Chick Sophie L, Holmans Peter, Cameron Darren, Grozeva Detelina, Sims Rebecca, Williams Julie, Bray Nicholas J, Owen Michael J, O'Donovan Michael C, Walters James T R, Rees Elliott
Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Nat Commun. 2025 Aug 2;16(1):7102. doi: 10.1038/s41467-025-62429-y.
Rare coding variants across many genes contribute to schizophrenia liability, but they have only been implicated in 12 genes at exome-wide levels of significance. To increase power for gene discovery, we analyse exome-sequencing data for rare coding variants in a new sample of 4650 schizophrenia cases and 5719 controls, and combine these with published sequencing data for a total of 28,898 cases, 103,041 controls and 3444 proband-parent trios. We identify associations for STAG1 and ZNF136 at exome-wide significance, genes that were previously implicated in schizophrenia by the SCHEMA study at a false discovery rate of 5%. We also find associations at a false discovery rate of 5% for six genes that did not pass this statistical threshold in the SCHEMA study (SLC6A1, PCLO, ZMYND11, BSCL2, KLC1 and CGREF1). Among these genes, SLC6A1 and KLC1 are associated with damaging missense variants alone. STAG1, SLC6A1, ZMYND11 and CGREF1 are also enriched for rare coding variants in other developmental and psychiatric disorders. Moreover, STAG1 and KLC1 have fine-mapped common variant signals in schizophrenia. These findings provide insights into the neurobiology of schizophrenia, including further evidence suggesting an aetiological role for disrupted chromatin organisation.
许多基因中的罕见编码变异会增加患精神分裂症的风险，但在全外显子组水平具有显著意义的情况下，它们仅与12个基因有关。为了提高基因发现的效力，我们分析了4650例精神分裂症病例和5719例对照的新样本中的罕见编码变异的外显子组测序数据，并将这些数据与已发表的测序数据相结合，总计有28898例病例、103041例对照和3444个先证者-父母三联体。我们在全外显子组水平上确定了STAG1和ZNF136与精神分裂症的关联，这两个基因在之前的SCHEMA研究中以5%的假发现率被认为与精神分裂症有关。我们还发现，在SCHEMA研究中未达到该统计阈值的六个基因（SLC6A1、PCLO、ZMYND11、BSCL2、KLC1和CGREF1）在5%的假发现率水平上与精神分裂症有关。在这些基因中，SLC6A1和KLC1仅与有害的错义变异有关。STAG1、SLC6A1、ZMYND11和CGREF1在其他发育和精神疾病中也富含罕见编码变异。此外，STAG1和KLC1在精神分裂症中具有精细定位的常见变异信号。这些发现为精神分裂症的神经生物学提供了见解，包括进一步的证据表明染色质组织紊乱在病因学上起作用。
