Excess of rare, inherited truncating mutations in autism.
Excess of rare, inherited truncating mutations in autism.
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DOI：
10.1038/ng.3303
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发表时间：
2015-06
期刊：
影响因子：
30.8
通讯作者：
Eichler, Evan E.
中科院分区：
文献类型：
--
作者：
Krumm, Niklas;Turner, Tychele N.;Baker, Carl;Vives, Laura;Mohajeri, Kiana;Witherspoon, Kali;Raja, Archana;Coe, Bradley P.;Stessman, Holly A.;He, Zong-Xiao;Leal, Suzanne M.;Bernier, Raphael;Eichler, Evan E.
为了评估遗传性变异和新生变异对自闭症风险的相对影响，我们从2377个自闭症家庭中生成了一套全面的外显子单核苷酸变异（SNV）和拷贝数变异（CNV）。我们发现，与未受影响的兄弟姐妹相比，在保守基因中个体特有的遗传性截断SNV在患者中更为富集（优势比 = 1.14，p = 0.0002），并且存在明显的母亲向儿子的遗传偏向。我们还观察到遗传性CNV存在偏向，特别是对于小型（<100kbp）、母系遗传的事件（p = 0.01），这些事件在CHD8靶基因中更为富集（p = 7.4×10⁻³）。使用逻辑回归模型，我们表明个体特有的截断SNV和罕见的遗传性CNV是统计学上独立的自闭症风险因素，优势比分别为1.11（p = 0.0002）和1.23（p = 0.01）。这项分析确定了第二类候选基因（例如，RIMS1、CUL7和LZTR1），其中传递的突变可能会产生一种敏感背景，但不太可能是完全外显的。
To assess the relative impact of inherited and de novo variants on autism risk, we generated a comprehensive set of exonic single nucleotide variants (SNVs) and copy number variants (CNVs) from 2,377 autism families. We find that private, inherited truncating SNVs in conserved genes are enriched in probands (odds ratio=1.14, p=0.0002) compared to unaffected siblings, an effect with significant maternal transmission bias to sons. We also observe a bias for inherited CNVs, specifically for small (<100 kbp), maternally inherited events (p=0.01) that are enriched in CHD8 target genes (p=7.4×10−3). Using a logistic regression model, we show that private truncating SNVs and rare, inherited CNVs are statistically independent autism risk factors, with odds ratios of 1.11 (p=0.0002) and 1.23 (p=0.01), respectively. This analysis identifies a second class of candidate genes (e.g., RIMS1, CUL7, and LZTR1) where transmitted mutations may create a sensitized background but are unlikely to be completely penetrant.
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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
自闭症谱系障碍中基因和细胞途径的收敛性。
影响因子：
9.8
作者：
Pinto D;Delaby E;Merico D;Barbosa M;Merikangas A;Klei L;Thiruvahindrapuram B;Xu X;Ziman R;Wang Z;Vorstman JA;Thompson A;Regan R;Pilorge M;Pellecchia G;Pagnamenta AT;Oliveira B;Marshall CR;Magalhaes TR;Lowe JK;Howe JL;Griswold AJ;Gilbert J;Duketis E;Dombroski BA;De Jonge MV;Cuccaro M;Crawford EL;Correia CT;Conroy J;Conceição IC;Chiocchetti AG;Casey JP;Cai G;Cabrol C;Bolshakova N;Bacchelli E;Anney R;Gallinger S;Cotterchio M;Casey G;Zwaigenbaum L;Wittemeyer K;Wing K;Wallace S;van Engeland H;Tryfon A;Thomson S;Soorya L;Rogé B;Roberts W;Poustka F;Mouga S;Minshew N;McInnes LA;McGrew SG;Lord C;Leboyer M;Le Couteur AS;Kolevzon A;Jiménez González P;Jacob S;Holt R;Guter S;Green J;Green A;Gillberg C;Fernandez BA;Duque F;Delorme R;Dawson G;Chaste P;Café C;Brennan S;Bourgeron T;Bolton PF;Bölte S;Bernier R;Baird G;Bailey AJ;Anagnostou E;Almeida J;Wijsman EM;Vieland VJ;Vicente AM;Schellenberg GD;Pericak-Vance M;Paterson AD;Parr JR;Oliveira G;Nurnberger JI;Monaco AP;Maestrini E;Klauck SM;Hakonarson H;Haines JL;Geschwind DH;Freitag CM;Folstein SE;Ennis S;Coon H;Battaglia A;Szatmari P;Sutcliffe JS;Hallmayer J;Gill M;Cook EH;Buxbaum JD;Devlin B;Gallagher L;Betancur C;Scherer SW
通讯作者：
Scherer SW
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
6.2
作者：
Bozdagi O;Tavassoli T;Buxbaum JD
通讯作者：
Buxbaum JD
影响因子：
6.2
作者：
Cukier HN;Dueker ND;Slifer SH;Lee JM;Whitehead PL;Lalanne E;Leyva N;Konidari I;Gentry RC;Hulme WF;Booven DV;Mayo V;Hofmann NK;Schmidt MA;Martin ER;Haines JL;Cuccaro ML;Gilbert JR;Pericak-Vance MA
通讯作者：
Pericak-Vance MA