No Effect of Genome-Wide Copy Number Variation on Measures of Intelligence in a New Zealand Birth Cohort

Variation in human intelligence is approximately 50% heritable, but understanding of the genes involved is limited. Several forms of genetic variation remain under-studied in relation to intelligence, one of which is copy number variation (CNV). Using single-nucleotide polymorphism (SNP) -based microarrays, we genotyped CNVs genome-wide in a birth cohort of 723 New Zealanders, and correlated them with four intelligence-related phenotypes. We found no significant association for any common CNV after false discovery correction, which is consistent with previous work. In contrast to a previous study, however, we found no effect on any cognitive measure of rare CNV burden, defined as total number of bases inserted or deleted in CNVs rarer than 5%. We discuss possible reasons for this failure to replicate, including interaction between CNV and aging in determining the effects of rare CNVs. While our results suggest that no CNV assayable by SNP chips contributes more than a very small amount to variation in human intelligence, it remains possible that common CNVs in segmental duplication arrays, which are not well covered by SNP chips, are important contributors.

人类智力的变异约有50%具有遗传性，但当前对其所涉及的基因的认知仍存在局限。目前有多种遗传变异类型与智力的关联尚未得到充分研究，其中之一便是拷贝数变异（copy number variation, CNV）。本研究采用基于单核苷酸多态性（single-nucleotide polymorphism, SNP）的微阵列技术，对723名新西兰人组成的出生队列开展全基因组CNV基因分型，并将分型结果与四种智力相关表型进行关联分析。经错误发现校正后，未发现任何常见CNV存在显著关联，该结果与既往研究结论一致。但与此前一项研究不同的是，本研究未观察到罕见CNV负荷（定义为频率低于5%的CNV所插入或缺失的碱基总数量）对任意认知测量指标存在影响。本文探讨了本次未能重复既往研究结果的潜在原因，包括CNV与衰老之间的交互作用对罕见CNV效应的调控。尽管本研究结果表明，通过SNP芯片可检测到的CNV均不会对人类智力变异产生超出极小程度的影响，但仍存在一种可能性：即SNP芯片覆盖度较差的片段重复阵列中的常见CNV，可能是智力变异的重要贡献因素。