Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nat Commun. 2023 May 15;14(1):2613. doi: 10.1038/s41467-023-38140-1.
Our earlier work has shown that genomic risk for schizophrenia converges with early life complications in affecting risk for the disorder and sex-biased neurodevelopmental trajectories. Here, we identify specific genes and potential mechanisms that, in placenta, may mediate such outcomes. We performed TWAS in healthy term placentae (N = 147) to derive candidate placental causal genes that we confirmed with SMR; to search for placenta and schizophrenia-specific associations, we performed an analogous analysis in fetal brain (N = 166) and additional placenta TWAS for other disorders/traits. The analyses in the whole sample and stratifying by sex ultimately highlight 139 placenta and schizophrenia-specific risk genes, many being sex-biased; the candidate molecular mechanisms converge on the nutrient-sensing capabilities of placenta and trophoblast invasiveness. These genes also implicate the Coronavirus-pathogenesis pathway and showed increased expression in placentae from a small sample of SARS-CoV-2-positive pregnancies. Investigating placental risk genes for schizophrenia and candidate mechanisms may lead to opportunities for prevention that would not be suggested by study of the brain alone.
我们之前的研究表明，精神分裂症的基因组风险与生命早期的并发症一起影响了该疾病的风险和性别偏倚的神经发育轨迹。在这里，我们确定了特定的基因和潜在的机制，这些基因和机制可能在胎盘中介导这些结果。我们在健康的足月胎盘中进行了 TWAS（N=147），以得出候选的胎盘因果基因，并用 SMR 进行了验证；为了寻找胎盘和精神分裂症特异性的关联，我们在胎儿大脑（N=166）中进行了类似的分析，并对其他疾病/特征进行了额外的胎盘 TWAS。在全样本中的分析以及按性别分层的分析最终突出了 139 个胎盘和精神分裂症特异性的风险基因，其中许多是性别偏倚的；候选的分子机制集中在胎盘和滋养细胞侵袭的营养感应能力上。这些基因还涉及冠状病毒发病机制途径，并在来自 SARS-CoV-2 阳性妊娠的小样本胎盘组织中显示出增加的表达。研究精神分裂症的胎盘风险基因和候选机制可能会为预防提供机会，而这单凭研究大脑是无法得出的。
