Autism spectrum disorder severity reflects the average contribution of de novo and familial influences
Autism spectrum disorder severity reflects the average contribution of de novo and familial influences
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DOI：
10.1073/pnas.1409204111
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发表时间：
2014-10-21
影响因子：
11.1
通讯作者：
Daly, Mark J.
中科院分区：
文献类型：
--
作者：
Robinson, Elise B.;Samocha, Kaitlin E.;Daly, Mark J.
自闭症谱系障碍（ASD）是一组在表型和遗传上高度异质的疾病，尽管表型变异和遗传结构差异之间的联系尚不清楚。本研究旨在确定认知障碍和症状严重程度的差异是否反映了自闭症谱系障碍病例反映新发或家族影响程度的差异。我们利用 2000 多例自闭症谱系障碍 (ASD) 单发病例的数据，研究了智商 (IQ)、行为和语言评估、新发功能丧失 (LOF) 突变率和广义精神疾病（抑郁症、双相情感障碍和精神分裂症；精神科住院史）家族史之间的关系。先证者智商与新发LOF率呈负相关（P=0.03），与精神疾病家族史呈正相关（P=0.003）。在整个严重程度分布中，女性病例的散发性遗传事件发生频率较高（P = 0.01）。在无法完成传统智商测试的个体（语言和行为障碍程度最高的群体）中，LOF 突变率高，精神疾病家族史频率低。这些分析提供了强有力的证据，表明随着病例功能的提高，神经精神疾病的家族风险与自闭症谱系障碍的病因学变得更加相关。这项研究的结果强化了自闭症诊断类别有多种途径，并且可能导致基因研究对个体病例有更具体的了解。
Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions-phenotypically and genetically-although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.