Genome-wide Copy Number Variant Screening of Saudi Schizophrenia Patients Reveals Larger Deletions in Cases versus Controls

Genome-wide association studies have discovered common polymorphisms in regions associated with schizophrenia. No genome-wide analyses have been performed in Saudi schizophrenia subjects. Genome-wide genotyping data from 136 Saudi schizophrenia cases and 97 Saudi controls (97 Saudi and in addition to 4,625 United States/EuropeansAmerican,) were studied andexamined for copy number variants (CNVs) were examined across the genomes. A hidden Markov model approach was used to call CNVs. CNVs in schizophrenia cases were twice as large on average than CNVs in the controls (p = 0.04). The analyses focused on extremely large >250 kilobases CNVs or homozygous deletions of any size. One extremely large deletion was noted in a single case (16.5 megabases on chromosome 10). Two cases had an 814 kb duplication of chromosome 7 spanning a cluster of genes, including circadian-related loci, and two other cases had 277 kb deletions of chromosome 9 encompassing an olfactory receptors gene family. A single case carried a CNVs were also seen in locithat was previously associated with schizophrenia, namely a 16p11 proximal duplication and two 22q11.2 deletions. Runs of homozygosity (ROHs) were analyzed across the genome to investigate any correlation with schizophrenia risk. While rates and sizes of these ROHs were similar in cases and controls, we identified ten regions where multiple cases had more significant ROHs and controls did notversus controls.

全基因组关联研究已在与精神分裂症相关的基因组区域中发现了常见多态性。目前尚无针对沙特阿拉伯精神分裂症患者的全基因组分析研究。本研究对136名沙特精神分裂症患者、97名沙特健康对照者，以及额外的4625名欧美裔美国人的全基因组分型数据进行了分析，并对全基因组范围内的拷贝数变异（copy number variants, CNVs）进行了检测。研究采用隐马尔可夫模型进行CNVs的分型。结果显示，精神分裂症患者的CNVs平均长度是对照者的两倍（p=0.04）。本分析重点关注长度超过250千碱基的超大CNVs，或任意大小的纯合缺失。在1例患者中发现了1个位于10号染色体上的16.5兆碱基的超大缺失。另有2例患者存在7号染色体上814kb的重复区域，该区域包含多个基因簇，其中包括昼夜节律相关基因座；还有2例患者存在9号染色体上277kb的缺失区域，该区域涵盖嗅觉受体基因家族。此外，1例患者携带了此前已被报道与精神分裂症相关的CNVs，具体为16p11近端重复，另有2例患者存在22q11.2缺失。本研究还对全基因组范围内的纯合子区域序列（Runs of homozygosity, ROHs）进行了分析，以探究其与精神分裂症患病风险的相关性。尽管患者与对照者的ROHs发生率及长度均无显著差异，但我们在10个基因组区域中发现，多个患者的ROHs显著性水平显著高于对照者。