Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions.
Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions.
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DOI：
10.1016/j.xgen.2023.100356
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发表时间：
2023-08-09
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影响因子：
--
通讯作者：
Walsh, Christopher A.
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作者：
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.
虽然种系拷贝数变异（cnv）会增加精神分裂症（SCZ）的风险，但体细胞拷贝数变异（sCNVs）的作用仍然未知，体细胞拷贝数变异存在于某些细胞中，但并非所有细胞。我们使用来自12834例SCZ病例和11648例对照的血液来源基因型阵列鉴定了scnv，过滤了在克隆性血液病中反复突变的位点上的scnv。可能的早期发育scnv在病例中（0.91%）比对照组（0.51%,p = 2.68e−4）更常见，在5例SCZ病例中，NRXN1基因外显子1-5反复出现体细胞缺失。Hi-C图谱显示，在NRXN1中5 '缺失时，潜在的隐启动子和非编码顺式调控元件之间形成异位的等位基因特异性环。我们还观察到，在5例治疗耐药的SCZ病例中，ABCB11基因内反复缺失，该基因编码一种与抗精神病反应有关的转运蛋白，并表明ABCB11在形成中脑皮层和中脑边缘多巴胺能投射的神经元中特异性富集。我们的研究结果表明scnv在SCZ风险中的潜在作用。体细胞拷贝数变异在SCZ病例中比在对照组中更为常见NRXN1外显子1-5的复发性体细胞缺失在SCZ病例中ABCB11基因内缺失在SCZ病例中ABCB11在人脑多巴胺能神经元的一个亚群中特异性富集。Maury等人利用血液来源的snp阵列数据，研究了12834例精神分裂症患者和11648例对照者的体细胞拷贝数变异（sCNVs）。他们发现，与对照组相比，这些病例的早期发育sCNV发病率更高，同时NRXN1和ABCB11的特定基因内事件可能导致SCZ疾病。
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 NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk. Somatic copy-number variants are more common in SCZ cases than in controls Recurrent somatic deletions of NRXN1 exons 1–5 in SCZ cases Recurrent intragenic deletions of ABCB11 in SCZ cases ABCB11 is specifically enriched in a subset of dopaminergic neurons in human brain Maury et al. leveraged blood-derived SNP-array data across 12,834 schizophrenia cases and 11,648 controls to explore somatic copy-number variants (sCNVs). They found higher early-developmental sCNV incidence in cases compared with controls, along with specific intragenic events in NRXN1 and ABCB11 that could potentially contribute to SCZ disease.
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影响因子：
4
作者：
Maury EA;Walsh CA
通讯作者：
Walsh CA
影响因子：
25
作者：
Kamath, Tushar;Abdulraouf, Abdulraouf;Burris, S. J.;Langlieb, Jonah;Gazestani, Vahid;Nadaf, Naeem M.;Balderrama, Karol;Vanderburg, Charles;Macosko, Evan Z.
通讯作者：
Macosko, Evan Z.
DOI：
10.1093/bioinformatics/btv562
发表时间：
2016-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
Gel B;Díez-Villanueva A;Serra E;Buschbeck M;Peinado MA;Malinverni R
通讯作者：
Malinverni R
DOI：
10.1002/ajmg.b.31063
发表时间：
2010-06-05
影响因子：
2.8
作者：
Ching, Michael S. L.;Shen, Yiping;Tan, Wen-Hann;Jeste, Shafali S.;Morrow, Eric M.;Chen, Xiaoli;Mukaddes, Nahit M.;Yoo, Seung-Yun;Hanson, Ellen;Hundley, Rachel;Austin, Christina;Becker, Ronald E.;Berry, Gerard T.;Driscoll, Katherine;Engle, Elizabeth C.;Friedman, Sandra;Gusella, James F.;Hisama, Fuki M.;Irons, Mira B.;Lafiosca, Tina;LeClair, Elaine;Miller, David T.;Neessen, Michael;Picker, Jonathan D.;Rappaport, Leonard;Rooney, Cynthia M.;Sarco, Dean P.;Stoler, Joan M.;Walsh, Christopher A.;Wolff, Robert R.;Zhang, Ting;Nasir, Ramzi H.;Wu, Bai-Lin
通讯作者：
Wu, Bai-Lin
DOI：
10.1126/science.abe0981
发表时间：
2021-03-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fasching L;Jang Y;Tomasi S;Schreiner J;Tomasini L;Brady MV;Bae T;Sarangi V;Vasmatzis N;Wang Y;Szekely A;Fernandez TV;Leckman JF;Abyzov A;Vaccarino FM
通讯作者：
Vaccarino FM