Maury Eduardo A, Sherman Maxwell A, Genovese Giulio, Gilgenast Thomas G, Kamath Tushar, Burris S J, Rajarajan Prashanth, Flaherty Erin, Akbarian Schahram, Chess Andrew, McCarroll Steven A, Loh Po-Ru, Phillips-Cremins Jennifer E, Brennand Kristen J, Macosko Evan Z, Walters James T R, O'Donovan Michael, Sullivan Patrick, Sebat Jonathan, Lee Eunjung A, Walsh Christopher A
Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children's Hospital, Boston, MA, USA.
Bioinformatics & Integrative Genomics Program and Harvard/MIT MD-PHD Program, Harvard Medical School, Boston, MA, USA.
Cell Genom. 2023 Jul 6;3(8):100356. doi: 10.1016/j.xgen.2023.100356. eCollection 2023 Aug 9.
While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)-present in some but not all cells-remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e-4), with recurrent somatic deletions of exons 1-5 of the gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding -regulatory elements upon 5' deletions in . We also observed recurrent intragenic deletions of , encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk.
虽然种系拷贝数变异（CNV）会增加精神分裂症（SCZ）的患病风险，但体细胞CNV（sCNV，存在于部分而非全部细胞中）的作用尚不清楚。我们使用来自12834例SCZ病例和11648例对照的血液基因型阵列来识别sCNV，并在克隆性血液疾病中反复发生突变的基因座处筛选sCNV。可能发生在早期发育阶段的sCNV在病例中（0.91%）比在对照中（0.51%，p = 2.68e-4）更为常见，在5例SCZ病例中存在该基因外显子1-5的反复体细胞缺失。Hi-C图谱显示，在发生5'端缺失时，在一个潜在的隐蔽启动子和非编码调控元件之间形成了异位的、等位基因特异性的环。我们还在5例难治性SCZ病例中观察到编码一种与抗精神病反应有关的转运蛋白的基因发生反复的基因内缺失，并表明该基因在形成中脑皮质和中脑边缘多巴胺能投射的神经元中特异性富集。我们的结果表明sCNV在SCZ风险中具有潜在作用。
