Copy Number Variations and Cognitive Phenotypes in Unselected Populations

Abstract

In the human genome, genetic sequences that differ in the numbers of copies, or so-called copy number variations (CNVs), can be associated with intellectual disability and developmental delay. Large, recurrent CNVs are particularly associated with these complex disorders. Previous studies of the effects of large CNVs have generally pediatric subjects with clinical disordered, and there are more limited data on the population frequency in asymptomatic adults. This study looks at the adult carriers of CNVs and aims to assess the consequences of rare CNVs.The study utilized the Estonian Genome Center at the University of Tartu, which includes 52,000 participants. For CVanalysis, genomic DNA from 6819 individuals was used for the discovery cohort and 1058 for the replication cohorts. The phenotypes of CNV carriers were compared with phenotypes in the general population. A third "high-functioning replication cohort" of 933, as well as a UK cohort of 5218, a US cohort of 2390, and an Italian cohort of 451, was used for replication for further analysis regarding education attainment.In the Estonian cohort, 56 of 7877 participants were identified as carriers of known autosomal genomic disorders. Of the 6819 individuals in the discovery cohort, 509 were identified as duplication carriers, and 216 were identified as deletion carriers. Of the 216 deletion carriers of at least 250 kb, 11 (5.1%) had an intellectual disability (odds ratio [OR], 3.16%; 95% confidence interval [CI], 1.51-5.98; P = 1.5E−03). Of 102 carrier with a duplication of at least 1 Mb, 6 (5.9%) had an intellectual disability (OR, 3.67; 95% CI, 1.29-8.54; P = 0.008). This was compared with 114 in the Estonian cohort of 6819 (1.7%); 3.2% of rare CNV carriers were diagnosed with intellectual disabilities, whereas 1.7% of the Estonian cohort was diagnosed with intellectual disability (OR, 1.93; 95% CI, 1.17-3.06; P = 0.007). Larger CNV size was shown to be associated with frequency of intellectual disability; 33.5% of deletion carriers (OR, 1.48; 95% CI, 1.12-1.95; P = 0.005) and 39.1% of duplication carriers (OR; 1.89; 95% CI, 1.27-2.8; P = 1.6e−03) did not graduate from high school.Evidence supporting an association between prevalence of intellectual disability and carrier status was found. Analysis of the Italian, United States, and United Kingdom cohorts supported the association between rare CNVs and lower educational attainment, but further replication of the study's findings is needed.

Cognitive Phenotypes and Genomic Copy Number Variations

“…In this issue of JAMA , Männik and colleagues 1 report that large (>250 kilobase [kb] pairs) structural variants in the genome, specifically deletion and duplication copy number variations (CNVs), were associated with cognitive phenotypes including intellectual disability and reduced educational achievement. These CNVs are deletions and duplications of DNA sequences in the human genome that can be considered as deviations from the normal diploid state at a given location in the genome and represent differing numbers of copies of genetic sequences.…”

“…The investigators identified 56 carriers of CNVs associated with known genomic disorders, previously cataloged in the Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER) 4 within a combined discovery and replication sample of 7877 unrelated individuals, which repre sented a rate of 7.1 per 1000 personal genomes assayed, or approximately 1 in every 141 individuals studied. 1 …”

Investigating the child with intellectual disability

“…This model is supported by studies in individuals who have the common 15q11.2 deletion ascertained from the general population, who have been found to have lower functioning on neuropsychological measures compared to population controls . More generally, in the population, the presence of larger CNVs has been shown to be associated with lower educational achievement in the absence of a diagnosed neurodevelopmental disorder …”

Chromosomal Microarrays: Understanding Genetics of Neurodevelopmental Disorders and Congenital Anomalies

“…This is supported by recent studies of general populations that showed negative effects of such CNVs, including cognitive impairments, other neuropsychiatric features, alterations in body weight, and reduced fecundity. 72,73 Therefore, it is likely that most of these CNVs have some type of negative impact on an individual's development and neurologic function, although these impacts may not always be sufficient to bring the individual to clinical attention. Fig.…”