Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Proc Natl Acad Sci U S A. 2021 Feb 16;118(7). doi: 10.1073/pnas.2019789118.
Tracing the early paths leading to developmental disorders is critical for prevention. In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence. This interaction was specifically driven by loci harboring genes highly expressed in placentae from normal and complicated pregnancies [G. Ursini et al., 24, 792-801 (2018)]. Here, we analyze whether fractionated genomic risk scores for schizophrenia and other developmental disorders and traits, based on placental gene-expression loci (PlacGRSs), are linked with early neurodevelopmental outcomes in individuals with a history of ELCs. We found that schizophrenia's PlacGRSs are negatively associated with neonatal brain volume in singletons and offspring of multiple pregnancies and, in singletons, with cognitive development at 1 y and, less strongly, at 2 y, when cognitive scores become more sensitive to other factors. These negative associations are stronger in males, found only with GRSs fractionated by placental gene expression, and not found in PlacGRSs for other developmental disorders and traits. The relationship of PlacGRSs with brain volume persists as an anlage of placenta biology in adults with schizophrenia, again selectively in males. Higher placental genomic risk for schizophrenia, in the presence of ELCs and particularly in males, alters early brain growth and function, defining a potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia.
追踪导致发育障碍的早期途径对于预防至关重要。在之前的工作中，我们检测到精神分裂症基因组风险评分（GRS）与生命早期并发症（ELC）之间存在相互作用，因此与不存在 ELC 病史相比，基因组风险解释的疾病易感性在存在 ELC 病史的情况下更高。这种相互作用是由在正常和复杂妊娠胎盘高表达基因所包含的基因座特异性驱动的[G. Ursini 等人，24，792-801（2018）]。在这里，我们分析了基于胎盘基因表达基因座（PlacGRS）的精神分裂症和其他发育障碍和特征的分裂基因组风险评分是否与有 ELC 病史的个体的早期神经发育结果相关。我们发现，精神分裂症的 PlacGRS 与单胎和多胎妊娠后代的新生儿脑容量呈负相关，并且在单胎中与 1 岁时的认知发育呈负相关，而在 2 岁时的相关性较弱，此时认知评分对其他因素变得更加敏感。这些负相关在男性中更强，仅在通过胎盘基因表达分离的 GRS 中发现，而在其他发育障碍和特征的 PlacGRS 中未发现。在精神分裂症患者中，PlacGRS 与大脑体积的关系作为胎盘生物学的基础在成年期仍然存在，同样仅在男性中存在。在 ELC 存在的情况下，尤其是在男性中，较高的精神分裂症胎盘基因组风险会改变早期大脑生长和功能，定义了一种潜在的可逆转的风险神经发育途径，这可能是精神分裂症所特有的。
