Chaste Pauline, Klei Lambertus, Sanders Stephan J, Hus Vanessa, Murtha Michael T, Lowe Jennifer K, Willsey A Jeremy, Moreno-De-Luca Daniel, Yu Timothy W, Fombonne Eric, Geschwind Daniel, Grice Dorothy E, Ledbetter David H, Mane Shrikant M, Martin Donna M, Morrow Eric M, Walsh Christopher A, Sutcliffe James S, Lese Martin Christa, Beaudet Arthur L, Lord Catherine, State Matthew W, Cook Edwin H, Devlin Bernie
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; FondaMental Foundation, Créteil; Centre Hospitalier Sainte Anne, Paris, France.
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Biol Psychiatry. 2015 May 1;77(9):775-84. doi: 10.1016/j.biopsych.2014.09.017. Epub 2014 Sep 30.
Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD.
Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup.
Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups.
In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.
长期以来，人们一直推测自闭症的表型异质性是发现遗传风险因素的主要障碍，这导致了无数次尝试根据表型对儿童进行分层，以提高发现性研究的效力。然而，这种方法基于表型异质性与遗传变异紧密相关的假设，而这一假设尚未得到验证。我们的研究考察了对一个特征明确的自闭症谱系障碍（ASD）样本进行亚分型，对遗传同质性以及发现赋予ASD易感性的常见遗传变异的能力的影响。
对来自西蒙斯单纯型病例集的2576个家庭的全基因组基因型数据在总体样本以及基于诊断、智商和症状谱定义的表型亚组中进行分析。我们开展了一项基于家系的关联研究，同时估计了遗传力，并评估了每个表型亚组的等位基因分数。
关联分析未发现全基因组显著的关联信号。亚分型并没有显著提高效力。此外，基于全样本中的优势比，由最相关的单核苷酸多态性构建的等位基因分数，对样本子集的病例状态预测效果同样良好，并且所有亚组的遗传力估计值非常相似。
在对西蒙斯单纯型病例集样本进行全基因组关联分析时，减少表型异质性对遗传同质性的影响至多是适度的。我们的结果基于一个相对较小的样本，该样本比整个人口具有更高的同质性；如果它们更广泛适用，这意味着对亚表型的分析并非发现ASD遗传风险变异的有效途径。
