A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
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DOI：
10.1007/s00439-011-1094-6
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发表时间：
2012-04
期刊：
影响因子：
5.3
通讯作者：
Ennis S
中科院分区：
文献类型：
--
作者：
Casey JP;Magalhaes T;Conroy JM;Regan R;Shah N;Anney R;Shields DC;Abrahams BS;Almeida J;Bacchelli E;Bailey AJ;Baird G;Battaglia A;Berney T;Bolshakova N;Bolton PF;Bourgeron T;Brennan S;Cali P;Correia C;Corsello C;Coutanche M;Dawson G;de Jonge M;Delorme R;Duketis E;Duque F;Estes A;Farrar P;Fernandez BA;Folstein SE;Foley S;Fombonne E;Freitag CM;Gilbert J;Gillberg C;Glessner JT;Green J;Guter SJ;Hakonarson H;Holt R;Hughes G;Hus V;Igliozzi R;Kim C;Klauck SM;Kolevzon A;Lamb JA;Leboyer M;Le Couteur A;Leventhal BL;Lord C;Lund SC;Maestrini E;Mantoulan C;Marshall CR;McConachie H;McDougle CJ;McGrath J;McMahon WM;Merikangas A;Miller J;Minopoli F;Mirza GK;Munson J;Nelson SF;Nygren G;Oliveira G;Pagnamenta AT;Papanikolaou K;Parr JR;Parrini B;Pickles A;Pinto D;Piven J;Posey DJ;Poustka A;Poustka F;Ragoussis J;Roge B;Rutter ML;Sequeira AF;Soorya L;Sousa I;Sykes N;Stoppioni V;Tancredi R;Tauber M;Thompson AP;Thomson S;Tsiantis J;Van Engeland H;Vincent JB;Volkmar F;Vorstman JA;Wallace S;Wang K;Wassink TH;White K;Wing K;Wittemeyer K;Yaspan BL;Zwaigenbaum L;Betancur C;Buxbaum JD;Cantor RM;Cook EH;Coon H;Cuccaro ML;Geschwind DH;Haines JL;Hallmayer J;Monaco AP;Nurnberger JI Jr;Pericak-Vance MA;Schellenberg GD;Scherer SW;Sutcliffe JS;Szatmari P;Vieland VJ;Wijsman EM;Green A;Gill M;Gallagher L;Vicente A;Ennis S
自闭症谱系障碍（ASD）是一种病因复杂且多样、具有高度遗传性的疾病。它主要表现为认知能力改变，包括语言和沟通技能受损以及社交互动方面的基本缺陷。尽管在神经精神遗传学方面取得了一些显著成就，但总体而言，常见的遗传风险变异对自闭症谱系障碍约90%的高遗传率解释力很差。然而，近期研究表明，罕见的基因组变异，特别是拷贝数变异，可能在自闭症谱系障碍的遗传基础中占很大比例。我们进行了一项大规模分析，以识别可能包含导致自闭症谱系障碍的低频隐性变异的候选基因，同时考虑到群体差异对自闭症谱系障碍遗传异质性的潜在影响。我们的策略——纯合单倍型（HH）图谱分析，旨在检测在自闭症谱系障碍患者中比其父母对照组更频繁出现的具有相同单倍型结构的纯合片段。该分析是对1402个自闭症基因组计划的三联体进行的，这些三联体针对100万个单核苷酸多态性（SNP）进行了基因分型。我们在发现性分析中确定了25个已知的和1218个新的自闭症谱系障碍候选基因，包括CADM2、ABHD14A、CHRFAM7A、GRIK2、GRM3、EPHA3、FGF10、KCND2、PDZK1、IMMP2L和FOXP2。此外，在发现性分析中确定的先前报道的10个自闭症谱系障碍基因和300个新的候选基因在1182个三联体的独立样本中得到了验证。我们的研究结果表明，HH区域中先前报道的自闭症谱系障碍候选基因显著富集，且观察到的关联与基因大小无关（优势比为2.10）。我们的研究结果突显了HH图谱分析在自闭症谱系障碍等复杂疾病中的适用性，并为全基因组关联数据的分析提供了一种替代方法。
本文的网络版（doi:10.1007/s00439 - 011 - 1094 - 6）包含补充材料，授权用户可获取。
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data. The online version of this article (doi:10.1007/s00439-011-1094-6) contains supplementary material, which is available to authorized users.
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影响因子：
30.8
作者：
Durand, Christelle M.;Betancur, Catalina;Bourgeron, Thomas
通讯作者：
Bourgeron, Thomas
影响因子：
10.6
作者：
Liu, Xiao-Qing;Paterson, Andrew D.;Szatmari, Peter
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影响因子：
64.8
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Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
DOI：
10.1002/ajmg.b.30306
发表时间：
2006-09-05
影响因子：
2.8
作者：
Flomen, Rachel H.;Collier, David A.;Makoff, Andrew J.
通讯作者：
Makoff, Andrew J.
影响因子：
56.9
作者：
Gabriel, SB;Schaffner, SF;Altshuler, D
通讯作者：
Altshuler, D