Schizophrenia is a severe psychiatric disorder with strong heritability and marked heterogeneity in symptoms, course, and treatment response. There is strong interest in identifying genetic risk factors that can help to elucidate the pathophysiology and that might result in the development of improved treatments. Linkage and genome-wide association studies (GWASs) suggest that the genetic basis of schizophrenia is heterogeneous. However, it remains unclear whether the underlying genetic variants are mostly moderately rare and can be identified by the genotyping of variants observed in sequenced cases in large follow-up cohorts or whether they will typically be much rarer and therefore more effectively identified by gene-based methods that seek to combine candidate variants. Here, we consider 166 persons who have schizophrenia or schizoaffective disorder and who have had either their genomes or their exomes sequenced to high coverage. From these data, we selected 5,155 variants that were further evaluated in an independent cohort of 2,617 cases and 1,800 controls. No single variant showed a study-wide significant association in the initial or follow-up cohorts. However, we identified a number of case-specific variants, some of which might be real risk factors for schizophrenia, and these can be readily interrogated in other data sets. Our results indicate that schizophrenia risk is unlikely to be predominantly influenced by variants just outside the range detectable by GWASs. Rather, multiple rarer genetic variants must contribute substantially to the predisposition to schizophrenia, suggesting that both very large sample sizes and gene-based association tests will be required for securely identifying genetic risk factors.

译文

精神分裂症是一种严重的精神疾病,具有很强的遗传力,在症状,病程和治疗反应方面具有明显的异质性。人们对确定遗传危险因素非常感兴趣,这些因素可以帮助阐明病理生理学,并可能导致改进的治疗方法的发展。连锁和全基因组关联研究 (GWASs) 表明,精神分裂症的遗传基础是异质的。然而,尚不清楚潜在的遗传变异是否大多数是中度罕见的,并且可以通过在大型随访队列中的测序病例中观察到的变异的基因分型来鉴定,或者它们是否通常会更加罕见,因此通过寻求结合候选变异的基于基因的方法更有效地鉴定。在这里,我们考虑166患有精神分裂症或分裂情感障碍的人,他们的基因组或外显子测序到高覆盖率。从这些数据中,我们选择了在2,617例病例和1,800对照的独立队列中进一步评估的5,155变异。在初始或随访队列中,没有单一变异显示出研究范围内的显着关联。但是,我们确定了许多特定于病例的变异,其中一些可能是精神分裂症的真正危险因素,并且可以在其他数据集中容易地询问这些变异。我们的结果表明,精神分裂症的风险不太可能主要受到GWASs可检测范围之外的变异的影响。相反,多个较罕见的遗传变异必须对精神分裂症的易感性做出重大贡献,这表明需要非常大的样本量和基于基因的关联测试才能安全地识别遗传风险因素。

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