Copy number variations and cognitive phenotypes in unselected populations.
Copy number variations and cognitive phenotypes in unselected populations.
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DOI：
10.1001/jama.2015.4845
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发表时间：
2015-05-26
期刊：
影响因子：
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通讯作者：
Reymond A
中科院分区：
文献类型：
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作者：
Männik K;Mägi R;Macé A;Cole B;Guyatt AL;Shihab HA;Maillard AM;Alavere H;Kolk A;Reigo A;Mihailov E;Leitsalu L;Ferreira AM;Nõukas M;Teumer A;Salvi E;Cusi D;McGue M;Iacono WG;Gaunt TR;Beckmann JS;Jacquemont S;Kutalik Z;Pankratz N;Timpson N;Metspalu A;Reymond A
罕见拷贝数变异（CNVs）与复杂疾病的关联几乎完全使用临床确定的队列进行评估。因此，这些遗传变异对一般人群认知表型的贡献仍不清楚。- 探讨未经临床预选的成人携带者基因组疾病的临床特征。- 评估普通人群中罕见CNV对携带者教育程度和智力残疾患病率的全基因组负担。爱沙尼亚人口生物库（EGCUT）包含52，000名参与者，占2002-2010年登记的爱沙尼亚成年人的5%。全科医生对参与者进行检查，并填写了一份健康和生活方式相关问题的问卷，以及报告的诊断。由于EGCUT是该国人口的代表，我们调查了7877人的CNV分析和基因型-表型与教育和疾病特征的关联的随机样本。一般人群中基因组疾病的表型，常染色体CNV的患病率，以及后者变异与教育程度降低和智力残疾患病率增加的相关性。我们确定了56个基因组疾病的携带者。他们的表型让人想起那些描述的载体相同的重排确定在临床队列。我们还生成了罕见（频率≤0.05%）常染色体CNV的全基因组图谱，并将10.5%的筛查普通人群（n=831）确定为≥ 250 kb CNV的携带者。与爱沙尼亚人口相比，缺失≥ 250 kb或重复≥ 1 Mb的携带者显示智力残疾的患病率更高（P=0.0015，OR=3.16，（95%CI：1.51-5.98）; P=0.0083，OR=3.67，（95%CI：1.29-8.54）），平均教育程度降低（智力的替代指标; P=1.06e-04; P=5.024e-05），中学未毕业的人数比例增加（P=0.005，OR=1.48（95%CI：1.12-1.95）; P=0.0016，OR=1.89（95%CI：1.27-2.8））。这些缺失显示了在神经发生、认知、学习、记忆和行为中起作用的基因富集的证据。罕见的CNVs和教育程度下降之间的关联的证据得到了意大利（HYPERGENES）和欧洲美国人（明尼苏达州双胞胎和家庭研究中心）个体的成人队列分析，以及雅芳父母和儿童纵向研究（ALSPAC）出生队列分析的证实。我们的研究结果挑战了在人群队列中发现的已知综合征CNVs携带者无症状的假设。他们还表明，个别罕见，但集体常见的中等大小的CNVs有助于教育程度的差异。考虑到这一观察结果对基因组学研究、临床护理和公共卫生的潜在影响，有必要在其他人群中对这些发现进行改进。
The association of rare copy number variants (CNVs) with complex disorders is almost exclusively evaluated using clinically ascertained cohorts. As a result, the contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. - To investigate the clinical features of genomic disorders in adult carriers without clinical pre-selection. - To assess the genome-wide burden of rare CNVs on carriers’ educational attainment and intellectual disability prevalence in the general population. The population biobank of Estonia (EGCUT) contains 52,000 participants, or 5% of the Estonian adults, enrolled in 2002-2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. As EGCUT is representative of the country's population, we investigated a random sample of 7877 individuals for CNV analysis and genotype-phenotype associations with education and disease traits. Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of the latter variants with decreased educational attainment and increased prevalence of intellectual disability. We identified 56 carriers of genomic disorders. Their phenotypes are reminiscent of those described for carriers of identical rearrangements ascertained in clinical cohorts. We also generated a genome-wide map of rare (frequency ≤0.05%) autosomal CNVs and identified 10.5% of the screened general population (n=831) as carriers of CNVs ≥250kb. Carriers of deletions ≥250kb or duplications ≥1Mb show, compared to the Estonian population, a greater prevalence of intellectual disability (P=0.0015, OR=3.16, (95%CI: 1.51-5.98); P=0.0083, OR=3.67, (95%CI: 1.29-8.54), respectively), reduced mean education attainment (a proxy for intelligence; P=1.06e-04; P=5.024e-05, respectively) and an increased fraction of individuals not graduating from secondary school (P=0.005, OR=1.48 (95%CI: 1.12-1.95); P=0.0016, OR=1.89 (95%CI: 1.27-2.8), respectively). The deletions show evidence of enrichment for genes with a role in neurogenesis, cognition, learning, memory and behavior. Evidence for an association between rare CNVs and decreased educational attainment was confirmed by analyses in adult cohorts of Italian (HYPERGENES) and European American (Minnesota Center for Twin and Family Research) individuals, as well as in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Our results challenge the assumption that carriers of known syndromic CNVs identified in population cohorts are asymptomatic. They also indicate that individually rare but collectively common intermediate-size CNVs contribute to the variance in educational attainment. Refinements of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.