Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., “second hits”) that may contribute to schizophrenia expression.

Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia.

Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci.

The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

染色体22q11.2缺失综合征（22q11.2DS）与患精神分裂症的风险增加了20倍以上。这项研究的目的是确定可能有助于精神分裂症表达的其他遗传因素（即“第二击”）。

通过一个国际财团，作者从329名具有22q11.2DS的精神病学表型受试者中获得了DNA样本。作者使用高分辨率微阵列平台和已建立的评估拷贝数变异（CNV）的方法，比较了两组之间在22q11.2缺失区域之外的罕见常染色体CNV在全基因组范围内的负担：精神分裂症组和精神分裂症组25岁以上无精神病。作者评估了与罕见CNV重叠的基因是否在与精神分裂症相关的功能途径中被过度表达。

重叠一个或多个蛋白质编码基因的罕见CNV显示出显着的组间差异。对于罕见的外显子重复，在精神分裂症组中测试的19个基因组中有6个富集。与神经系统异常表型相关的基因在逐步逻辑回归模型中仍然很重要，并且在连通性分析中显示出与22q11.2缺失区基因的显着相互作用。对于罕见的外显子缺失，精神分裂症组平均有更多的基因重叠。涉及的其他罕见CNV（例如GRM7，15q13.3、16p12.2）和新型精神分裂症的风险基因和基因位点也涉及到这种基因的表达。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。

结果表明，22q11.2缺失区之外的其他罕见CNV重叠基因与22q11.2DS中的精神分裂症风险有关，支持了精神分裂症的多基因假设。这些发现对于理解精神病的表达具有启示意义，并预示了全基因组测序对理解精神分裂症整体基因组结构的重要性。