BACKGROUND Self-reported consanguinity is associated with risk for schizophrenia (SZ) in several inbred populations, but estimates using DNA-based coefficients of inbreeding are unavailable. Further, it is not known whether recessively inherited risk mutations can be identified through homozygosity by descent (HBD) mapping. METHODS We studied self-reported and DNA-based estimates of inbreeding among Egyptian patients with SZ (n = 421, DSM IV criteria) and adult controls without psychosis (n = 301), who were evaluated using semi-structured diagnostic interview schedules and genotyped using the Illumina Infinium PsychArray. Following quality control checks, coefficients of inbreeding (F) and regions of homozygosity (ROH) were estimated using PLINK software for HBD analysis. Exome sequencing was conducted in selected cases. RESULTS Inbreeding was associated with schizophrenia based on self-reported consanguinity (χ2 = 4.506, 1 df, p = 0.034) and DNA-based estimates for inbreeding (F); the latter with a significant F × age interaction (β = 32.34, p = 0.0047). The association was most notable among patients older than age 40 years. Eleven ROH were over-represented in cases on chromosomes 1, 3, 6, 11, and 14; all but one region is novel for schizophrenia risk. Exome sequencing identified six recessively-acting genes in ROH with loss-of-function variants; one of which causes primary hereditary microcephaly. CONCLUSIONS We propose consanguinity as an age-dependent risk factor for SZ in Egypt. HBD mapping is feasible for SZ in adequately powered samples.

中文翻译：

---

埃及近亲繁殖与精神分裂症风险的年龄相关性


背景 在一些近交群体中，自我报告的近亲关系与精神分裂症 (SZ) 的风险相关，但无法使用基于 DNA 的近交系数进行估计。此外，尚不清楚是否可以通过血统纯合性（HBD）作图来识别隐性遗传风险突变。方法 我们研究了埃及 SZ 患者（n = 421，DSM IV 标准）和无精神病成人对照（n = 301）的自我报告和基于 DNA 的近亲繁殖估计，使用半结构化诊断访谈计划和基因分型对他们进行了评估使用 Illumina Infinium PsychArray。质量控制检查后，使用 PLINK 软件估算近交系数 (F) 和纯合性区域 (ROH)，进行 HBD 分析。在选定的病例中进行了外显子组测序。结果 根据自我报告的血缘关系（χ2 = 4.506，1 df，p = 0.034）和基于 DNA 的近亲繁殖估计，近亲繁殖与精神分裂症相关（F）；后者具有显着的 F × 年龄交互作用（β = 32.34，p = 0.0047）。这种关联在 40 岁以上的患者中最为显着。 1、3、6、11 和 14 号染色体上的病例中有 11 个 ROH 比例过高；除一个地区外，所有地区的精神分裂症风险都是新的。外显子组测序在 ROH 中鉴定出 6 个隐性作用基因，其中存在功能缺失变异；其中之一会导致原发性遗传性小头畸形。结论 我们建议近亲结婚是埃及 SZ 的年龄依赖性危险因素。 HBD 映射对于 SZ 在功率充足的样本中是可行的。