The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear.OBJECTIVE To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency Յ0.05%; size Ն250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTSThe population biobank of Estonia contains 52 000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health-and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURESPhenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTSOf the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, Յ0.05%; Ն250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (Ն250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (Ն1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom.CONCLUSIONS AND RELEVANCE Known pathogenic CNVs in unselected, but assumed to be healthy, adult popu...

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.