Copy Number Variations and Cognitive Phenotypes in Unselected Populations

IMPORTANCE 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!0.05%; size"250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS The 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 MEASURES Phenotypes of genomic disorders in the general population, prevalence of autosomalCNVs, and association of these variants with educational attainment (fromless than primary school through scientific degree) and prevalence of intellectual disability. RESULTS Of the 7877 in the Estonian cohort,we identified 56 carriers of CNVs associatedwith 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,!0.05%;"250 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) and6of 102 (5.9%) carriers of a duplicationof at least 1 Mb (OR, 3.67; 95%CI, 1.29-8.54; P = .008) had an intellectual disability comparedwith 114 of 6819 (1.7%) in the Estonian cohort. Themean education attainmentwas 3.81 (P = 1.06e-04)among 248 ("250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers ("1Mb). Of the deletion carriers, 33.5%did not graduate fromhigh 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).EvidenceforanassociationbetweenrareCNVsandlower educational attainmentwas supported by analyses of cohorts of adults fromItaly and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.