title: Copy number variations and cognitive phenotypes in unselected populations.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Phenotypes 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.
  
  
  RESULTS
  Of 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, ≤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) 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 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 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
  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.
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland2Estonian Genome Center, University of Tartu, Tartu.
authors.forename: Katrin
authors.initials: K
authors.lastname: Männik
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu.
authors.forename: Reedik
authors.initials: R
authors.lastname: Mägi
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland4Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Macé
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis.
authors.forename: Ben
authors.initials: B
authors.lastname: Cole
authors.affiliation: Bristol Genetic Epidemiology Laboratories, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Guyatt
authors.affiliation: Bristol Genetic Epidemiology Laboratories, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom7MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Hashem A
authors.initials: HA
authors.lastname: Shihab
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Maillard
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu.
authors.forename: Helene
authors.initials: H
authors.lastname: Alavere
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu8Department of Neurology and Neurorehabilitation, Children's Clinic, Tartu University Hospital, Tartu, Estonia.
authors.forename: Anneli
authors.initials: A
authors.lastname: Kolk
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu.
authors.forename: Anu
authors.initials: A
authors.lastname: Reigo
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu.
authors.forename: Evelin
authors.initials: E
authors.lastname: Mihailov
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu9Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Liis
authors.initials: L
authors.lastname: Leitsalu
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland4Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Anne-Maud
authors.initials: AM
authors.lastname: Ferreira
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu9Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Margit
authors.initials: M
authors.lastname: Nõukas
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.affiliation: Deparment of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Salvi
authors.affiliation: Deparment of Health Sciences, University of Milan, Milan, Italy12Institute of Biomedical Technologies, Italian National Research Council, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis.
authors.forename: Matt
authors.initials: M
authors.lastname: McGue
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis.
authors.forename: William G
authors.initials: WG
authors.lastname: Iacono
authors.affiliation: Bristol Genetic Epidemiology Laboratories, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom7MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Tom R
authors.initials: TR
authors.lastname: Gaunt
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacquemont
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland4Swiss Institute of Bioinformatics, Lausanne, Switzerland14Institute of Social and Preventive Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis.
authors.forename: Nathan
authors.initials: N
authors.lastname: Pankratz
authors.affiliation: Bristol Genetic Epidemiology Laboratories, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom7MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Timpson
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu9Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Reymond
mesh_terms: D000293:Adolescent; D000328:Adult; D003071:Cognition; D056915:DNA Copy Number Variations; D004522:Educational Status; D004827:Epilepsy / Q000235:genetics; D004957:Estonia; D005260:Female; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007558:Italy; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D009765:Obesity / Q000235:genetics; D010641:Phenotype; D006113:United Kingdom; D014481:United States