Genetic Copy Number Variation and General Cognitive Ability

Differences in genomic structure between individuals are ubiquitous features of human genetic variation. Specific copy number variants (CNVs) have been associated with susceptibility to numerous complex psychiatric disorders, including attention-deficit-hyperactivity disorder, autism-spectrum disorders and schizophrenia. These disorders often display co-morbidity with low intelligence. Rare chromosomal deletions and duplications are associated with these disorders, so it has been suggested that these deletions or duplications may be associated with differences in intelligence. Here we investigate associations between large (≥500kb), rare (<1% population frequency) CNVs and both fluid and crystallized intelligence in community-dwelling older people. We observe no significant associations between intelligence and total CNV load. Examining individual CNV regions previously implicated in neuropsychological disorders, we find suggestive evidence that CNV regions around SHANK3 are associated with fluid intelligence as derived from a battery of cognitive tests. This is the first study to examine the effects of rare CNVs as called by multiple algorithms on cognition in a large non-clinical sample, and finds no effects of such variants on general cognitive ability.

个体间基因组结构差异是人类遗传变异的普遍特征。特定拷贝数变异（copy number variants, CNVs）已被证实与多种复杂精神疾病的易感性相关，包括注意缺陷多动障碍（attention-deficit-hyperactivity disorder）、孤独症谱系障碍（autism-spectrum disorders）及精神分裂症（schizophrenia）。此类疾病往往与低智力水平存在共病现象。鉴于罕见染色体缺失与重复事件与上述疾病存在关联，据此推测这类缺失或重复变异可能与智力水平差异相关。本研究针对社区居住的老年人群体，探究了大片段（≥500kb）、低频（人群频率<1%）拷贝数变异与流体智力及晶体智力之间的关联。研究未发现智力水平与总拷贝数变异负荷存在显著关联。在对既往被证实与神经精神疾病相关的单个拷贝数变异区域进行分析后，我们发现提示性证据表明，SHANK3基因周边的拷贝数变异区域与通过一套认知测验组合评估得到的流体智力存在关联。本研究是首个在大型非临床样本中，探究多种算法鉴定的低频拷贝数变异对认知功能影响的研究，结果未发现此类变异对一般认知能力存在影响。