Low-Frequency Copy-Number Variants and General Cognitive Ability: No Evidence of Association

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.