Targeting the schizophrenia genome: a fast track strategy from GWAS to clinic.
Targeting the schizophrenia genome: a fast track strategy from GWAS to clinic.
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DOI：
10.1038/mp.2015.28
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发表时间：
2015-07
影响因子：
11
通讯作者：
Malhotra, A. K.
中科院分区：
文献类型：
--
作者：
Lencz, T.;Malhotra, A. K.
精神病学基因组学联盟-精神分裂症工作组（PGC-SCZ）最近发表了一项全基因组关联研究（GWAS），确定了超过100个遗传位点，包括总共341个蛋白质编码基因，获得了精神分裂症易感性的全基因组意义。考虑到新型药物靶点的开发需要极长的时间（12-15年）和费用（> 10亿美元），重新利用具有已知且经过验证的靶点的药物可能是从这些GWAS发现中获得临床效用的最快捷途径。在本研究中，我们检查了PGC-SCZ GWAS与批准和注册药物化合物靶点数据库相关的基因座内的所有基因。我们确定了20个潜在的精神分裂症易感基因，这些基因编码作为批准药物靶点的蛋白质。其中，我们优先考虑明确的神经精神病学感兴趣的基因/靶标，并且它们也是PGC-SCZ GWAS命中周围连锁不平衡块的唯一成员。除了DRD 2，5个基因符合这些标准：CACNA 1C，CACNB 2，CACNA 1 I，GRIN 2A和HCN 1。另外还确定了20个编码蛋白质的基因，这些蛋白质是注册临床试验中药物的靶点，但没有批准的适应症。虽然仍需要大量的工作来充分阐明PGC-SCZ GWAS结果的生物学意义，但与这些已知的可药用靶点相关的途径可能是一个有希望的起点。
The Psychiatric Genomics Consortium–Schizophrenia Workgroup (PGC–SCZ) has recently published a genomewide association study (GWAS) identifying >100 genetic loci, encompassing a total of 341 protein-coding genes, attaining genomewide significance for susceptibility to schizophrenia. Given the extremely long time (12–15 years) and expense (>$1 billion) associated with the development of novel drug targets, repurposing of drugs with known and validated targets may be the most expeditious path toward deriving clinical utility from these GWAS findings. In the present study, we examined all genes within loci implicated by the PGC–SCZ GWAS against databases of targets of both approved and registered pharmaceutical compounds. We identified 20 potential schizophrenia susceptibility genes that encode proteins that are the targets of approved drugs. Of these, we prioritized genes/targets that are of clear neuropsychiatric interest and that are also sole members of the linkage disequilibrium block surrounding a PGC–SCZ GWAS hit. In addition to DRD2, 5 genes meet these criteria: CACNA1C, CACNB2, CACNA1I, GRIN2A and HCN1. An additional 20 genes coding for proteins that are the targets of drugs in registered clinical trials, but without approved indications, were also identified. Although considerable work is still required to fully explicate the biological implications of the PGC–SCZ GWAS results, pathways related to these known, druggable targets may represent a promising starting point.
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影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
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影响因子：
30.8
作者：
Kathiresan, Sekar;Melander, Olle;Guiducci, Candace;Surti, Aarti;Burtt, Noel P.;Rieder, Mark J.;Cooper, Gregory M.;Roos, Charlotta;Voight, Benjamin F.;Havulinna, Aki S.;Wahlstrand, Bjorn;Hedner, Thomas;Corella, Dolores;Tai, E. Shyong;Ordovas, Jose M.;Berglund, Goran;Vartiainen, Erkki;Jousilahti, Pekka;Hedblad, Bo;Taskinen, Marja-Riitta;Newton-Cheh, Christopher;Salomaa, Veikko;Peltonen, Leena;Groop, Leif;Altshuler, David M.;Orho-Melander, Marju
通讯作者：
Orho-Melander, Marju
影响因子：
11
作者：
Gershon, E. S.;Grennan, K.;Busnello, J.;Badner, J. A.;Ovsiew, F.;Memon, S.;Alliey-Rodriguez, N.;Cooper, J.;Romanos, B.;Liu, C.
通讯作者：
Liu, C.
影响因子：
1.7
作者：
Egan, Michael F.;Zhao, Xin;Michelson, David
通讯作者：
Michelson, David
影响因子：
17.1
作者：
Collins, Francis S.
通讯作者：
Collins, Francis S.