Genetic Copy Number Variation and General Cognitive Ability

MacLeod, Andy; Davies, Gail; Payton, Antony; Tenesa, Albert; Harris, Sarah E.; Liewald, David C.; Ke, Xiayi; Luciano, Michelle; Lopez, Lorna M.; Gow, Alan J.; Corley, Janie; Redmond, Paul; McNeill, Geraldine; Pickles, Andrew; Ollier, William; Horan, Michael A.; Starr, John M.; Pendleton, Neil; Thomson, Pippa A.; Porteous, David J.; Deary, Ian J.

doi:10.1371/journal.pone.0037385

Cited by 24 publications

(25 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

See 1 more Smart Citation

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

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussioncontrasting

confidence: 80%

“…One of these (MacLeod et al, 2012) was a study of both fluid and crystallized intelligence in a sample of over 3,000 older British adults genotyped on the Illumina 610-Quadv1 chip. MacLeod et al called CNVs using both PennCNV (Wang et al, 2007) and QuantiSNP (Colella et al, 2007), retaining only those calls produced by both.…”

mentioning

confidence: 99%

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…These studies have often been limited in scope, with only CNVs or exonic regions being considered, or being limited in statistical power because all rare variants were treated as having the same direction of effect through the use of burden tests [25][26][27][28][29]. Where such tests have found an association these have been in small samples and subsequently failed to replicate [30].…”

Section: Introductionmentioning

confidence: 99%

Genomic analysis of family data reveals additional genetic effects on intelligence and personality

et al. 2018

Self Cite

View full text Add to dashboard Cite

Pedigree-based analyses of intelligence have reported that genetic differences account for 50-80% of the phenotypic variation. For personality traits these effects are smaller, with 34-48% of the variance being explained by genetic differences. However, molecular genetic studies using unrelated individuals typically report a heritability estimate of around 30% for intelligence and between 0 and 15% for personality variables. Pedigree-based estimates and molecular genetic estimates may differ because current genotyping platforms are poor at tagging causal variants, variants with low minor allele frequency, copy number variants, and structural variants. Using~20,000 individuals in the Generation Scotland family cohort genotyped for~700,000 single-nucleotide polymorphisms (SNPs), we exploit the high levels of linkage disequilibrium (LD) found in members of the same family to quantify the total effect of genetic variants that are not tagged in GWAS of unrelated individuals. In our models, genetic variants in low LD with genotyped SNPs explain over half of the genetic variance in intelligence, education, and neuroticism. By capturing these additional genetic effects our models closely approximate the heritability estimates from twin studies for intelligence and education, but not for neuroticism and extraversion. We then replicated our finding using imputed molecular genetic data from unrelated individuals to show that 50% of differences in intelligence, and~40% of the differences in education, can be explained by genetic effects when a larger number of rare SNPs are included. From an evolutionary genetic perspective, a substantial contribution of rare genetic variants to individual differences in intelligence, and education is consistent with mutation-selection balance.

show abstract

“…[10][11][12][13][14][15][16][17][18][19][20][21][22] In addition to disease risk, these differences, furthermore, explain a significant proportion of normal phenotypic variation. [23][24][25][26] In this context, we characterized the genome-wide architecture of CNVs in 286 healthy, unrelated subjects characterized for musical aptitude and related traits. 27 We wanted to essentially evaluate the role of CNV enrichment in music-related phenotypes.…”

Section: Introductionmentioning

confidence: 99%

The genome-wide landscape of copy number variations in the MUSGEN study provides evidence for a founder effect in the isolated Finnish population

et al. 2013

View full text Add to dashboard Cite

Here we characterized the genome-wide architecture of copy number variations (CNVs) in 286 healthy, unrelated Finnish individuals belonging to the MUSGEN study, where molecular background underlying musical aptitude and related traits are studied. By using Illumina HumanOmniExpress-12v.1.0 beadchip, we identified 5493 CNVs that were spread across 467 different cytogenetic regions, spanning a total size of 287.83 Mb (B9.6% of the human genome). Merging the overlapping CNVs across samples resulted in 999 discrete copy number variable regions (CNVRs), of which B6.9% were putatively novel. The average number of CNVs per person was 20, whereas the average size of CNV per locus was 52.39 kb. Large CNVs (41 Mb) were present in 4% of the samples. The proportion of homozygous deletions in this data set (B12.4%) seemed to be higher when compared with three other populations. Interestingly, several CNVRs were significantly enriched in this sample set, whereas several others were totally depleted. For example, a CNVR at chr2p22.1 intersecting GALM was more common in this population (P ¼ 3.3706 Â 10 À44 ) than in African and other European populations. The enriched CNVRs, however, showed no significant association with music-related phenotypes. Moreover, the most common CNV locations in world's normal population cohorts (6q14.1, 11q11) were overrepresented in this population. Thus, the genome-wide CNV investigation in this Finnish sample set demonstrated features that are characteristic to isolated populations. Novel CNVRs and the functional implications of CNVs revealed in this study elucidate structural variation present in this population isolate, and may also serve as candidate gene loci for music-related traits.

show abstract

Genetic Copy Number Variation and General Cognitive Ability

Cited by 24 publications

References 78 publications

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

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

Genomic analysis of family data reveals additional genetic effects on intelligence and personality

The genome-wide landscape of copy number variations in the MUSGEN study provides evidence for a founder effect in the isolated Finnish population

Contact Info

Product

Resources

About