Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
Center Hospitalier Universitaire Sainte-Justine Research Center, Montreal, Quebec, Canada.
JAMA Psychiatry. 2018 May 1;75(5):447-457. doi: 10.1001/jamapsychiatry.2018.0039.
IMPORTANCE;: Copy number variants (CNVs) classified as pathogenic are identified in 10% to 15% of patients referred for neurodevelopmental disorders. However, their effect sizes on cognitive traits measured as a continuum remain mostly unknown because most of them are too rare to be studied individually using association studies.
To measure and estimate the effect sizes of recurrent and nonrecurrent CNVs on IQ.
DESIGN, SETTING, AND PARTICIPANTS: This study identified all CNVs that were 50 kilobases (kb) or larger in 2 general population cohorts (the IMAGEN project and the Saguenay Youth Study) with measures of IQ. Linear regressions, including functional annotations of genes included in CNVs, were used to identify features to explain their association with IQ. Validation was performed using intraclass correlation that compared IQ estimated by the model with empirical data.
Performance IQ (PIQ), verbal IQ (VIQ), and frequency of de novo CNV events.
The study included 2090 European adolescents from the IMAGEN study and 1983 children and parents from the Saguenay Youth Study. Of these, genotyping was performed on 1804 individuals from IMAGEN and 977 adolescents, 445 mothers, and 448 fathers (484 families) from the Saguenay Youth Study. We observed 4928 autosomal CNVs larger than 50 kb across both cohorts. For rare deletions, size, number of genes, and exons affect IQ, and each deleted gene is associated with a mean (SE) decrease in PIQ of 0.67 (0.19) points (P = 6 × 10-4); this is not so for rare duplications and frequent CNVs. Among 10 functional annotations, haploinsufficiency scores best explain the association of any deletions with PIQ with a mean (SE) decrease of 2.74 (0.68) points per unit of the probability of being loss-of-function intolerant (P = 8 × 10-5). Results are consistent across cohorts and unaffected by sensitivity analyses removing pathogenic CNVs. There is a 0.75 concordance (95% CI, 0.39-0.91) between the effect size on IQ estimated by our model and IQ loss calculated in previous studies of 15 recurrent CNVs. There is a close association between effect size on IQ and the frequency at which deletions occur de novo (odds ratio, 0.86; 95% CI, 0.84-0.87; P = 2.7 × 10-88). There is a 0.76 concordance (95% CI, 0.41-0.91) between de novo frequency estimated by the model and calculated using data from the DECIPHER database.
Models trained on nonpathogenic deletions in the general population reliably estimate the effect size of pathogenic deletions and suggest omnigenic associations of haploinsufficiency with IQ. This represents a new framework to study variants too rare to perform individual association studies and can help estimate the cognitive effect of undocumented deletions in the neurodevelopmental clinic.
在因神经发育障碍而就诊的患者中,有 10%至 15%被鉴定出存在致病性拷贝数变异 (CNVs)。然而,由于大多数 CNVs 太罕见,无法使用关联研究逐个进行研究,因此它们对作为连续体测量的认知特征的效应大小大多仍不清楚。
测量和估计反复出现和非反复出现的 CNVs 对智商的影响大小。
设计、设置和参与者:本研究在具有智商测量值的 2 个普通人群队列(IMAGEN 项目和 Saguenay 青年研究)中确定了所有大小为 50 千碱基 (kb) 或更大的 CNVs。线性回归,包括包含在 CNVs 中的基因的功能注释,用于识别解释它们与智商关联的特征。验证是通过比较模型估计的智商与经验数据的内类相关来进行的。
表现智商 (PIQ)、言语智商 (VIQ) 和新生 CNV 事件的频率。
该研究包括来自 IMAGEN 研究的 2090 名欧洲青少年和来自 Saguenay 青年研究的 1983 名儿童及其父母。其中,对 1804 名来自 IMAGEN 的个体和 977 名青少年、445 名母亲和 448 名父亲(484 个家庭)进行了基因分型。我们在两个队列中观察到 4928 个大于 50 kb 的常染色体 CNVs。对于罕见缺失,大小、基因数量和外显子会影响智商,每个缺失的基因与 PIQ 平均(SE)降低 0.67(0.19)点相关(P = 6×10-4);对于罕见重复和常见 CNVs 则不是这样。在 10 种功能注释中,杂合不足评分最好地解释了任何缺失与 PIQ 的关联,每个单位的概率降低 2.74(0.68)点,丧失功能不耐受(P = 8×10-5)。结果在队列之间是一致的,不受去除致病性 CNVs 的敏感性分析的影响。我们的模型估计的对智商的影响大小与以前对 15 个反复出现的 CNVs 的研究中计算的智商损失之间存在 0.75 的一致性(95%CI,0.39-0.91)。在 IQ 上的效应大小与新生缺失发生的频率之间存在密切关联(比值比,0.86;95%CI,0.84-0.87;P = 2.7×10-88)。通过模型估计的新生频率与从 DECIPHER 数据库计算的频率之间存在 0.76 的一致性(95%CI,0.41-0.91)。
在普通人群中非致病性缺失上训练的模型可靠地估计了致病性缺失的效应大小,并表明杂合不足与智商存在全基因组关联。这代表了一种研究太罕见而无法进行个体关联研究的变体的新框架,并有助于估计神经发育诊所中未记录缺失对认知的影响。