Cognitive Performance 认知表现 Among Carriers of Pathogenic Copy Number Variants: Analysis of 152,000 UK Biobank Subjects

Copy number variants (CNVs) are >1000 base pair DNA segments that are present at a variable copy number in comparison with a reference genome (1,2). CNVs may be recurrent （多发型） and have similar breakpoints when they are formed by nonallelic homologous recombination between sites of low copy repeats, or nonrecurrent （希发型）, with variable breakpoints, when formed as a result of defects in DNA replication or repair (3). There is an increased rate of CNVs in neurodevelopmental spectrum disorders, including intellectual disability (ID), autism spectrum disorder (ASD) (4,5), epilepsy 癫痫 (6), and schizophrenia (7). To date, 12 CNVs have been robustly associated with risk of schizophrenia, and they also increase risk of ASD and ID (7,8). Many more CNVs are implicated in ID, ASD, and cases with congenital anomalies 先天畸形 (4,5) but they have not been implicated in schizophrenia, although this could be due to insufficient statistical power (8).

CNV不应设定绝对的大小范围。依据其发生机制，可以单独讨论NAHR CNV。

The phenotypes of many highly penetrant CNVs 研究透彻的CNVs, such as those implicated in Prader-Willi syndrome/Angelman syndrome 在我国第一批罕见病目录里有介绍 or DiGeorge syndrome 发育不完全，畸形, are well established. Many others have incomplete penetrance (9), and their phenotypic spectrum is not fully established (e.g., 1q21.1 duplication, 15q11.2 deletion). There are many adult carriers of incompletely penetrant CNVs in the general population, who have escaped the development of early-onset developmental disorders and are apparently healthy. However, they might still have an increased burden of cognitive or physical impairments 认知与身体损伤.

Limited data, based on relatively small sample sizes, are available on the cognitive phenotypes of CNVs in adults. An Icelandic study of 144 carriers of 11 pathogenic CNVs found that healthy CNV carriers had impaired cognition and performed intermediately between CNV noncarriers and individuals with schizophrenia (10). An Estonian study of 56 CNV carriers found an association between rare CNVs （此处与nonrecurrent CNVs是同一概念？） and lower educational attainment (11).

The UK Biobank provides a great opportunity to study the effects of pathogenic CNVs on physical and mental health characteristics, especially the incompletely penetrant ones. The half a million individuals recruited by the Biobank have provided extensive demographic 人口统计学, health, and cognitive data; will be followed up prospectively; and are being genotyped on Affymetrix microarrays. We aimed to identify pathogenic CNVs in the first 152,728 individuals in the UK Biobank for whom genotype data have been released so far and to analyze the cognitive consequences of neurodevelopmental CNVs.