Convergence of placenta biology and genetic risk for schizophrenia | Nature Medicine

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.