No Effect of Genome-Wide Copy Number Variation on Measures of Intelligence in a New Zealand Birth Cohort

Bagshaw, Andrew T. M.; Horwood, L. John; Liu, Youfang; Fergusson, David M.; Sullivan, Patrick F.; Kennedy, Martin A.

doi:10.1371/journal.pone.0055208

Cited by 11 publications

(16 citation statements)

References 53 publications

(64 reference statements)

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“…For example, three individual SNPs each with an approximate effect size of one month of schooling per allele have been identified in a GWAS encompassing >126,000 individuals (largest estimated effect = 0.02%) 17 and only a polygenic model including ~300,000 common SNPs genome-wide explained 28-29% of variation in general cognition 54 . While earlier studies failed to identify common CNVs as major contributors to the above heritabilities 55-58 , our results suggest that rare structural variants ≥250kb for deletions and ≥1Mb for duplications are associated with complex social-science traits in population cohorts. About 2% of the analyzed biobank participants carry a rare CNV ≥1Mb.…”

Section: Discussioncontrasting

confidence: 83%

Copy Number Variations and Cognitive Phenotypes in Unselected Populations

Männik

Mägi

Macé

et al. 2015

JAMA

151

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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...

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Section: Discussioncontrasting

confidence: 83%

Copy Number Variations and Cognitive Phenotypes in Unselected Populations

Männik

Mägi

Macé

et al. 2015

JAMA

151

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“…Thus, we did not replicate the mutational-burden results of Yeo et al (2011). Instead, our results were much like those of recent studies (MacLeod et al, 2012; Bagshaw et al, 2013; McRae et al, 2013), all of which had larger samples than Yeo et al (2011). Both our data and those of these recent studies suggest it is unlikely that CNVs will provide a missing piece in the puzzle of what has become known as “missing heritability” (Maher, 2008) for this particular quantitative trait.…”

Section: Discussioncontrasting

confidence: 80%

“…Bagshaw et al (2013) reported a study of IQ and academic achievement conducted in a sample of 717 participants from the longitudinal Christchurch Health and Development Study in New Zealand. These participants were genotyped on the Illumina 660W-Quad chip.…”

mentioning

confidence: 99%

Low-frequency copy-number variants and general cognitive ability: No evidence of association

et al. 2014

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Although twin, family, and adoption studies have shown that general cognitive ability (GCA) is substantially heritable, GWAS has not uncovered a genetic polymorphism replicably associated with this phenotype. However, most polymorphisms used in GWAS are common SNPs. The present study explores use of a different class of genetic variant, the copy-number variant (CNV), to predict GCA in a sample of 6,199 participants, combined from two longitudinal family studies. We aggregated low-frequency (<5%) CNV calls into eight different mutational burden scores, each reflecting a different operationalization of mutational burden. We further conducted three genome-wide association scans, each of which utilized a different subset of identified low-frequency CNVs. Association signals from the burden analyses were generally small in effect size, and none were statistically significant after a careful Type I error correction was applied. No signal from the genome-wide scans significantly differed from zero at the adjusted Type I error rate. Thus, the present study provides no evidence that CNVs underlie heritable variance in GCA, though we cannot rule out the possibility of very rare or small-effect CNVs for this trait, which would require even larger samples to detect. We interpret these null results in light of recent breakthroughs that aggregate SNP effects to explain much, but not all, of the heritable variance in some quantitative traits.

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“…Genetic research has been undertaken by many of the studies. Based on the 736 full-text articles included in this review that span the 23 studies, genetic research has focused on intelligence [ 93 ], obesity and adiposity [ 85 , 94 , 95 ], mental and behavioural disorders [ 96 – 100 ], epigenetic changes [ 39 ], dyslexia [ 101 ] and eye health [ 102 ] ( Table 5 ).…”

Section: Resultsmentioning

confidence: 99%

Longitudinal Intergenerational Birth Cohort Designs: A Systematic Review of Australian and New Zealand Studies

et al. 2016

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BackgroundThe longitudinal birth cohort design has yielded a substantial contribution to knowledge of child health and development. The last full review in New Zealand and Australia in 2004 identified 13 studies. Since then, birth cohort designs continue to be an important tool in understanding how intrauterine, infant and childhood development affect long-term health and well-being. This updated review in a defined geographical area was conducted to better understand the factors associated with successful quality and productivity, and greater scientific and policy contribution and scope.MethodsWe adopted the preferred reporting items for systematic reviews and meta-analyses (PRISMA) approach, searching PubMed, Scopus, Cinahl, Medline, Science Direct and ProQuest between 1963 and 2013. Experts were consulted regarding further studies. Five inclusion criteria were used: (1) have longitudinally tracked a birth cohort, (2) have collected data on the child and at least one parent or caregiver (3) be based in Australia or New Zealand, (4) be empirical in design, and (5) have been published in English.Results10665 records were initially retrieved from which 23 birth cohort studies met the selection criteria. Together these studies recruited 91,196 participants, with 38,600 mothers, 14,206 fathers and 38,390 live births. Seventeen studies were located in Australia and six in New Zealand. Research questions initially focused on the perinatal period, but as studies matured, longer-term effects and outcomes were examined.ConclusionsThis review demonstrates the significant yield from this effort both in terms of scientific discovery and social policy impact. Further opportunities have been recognised with cross-study collaboration and pooling of data between established and newer studies and international studies to investigate global health determinants.

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No Effect of Genome-Wide Copy Number Variation on Measures of Intelligence in a New Zealand Birth Cohort

Cited by 11 publications

References 53 publications

Copy Number Variations and Cognitive Phenotypes in Unselected Populations

Copy Number Variations and Cognitive Phenotypes in Unselected Populations

Low-frequency copy-number variants and general cognitive ability: No evidence of association

Longitudinal Intergenerational Birth Cohort Designs: A Systematic Review of Australian and New Zealand Studies

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