Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion
Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion
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DOI：
10.1038/s41380-020-0654-3
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发表时间：
2020-02-03
影响因子：
11
通讯作者：
Bassett, Anne S.
中科院分区：
文献类型：
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作者：
Cleynen, Isabelle;Engchuan, Worrawat;Bassett, Anne S.
精神分裂症发生在约四分之一的22q11.2缺失综合征（22q11.2DS）患者中。这项国际脑与行为22q11.2DS联盟（IBBC）研究的目的是确定导致精神分裂症的遗传因素，除了22q11.2缺失所传达的风险增加20倍之外。使用来自519名22q11.2DS无关个体的全基因组测序数据，我们对年龄≥ 25岁的精神分裂症患者和非精神病患者之间的常见和罕见变异进行了全基因组比较。现有的微阵列数据能够直接比较22q11.2DS和无22q11.2缺失的独立人群样本之间精神分裂症的多基因风险，有和没有精神分裂症（总n = 35，182）。22q11.2DS内精神分裂症的多基因风险在精神分裂症患者中显著更高（p（adj）= 6.73 x 10（-6））。22q11.2DS和基于人群的队列之间的新的相互病例对照比较显示，无论是否存在22q11.2缺失，精神病患者的多基因风险评分显著更高。在22q11.2DS队列中，基因集分析的结果显示了对影响突触基因的罕见变异的一些支持。在22q11.2缺失区域内没有常见或罕见的变异与精神分裂症显著相关。这些结果表明，除了删除赋予精神分裂症的风险大大增加，风险更高时，22q11.2缺失和常见的多基因危险因素，有助于精神分裂症在一般人群都存在。
Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the similar to 20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age >= 25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p(adj) = 6.73 x 10(-6)). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.