Abstract
We carried out a genome-wide association study (GWAS) for general cognitive ability (GCA) plus three other analyses of GWAS data that aggregate the effects of multiple single-nucleotide polymorphisms (SNPs) in various ways. Our multigenerational sample comprised 7,100 Caucasian participants, drawn from two longitudinal family studies, who had been assessed with an age-appropriate IQ test and had provided DNA samples passing quality screens. We conducted the GWAS across ∼2.5 million SNPs (both typed and imputed), using a generalized least-squares method appropriate for the different family structures present in our sample, and subsequently conducted gene-based association tests. We also conducted polygenic prediction analyses under five-fold cross-validation, using two different schemes of weighting SNPs. Using parametric bootstrapping, we assessed the performance of this prediction procedure under the null. Finally, we estimated the proportion of variance attributable to all genotyped SNPs as random effects with software GCTA. The study is limited chiefly by its power to detect realistic single-SNP or single-gene effects, none of which reached genome-wide significance, though some genomic inflation was evident from the GWAS. Unit SNP weights performed about as well as least-squares regression weights under cross-validation, but the performance of both increased as more SNPs were included in calculating the polygenic score. Estimates from GCTA were 35% of phenotypic variance at the recommended biological-relatedness ceiling. Taken together, our results concur with other recent studies: they support a substantial heritability of GCA, arising from a very large number of causal SNPs, each of very small effect. We place our study in the context of the literature–both contemporary and historical–and provide accessible explication of our statistical methods.
Highlights
Candidate-Gene Association General cognitive ability (GCA) is that mental capacity which is involved to some extent in every cognitively demanding task
We refer to genome-wide association study (GWAS), combined with analyses that aggregate across multiple single-nucleotide polymorphisms (SNPs) in some fashion, as ‘‘GWAS plus.’’ We describe three such multi-SNP analyses: VEGAS, polygenic scoring, and GCTA
P-values from the GWAS are depicted in Figures 1, 2, S1, and S2
Summary
Candidate-Gene Association General cognitive ability (GCA) is that mental capacity which is involved to some extent in every cognitively demanding task. Association analysis is merely a test for whether the allelic state of a genetic polymorphism systematically covaries with the disease or quantitative trait of interest (typically via regression analysis) It can implicate a specific polymorphism provided that the ‘‘causal’’ polymorphism be typed, or alternately, lie in close chromosomal proximity–linkage disequilibrium (LD)–to a marker that is typed. The result is that loci very close to one another on a chromosome are least likely to be sundered by a recombination event, and polymorphisms within small ‘‘blocks’’ of DNA on a given chromosome tend to be transmitted together in the population This essentially induces correlation between markers in tight proximity to one another on the same chromosome.) For a number of years, the dense genotyping needed for association analysis was costly, so association analysis saw use primarily in candidate-gene studies
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