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PMID- 26010633 | ||
OWN - NLM | ||
STAT- MEDLINE | ||
DA - 20150527 | ||
DCOM- 20150529 | ||
LR - 20150708 | ||
IS - 1538-3598 (Electronic) | ||
IS - 0098-7484 (Linking) | ||
VI - 313 | ||
IP - 20 | ||
DP - 2015 May 26 | ||
TI - Copy number variations and cognitive phenotypes in unselected populations. | ||
PG - 2044-54 | ||
LID - 10.1001/jama.2015.4845 [doi] | ||
AB - 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 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 | ||
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. | ||
FAU - Mannik, Katrin | ||
AU - Mannik K | ||
AD - Center for Integrative Genomics, University of Lausanne, Lausanne, | ||
Switzerland2Estonian Genome Center, University of Tartu, Tartu. | ||
FAU - Magi, Reedik | ||
AU - Magi R | ||
AD - Estonian Genome Center, University of Tartu, Tartu. | ||
FAU - Mace, Aurelien | ||
AU - Mace A | ||
AD - Department of Medical Genetics, University of Lausanne, Lausanne, | ||
Switzerland4Swiss Institute of Bioinformatics, Lausanne, Switzerland. | ||
FAU - Cole, Ben | ||
AU - Cole B | ||
AD - Department of Laboratory Medicine and Pathology, University of Minnesota Medical | ||
School, Minneapolis. | ||
FAU - Guyatt, Anna L | ||
AU - Guyatt AL | ||
AD - Bristol Genetic Epidemiology Laboratories, School of Social and Community | ||
Medicine, University of Bristol, Bristol, United Kingdom. | ||
FAU - Shihab, Hashem A | ||
AU - Shihab HA | ||
AD - 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. | ||
FAU - Maillard, Anne M | ||
AU - Maillard AM | ||
AD - Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland. | ||
FAU - Alavere, Helene | ||
AU - Alavere H | ||
AD - Estonian Genome Center, University of Tartu, Tartu. | ||
FAU - Kolk, Anneli | ||
AU - Kolk A | ||
AD - Estonian Genome Center, University of Tartu, Tartu8Department of Neurology and | ||
Neurorehabilitation, Children's Clinic, Tartu University Hospital, Tartu, | ||
Estonia. | ||
FAU - Reigo, Anu | ||
AU - Reigo A | ||
AD - Estonian Genome Center, University of Tartu, Tartu. | ||
FAU - Mihailov, Evelin | ||
AU - Mihailov E | ||
AD - Estonian Genome Center, University of Tartu, Tartu. | ||
FAU - Leitsalu, Liis | ||
AU - Leitsalu L | ||
AD - Estonian Genome Center, University of Tartu, Tartu9Institute of Molecular and | ||
Cell Biology, University of Tartu, Tartu, Estonia. | ||
FAU - Ferreira, Anne-Maud | ||
AU - Ferreira AM | ||
AD - Center for Integrative Genomics, University of Lausanne, Lausanne, | ||
Switzerland4Swiss Institute of Bioinformatics, Lausanne, Switzerland. | ||
FAU - Noukas, Margit | ||
AU - Noukas M | ||
AD - Estonian Genome Center, University of Tartu, Tartu9Institute of Molecular and | ||
Cell Biology, University of Tartu, Tartu, Estonia. | ||
FAU - Teumer, Alexander | ||
AU - Teumer A | ||
AD - Institute for Community Medicine, University Medicine Greifswald, Greifswald, | ||
Germany. | ||
FAU - Salvi, Erika | ||
AU - Salvi E | ||
AD - Deparment of Health Sciences, University of Milan, Milan, Italy. | ||
FAU - Cusi, Daniele | ||
AU - Cusi D | ||
AD - Deparment of Health Sciences, University of Milan, Milan, Italy12Institute of | ||
Biomedical Technologies, Italian National Research Council, Milan, Italy. | ||
FAU - McGue, Matt | ||
AU - McGue M | ||
AD - Department of Psychology, University of Minnesota, Minneapolis. | ||
FAU - Iacono, William G | ||
AU - Iacono WG | ||
AD - Department of Psychology, University of Minnesota, Minneapolis. | ||
FAU - Gaunt, Tom R | ||
AU - Gaunt TR | ||
AD - 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. | ||
FAU - Beckmann, Jacques S | ||
AU - Beckmann JS | ||
AD - Swiss Institute of Bioinformatics, Lausanne, Switzerland. | ||
FAU - Jacquemont, Sebastien | ||
AU - Jacquemont S | ||
AD - Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland. | ||
FAU - Kutalik, Zoltan | ||
AU - Kutalik Z | ||
AD - 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. | ||
FAU - Pankratz, Nathan | ||
AU - Pankratz N | ||
AD - Department of Laboratory Medicine and Pathology, University of Minnesota Medical | ||
School, Minneapolis. | ||
FAU - Timpson, Nicholas | ||
AU - Timpson N | ||
AD - 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. | ||
FAU - Metspalu, Andres | ||
AU - Metspalu A | ||
AD - Estonian Genome Center, University of Tartu, Tartu9Institute of Molecular and | ||
Cell Biology, University of Tartu, Tartu, Estonia. | ||
FAU - Reymond, Alexandre | ||
AU - Reymond A | ||
AD - Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. | ||
LA - eng | ||
GR - 102433/Z/13/Z/Wellcome Trust/United Kingdom | ||
GR - AA09367/AA/NIAAA NIH HHS/United States | ||
GR - AA11886/AA/NIAAA NIH HHS/United States | ||
GR - DA024417/DA/NIDA NIH HHS/United States | ||
GR - DA05147/DA/NIDA NIH HHS/United States | ||
GR - DA13240/DA/NIDA NIH HHS/United States | ||
GR - MH066140/MH/NIMH NIH HHS/United States | ||
PT - Journal Article | ||
PT - Research Support, N.I.H., Extramural | ||
PT - Research Support, Non-U.S. Gov't | ||
PL - United States | ||
TA - JAMA | ||
JT - JAMA | ||
JID - 7501160 | ||
SB - AIM | ||
SB - IM | ||
CIN - JAMA. 2015 May 26;313(20):2029-30. PMID: 26010630 | ||
MH - Adolescent | ||
MH - Adult | ||
MH - Cognition | ||
MH - *DNA Copy Number Variations | ||
MH - Educational Status | ||
MH - Epilepsy/genetics | ||
MH - Estonia | ||
MH - Female | ||
MH - Genome-Wide Association Study | ||
MH - Great Britain | ||
MH - *Heterozygote | ||
MH - Humans | ||
MH - Intellectual Disability/*genetics | ||
MH - Italy | ||
MH - Male | ||
MH - Mental Disorders/*genetics | ||
MH - Obesity/genetics | ||
MH - Phenotype | ||
MH - United States | ||
EDAT- 2015/05/27 06:00 | ||
MHDA- 2015/05/30 06:00 | ||
CRDT- 2015/05/27 06:00 | ||
AID - 2297168 [pii] | ||
AID - 10.1001/jama.2015.4845 [doi] | ||
PST - ppublish | ||
SO - JAMA. 2015 May 26;313(20):2044-54. doi: 10.1001/jama.2015.4845. |
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