Genetic Association Between Schizophrenia and Cortical Brain Surface Area and Thickness
Genetic Association Between Schizophrenia and Cortical Brain Surface Area and Thickness
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DOI：
10.1001/jamapsychiatry.2021.1435
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发表时间：
2021-06-23
期刊：
影响因子：
25.8
通讯作者：
Andreassen, Ole A.
中科院分区：
文献类型：
--
作者：
Cheng, Weiqiu;Frei, Oleksandr;Andreassen, Ole A.
重要提示：精神分裂症是一种复杂的遗传性疾病，与许多遗传变异有关，每种变异都有很小的影响。虽然精神分裂症患者和健康对照之间的皮层差异一直被报道，但潜在的分子机制仍然是habitu.Objective调查精神分裂症和大脑皮层表面积（SA）和厚度（TH）之间共享的遗传结构的程度，并确定共享的基因组位点。精神分裂症独立全基因组关联研究数据（精神病学基因组学联盟和CLOZUK：n = 105 318）和SA和TH（UK生物库：n = 33 735）。使用MiXeR研究多基因重叠的程度。通过条件/联合错误发现率分析鉴定特异性共享基因组位点，并在3个独立队列中进一步检查。数据收集时间为2019年12月至2021年2月，数据分析时间为2020年5月至2021年2月。主要结果和指标主要结果是估计精神分裂症之间的多基因重叠分数，总SA和平均TH以及功能特征共享基因组位点列表。MiXeR估计精神分裂症比总SA（2101个SNV）和平均TH（1363个SNV）更具多基因性（9703个单核苷酸变异[SNV]）。与总SA（1966/2101 [93.6%]）和平均TH（1322/1363 [97.0%]）相关的大多数SNV可能与精神分裂症的发生相关。随后的联合错误发现率分析确定了44和23精神分裂症的风险位点共享总SA和平均TH分别。精神分裂症和总SA之间共享位点的SNV关联揭示了发现和独立队列之间的一致关联。在去除高连锁不平衡区域，如主要组织相容性复合体区域后，共享位点在免疫标记基因集中富集。多基因重叠和共享位点之间的精神分裂症和精神分裂症相关区域的利益SA（上级额颞中回）和TH（上级颞，颞下，和上级额回）也identified.CONCLUSIONS和相关性本研究表明，共享的遗传位点之间的皮质形态和精神分裂症，其中一个子集与免疫力。这些发现提供了一个深入了解复杂的遗传结构和与精神分裂症。
IMPORTANCESchizophrenia is a complex heritable disorder associated with many genetic variants, each with a small effect. While cortical differences between patients with schizophrenia and healthy controls are consistently reported, the underlying molecular mechanisms remain elusive.OBJECTIVE To investigate the extent of shared genetic architecture between schizophrenia and brain cortical surface area (SA) and thickness (TH) and to identify shared genomic loci.DESIGN, SETTING, AND PARTICIPANTS Independent genome-wide association study data on schizophrenia (Psychiatric Genomics Consortium and CLOZUK: n = 105 318) and SA and TH (UK Biobank: n = 33 735) were obtained. The extent of polygenic overlap was investigated using MiXeR. The specific shared genomic loci were identified by conditional/conjunctional false discovery rate analysis and were further examined in 3 independent cohorts. Data were collected from December 2019 to February 2021, and data analysis was performed from May 2020 to February 2021.MAIN OUTCOMES AND MEASURES The primary outcomes were estimated fractions of polygenic overlap between schizophrenia, total SA, and average TH and a list of functionally characterized shared genomic loci.RESULTS Based on genome-wide association study data from 139 053 participants, MiXeR estimated schizophrenia to be more polygenic (9703 single-nucleotide variants [SNVs]) than total SA (2101 SNVs) and average TH (1363 SNVs). Most SNVs associated with total SA (1966 of 2101 [93.6%]) and average TH (1322 of 1363 [97.0%]) may be associated with the development of schizophrenia. Subsequent conjunctional false discovery rate analysis identified 44 and 23 schizophrenia risk loci shared with total SA and average TH, respectively. The SNV associations of shared loci between schizophrenia and total SA revealed en masse concordant association between the discovery and independent cohorts. After removing high linkage disequilibrium regions, such as the major histocompatibility complex region, the shared loci were enriched in immunologic signature gene sets. Polygenic overlap and shared loci between schizophrenia and schizophrenia-associated regions of interest for SA (superior frontal and middle temporal gyri) and for TH (superior temporal, inferior temporal, and superior frontal gyri) were also identified.CONCLUSIONS AND RELEVANCE This study demonstrated shared genetic loci between cortical morphometry and schizophrenia, among which a subset are associated with immunity. These findings provide an insight into the complex genetic architecture and associated with schizophrenia.