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

Abstract

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.

Copy Number Variations and Cognitive Phenotypes in Unselected Populations

“…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.…”

Replication of a Gene–Environment Interaction Via Multimodel Inference: Additive-Genetic Variance in Adolescents’ General Cognitive Ability Increases with Family-of-Origin Socioeconomic Status

“…Written informed assent or consent was obtained from all participants, with parents providing written consent for their minor children. The primary sample is substantially identical to that of Kirkpatrick et al (2009), and MTFS and SIBS, their cognitive ability testing, and their zygosity determination and inclusion criteria have been described there and elsewhere (e.g., Kirkpatrick et al, 2014). We have therefore relegated many details concerning the sample and measurements to a Supplementary Methods section (Online Resource).…”

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

“…24 These studies have often been limited in scope, with only copy number variants 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. [24][25][26][27] Where such tests have found an association these have been in small samples and subsequently failed to replicate. 28 However, in large samples, rare variants found within regions of the genome under purifying selection have been found to be associated with educational success, 29 an effect that was greater for genes expressed in the brain.…”