorder) and ADHD (attentiondeficit/hyperactivity disorder) 74 . Weinberger's study showed that the set of genes within genomic risk loci for schizophrenia that have interaction with intra-uterine and perinatal complications is highly expressed in placenta 21 . Other studies also demonstrated that preeclampsia was associated with increased risk of offspring schizophrenia.…”

“…2E). Because PE has the most significant consequence on developmental brain impairments in offspring, which lead to intellectual disability, 15 epilepsy, 16 autism [17][18][19] and schizophrenia, 20,21 we performed the enrichment analyses of schizophrenia-associated genes in DEGs, and found that the disease-associated genes were significantly enriched ( Figure S2D). These results suggest that the differentially expressed genes are not only associated with PE, but also with consequence of PE on the offspring in their later life.…”

“…12,13 In the long term, PE affects brain development and functions of the offspring 14 , leading to intellectual disability, 15 epilepsy, 16 autism [17][18][19] and schizophrenia. 20,21 Since the symptoms of a pregnant woman with PE usually resolve after delivery and histopathological placental changes can be detected at that time, the placenta has been perceived as the root cause of PE. A widely accepted disease model for the placental origin includes two stages of PE development.…”

A perspective on pre‐eclampsia and neurodevelopmental outcomes in the offspring: Does maternal inflammation play a role?

“…It will also be important to not limit studies of potential mediators to IL‐6 and explore a range of other potential inflammatory mediators including but not limited to TNF‐α and IL‐17 (Choi et al, 2016; Jones et al, 2016). Moreover, given a recent study showing that most significant genetic variants associated with schizophrenia converge on a developmental trajectory sensitive to events that affect the placental response to in utero stressors, including pre‐eclampsia (Ursini et al, 2018), understanding the placental response in pre‐eclampsia and how this may predict or be associated with neurodevelopmental outcomes in pre‐eclampsia‐exposed offspring (O'Keeffe and Kenny, 2014), will be important questions for future research.…”