Novel autism subtype-dependent genetic variants are revealed by quantitative trait and subphenotype association analyses of published GWAS data.
Novel autism subtype-dependent genetic variants are revealed by quantitative trait and subphenotype association analyses of published GWAS data.
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DOI：
10.1371/journal.pone.0019067
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发表时间：
2011-04-27
期刊：
影响因子：
3.7
通讯作者：
Hyman A
中科院分区：
文献类型：
--
作者：
Hu VW;Addington A;Hyman A
自闭症谱系障碍（ASD）相关症状的异质性对遗传分析提出了重大挑战。即使已经确定了与遗传变异的关联，也很难将它们与自闭症的特定特征或特征联系起来。在这里，我们报告说，ASD症状的定量性状分析结合病例对照关联分析，使用不同的ASD亚表型的基础上确定的症状配置文件的结果，在识别高度显着的关联与18个新的单核苷酸多态性（SNP）。症状类别包括语言使用、非语言交流、社会发展和游戏技能方面的缺陷，以及坚持相同或仪式性行为。10个性状相关的SNP或数量性状位点（QTL）与一个以上的亚型相关，提供了所鉴定的QTL的部分复制。值得注意的是，没有一个新的SNP位于外显子区域内，这表明ASD的这些遗传成分更可能与基因调控过程（或基因表达）有关，而不是基因产物的结构或功能变化。其中7个QTL位于基因间染色体区域内，这些区域与先前在自闭症样本中报道的罕见拷贝数变异相关。与本研究中确定的QTL相关的基因的通路分析涉及与自闭症病理生理学相关的神经功能和障碍。这项研究强调了将数量性状和亚表型结合到复杂疾病的大规模全基因组分析中的优势。
The heterogeneity of symptoms associated with autism spectrum disorders (ASDs) has presented a significant challenge to genetic analyses. Even when associations with genetic variants have been identified, it has been difficult to associate them with a specific trait or characteristic of autism. Here, we report that quantitative trait analyses of ASD symptoms combined with case-control association analyses using distinct ASD subphenotypes identified on the basis of symptomatic profiles result in the identification of highly significant associations with 18 novel single nucleotide polymorphisms (SNPs). The symptom categories included deficits in language usage, non-verbal communication, social development, and play skills, as well as insistence on sameness or ritualistic behaviors. Ten of the trait-associated SNPs, or quantitative trait loci (QTL), were associated with more than one subtype, providing partial replication of the identified QTL. Notably, none of the novel SNPs is located within an exonic region, suggesting that these hereditary components of ASDs are more likely related to gene regulatory processes (or gene expression) than to structural or functional changes in gene products. Seven of the QTL reside within intergenic chromosomal regions associated with rare copy number variants that have been previously reported in autistic samples. Pathway analyses of the genes associated with the QTL identified in this study implicate neurological functions and disorders associated with autism pathophysiology. This study underscores the advantage of incorporating both quantitative traits as well as subphenotypes into large-scale genome-wide analyses of complex disorders.
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影响因子：
1.9
作者：
Ma D;Salyakina D;Jaworski JM;Konidari I;Whitehead PL;Andersen AN;Hoffman JD;Slifer SH;Hedges DJ;Cukier HN;Griswold AJ;McCauley JL;Beecham GW;Wright HH;Abramson RK;Martin ER;Hussman JP;Gilbert JR;Cuccaro ML;Haines JL;Pericak-Vance MA
通讯作者：
Pericak-Vance MA
影响因子：
6.9
作者：
BAILEY, A;LECOUTEUR, A;RUTTER, M
通讯作者：
RUTTER, M
DOI：
10.1097/01.chi.0000046868.56865.0f
发表时间：
2003-07-01
影响因子：
13.3
作者：
Nurmi, EL;Dowd, M;Sutcliffe, JS
通讯作者：
Sutcliffe, JS
影响因子：
8.6
作者：
Cao, Li;Zheng, Lan;Chen, Sheng-Di
通讯作者：
Chen, Sheng-Di
影响因子：
17.7
作者：
Duvall, Jacqueline A.;Lu, Ake;Geschwind, Daniel H.
通讯作者：
Geschwind, Daniel H.