Common genetic variants, acting additively, are a major source of risk for autism.
Common genetic variants, acting additively, are a major source of risk for autism.
复制标题
DOI：
10.1186/2040-2392-3-9
复制
发表时间：
2012-10-15
期刊：
影响因子：
6.2
通讯作者：
Devlin B
中科院分区：
文献类型：
--
作者：
Klei L;Sanders SJ;Murtha MT;Hus V;Lowe JK;Willsey AJ;Moreno-De-Luca D;Yu TW;Fombonne E;Geschwind D;Grice DE;Ledbetter DH;Lord C;Mane SM;Martin CL;Martin DM;Morrow EM;Walsh CA;Melhem NM;Chaste P;Sutcliffe JS;State MW;Cook EH Jr;Roeder K;Devlin B
自闭症谱系障碍（ASD）是一种早期发病的神经发育综合征，以互惠社会互动和沟通障碍为特征，伴有限制性和重复性行为。虽然已知罕见的，特别是新生的遗传变异会影响责任，但常见的遗传多态性是否起重要作用是一个悬而未决的问题，基因和环境的相对贡献是有争议的。罕见和常见变异以及环境的相对贡献可能在只有一个受影响个体（单纯性）的ASD家庭与有两个或更多受影响个体的多重家庭之间有所不同。通过使用定量遗传学技术和ASD受试者与对照组的对比，我们估计了可加性遗传效应可以解释的责任部分，即狭义遗传力。我们用同样的方法评估ASD受试者的亲属，以评估加性模型的假设，并通过单一/多重状态划分家庭，以确定遗传力如何随状态变化。通过分析整个基因组的共同变异，我们发现共同的遗传多态性对自闭症谱系障碍的易感性具有显著的加性遗传效应，而单纯性/多重性家庭状态对该风险的确定构成有影响。作为责任总变异的一部分，估计来自多重家庭的ASD个体的狭义遗传率超过60%，而来自单一家庭的狭义遗传率约为40%。通过分析父母、未受影响的兄弟姐妹和未从父母遗传给患病儿童的等位基因，我们得出结论，单纯性ASD家庭的数据与加性模型的预期密切相关。来自多重家庭的数据在某种程度上偏离了加性模型，可能是由于父母的分类交配。我们的研究结果，在全基因组关联研究的背景下，证明了无数的非常小的影响的常见变异影响ASD的倾向性。
Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.
登录
查看更多内容
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：
4.4
作者：
DEVLIN, B;RISCH, N
通讯作者：
RISCH, N
影响因子：
6.9
作者：
BAILEY, A;LECOUTEUR, A;RUTTER, M
通讯作者：
RUTTER, M
影响因子：
--
作者：
Hallmayer, Joachim;Cleveland, Sue;Torres, Andrea;Phillips, Jennifer;Cohen, Brianne;Torigoe, Tiffany;Miller, Janet;Fedele, Angie;Collins, Jack;Smith, Karen;Lotspeich, Linda;Croen, Lisa A.;Ozonoff, Sally;Lajonchere, Clara;Grether, Judith K.;Risch, Neil
通讯作者：
Risch, Neil
影响因子：
30.8
作者：
Berkel, Simone;Marshall, Christian R.;Rappold, Gudrun A.
通讯作者：
Rappold, Gudrun A.