Determining the causes of schizophrenia has been a notoriously intractable problem, resistant to a multitude of investigative approaches over centuries. In recent decades, genomic studies have delivered hundreds of robust findings that implicate nearly 300 common genetic variants (via genome-wide association studies) and more than 20 rare variants (via whole-exome sequencing and copy number variant studies) as risk factors for schizophrenia. In parallel, functional genomic and neurobiological studies have provided exceptionally detailed information about the cellular composition of the brain and its interconnections in neurotypical individuals and, increasingly, in those with schizophrenia. Taken together, these results suggest unexpected complexity in the mechanisms that drive schizophrenia, pointing to the involvement of ensembles of genes (polygenicity) rather than single-gene causation. In this Review, we describe what we now know about the genetics of schizophrenia and consider the neurobiological implications of this information.

确定精神分裂症的病因一直是一个众所周知的棘手问题，几个世纪以来多种研究方法都遇到了阻力。近几十年来，基因组研究已得出数百项强有力的发现，表明近 300 种常见遗传变异（通过全基因组关联研究）和 20 多种罕见变异（通过全外显子组测序和拷贝数变异研究）是精神分裂症的危险因素。与此同时，功能基因组和神经生物学研究提供了关于神经典型个体以及越来越多的精神分裂症患者的大脑细胞组成及其相互联系的极其详细的信息。总而言之，这些结果表明驱动精神分裂症的机制具有意想不到的复杂性，表明涉及基因组（多基因性）而不是单基因因果关系。在这篇综述中，我们描述了我们现在对精神分裂症遗传学的了解，并考虑了这些信息的神经生物学意义。