De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.
De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.
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DOI：
10.1038/mp.2014.29
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发表时间：
2014-06
影响因子：
11
通讯作者：
Corvin, A.
中科院分区：
文献类型：
--
作者：
McCarthy, S. E.;Gillis, J.;Kramer, M.;Lihm, J.;Yoon, S.;Berstein, Y.;Mistry, M.;Pavlidis, P.;Solomon, R.;Ghiban, E.;Antoniou, E.;Kelleher, E.;O'Brien, C.;Donohoe, G.;Gill, M.;Morris, D. W.;McCombie, W. R.;Corvin, A.
精神分裂症是一种严重的精神疾病，其遗传病因尚未被发现。最近对精神分裂症和自闭症的从头突变(DNM)的研究加强了这样一个假设，即罕见的基因变异有助于风险。我们对57例散发性或家族性精神分裂症患者进行了外显子组测序。在散发性三联体中，我们观察到无义从头突变(DNM)的比例增加了约3.5%(0.101比0.031，经验证性P=0.01BH校正P=0.044)。这些突变更有可能发生在单倍体功能不全的高概率基因中(P=0.0029，校正后P=0.006)。对罕见变异的耐受性较差(P=2.0 1×10−5，校正后P=2.1×10−3)。DNMS的基因与自闭症(例如AUTS2、CDH8、MECP2)和智能障碍(ID)(例如HUWE1和TRAPPC9)有关的基因重叠，支持这些疾病之间的共同遗传病因。在功能上，CHD8、MECP2和HUWE1在转录的表观遗传调控上趋同，提示这可能是一个重要的风险机制。我们的结果在对其他神经发育障碍的基于外显子组的测序研究的分析中是一致的。这些发现表明，在大脑发育和认知的表观遗传调节中起作用的基因的扰动可能在精神障碍的易感性、发病机制和治疗中发挥核心作用。
Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNM) in schizophrenia and autism have reinforced the hypothesis that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense de novo mutations (DNMs) (0.101 vs. 0.031, empirical P=0.01, BH-corrected P=0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency (P=0.0029, corrected P=0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation (P=2.01×10−5, corrected P =2.1×10−3). Genes with DNMs overlapped with genes implicated in autism (e.g. AUTS2, CDH8, MECP2) and intellectual disability (ID) (e.g. HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders. Functionally CHD8, MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes which function in the epigenetic regulation of brain development and cognition could have a central role in the susceptibility to, pathogenesis, and treatment of mental disorders.
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DOI：
10.1126/science.1215040
发表时间：
2012-02-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
MacArthur DG;Balasubramanian S;Frankish A;Huang N;Morris J;Walter K;Jostins L;Habegger L;Pickrell JK;Montgomery SB;Albers CA;Zhang ZD;Conrad DF;Lunter G;Zheng H;Ayub Q;DePristo MA;Banks E;Hu M;Handsaker RE;Rosenfeld JA;Fromer M;Jin M;Mu XJ;Khurana E;Ye K;Kay M;Saunders GI;Suner MM;Hunt T;Barnes IH;Amid C;Carvalho-Silva DR;Bignell AH;Snow C;Yngvadottir B;Bumpstead S;Cooper DN;Xue Y;Romero IG;1000 Genomes Project Consortium;Wang J;Li Y;Gibbs RA;McCarroll SA;Dermitzakis ET;Pritchard JK;Barrett JC;Harrow J;Hurles ME;Gerstein MB;Tyler-Smith C
通讯作者：
Tyler-Smith C
影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
影响因子：
5.8
作者：
Barnett, Derek W.;Garrison, Erik K.;Marth, Gabor T.
通讯作者：
Marth, Gabor T.
影响因子：
16.2
作者：
Malhotra D;McCarthy S;Michaelson JJ;Vacic V;Burdick KE;Yoon S;Cichon S;Corvin A;Gary S;Gershon ES;Gill M;Karayiorgou M;Kelsoe JR;Krastoshevsky O;Krause V;Leibenluft E;Levy DL;Makarov V;Bhandari A;Malhotra AK;McMahon FJ;Nöthen MM;Potash JB;Rietschel M;Schulze TG;Sebat J
通讯作者：
Sebat J
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.