Genome-wide association studies of intelligence: a review of the literature

Abstract

AbstractThere has long been controversy concerning whether genes influence human intelligence, and if so, which genes influence it, and to what extent. Many genome-wide association studies (GWASs) have attempted to find single nucleotide polymorphisms (SNPs) that are significantly associated with to shed light on this issue. My aim is to examine whether these studies have generated replicable findings concerning associations between one or more SNPs and variation in as it has generally been defined. Data on 17 published GWASs (3 of which reported no associations whatsoever) were downloaded from the GWAS Catalog and analyzed in the current study. Results show a generally low rate of replication: over 87% of the 2,335 included SNPs were reported only once, and only 4 of the 17 studies included follow-up testing in a replication sample. Of these 4, none found any replicable genome-wide significant hits. The literature was also found to be severely lacking in diversity: all study samples in which ancestry was described were of European and/or British ancestry. Additionally, evidence of a winner's curse was found: among the minority of SNPs reported more than once, the associated p-value tended to be higher in subsequent studies than in the study in which it was originally reported, corresponding to weaker SNP-intelligence associations in later studies.IntroductionMany studies have previously reported evidence that the trait of human is under significant genetic influence. Specifically, it has long been estimated that has a high heritability (i.e. proportion of variation associated with genetic variation), with twin and family studies typically narrow-sense heritability estimates of between 50% and 80%.\cite{Hill_2018} This conclusion, combined with the prevailing interpretation of heritability estimates as reflecting a genetic basis for a given trait, implies that between 50 and 80% of variation in is due to additive genetic factors specifically. This is because narrow-sense heritability estimates only include additive genetic effects.\cite{Hill_2018}\cite{Plomin_2014}However, genome-wide association studies (GWASs) have generally failed to reveal genes that account for all, or even most, of the reported heritability of intelligence. Instead, genetic variants reported to be associated with in GWASs invariably have very small effects, typically explaining no more than 1% of trait variance individually.\cite{Plomin_2014} Even when taken together, only about 20% of the heritability of can be accounted for by known DNA differences.\cite{Plomin_2018} There are two schools of thought to why the heritability of remains missing, that is, unable to be accounted for by even the combination of all SNPs known to be associated with intelligence. The first is that the heritability of this trait, like that of most complex traits, is due to many genes of very small effect (e.g. \cite{Chabris_2015}, \cite{Plomin_2012}). The second is that the original estimates of heritability have been inaccurate, thereby misleading researchers into searching for genes to explain the heritability of IQ, when in fact such heritability estimates may be fatally confounded by environmental factors.\cite{Feldman2018} Distinguishing between these possibilities is difficult, but if the first explanation is true, then we should see a relatively high rate of replication of associations, especially with such higher-powered studies as are needed to detect the expected small effects.\cite{Chabris_2015}In this paper I aim to comprehensively assess whether GWASs of have generated replicable findings. In doing so, I hope to shed light on the extent to which genetic associations with reported in GWASs are false positives, as is known to be the case with many candidate gene studies,\cite{Chabris_2012} or whether the identified SNPs in GWASs actually contribute to differences in human intelligence. I will also examine other patterns in the GWAS literature on intelligence, such as whether these studies are done on populations of diverse ancestries, and whether there is a winner's curse in this literature with earlier studies stronger associations than later ones.\cite{Xiao2009}MethodsOn April 7, 2019, I downloaded all data on the GWAS Catalog\cite{Buniello2019} for the trait of intelligence (URL: https://www.ebi.ac.uk/gwas/efotraits/EFO_0004337). This was done simply by clicking the button on the page linked in the previous sentence labeled Download Catalog Data. I then assessed whether these associations had been replicable across different studies, as well as whether there was significant ancestral diversity in the populations on which the studies were conducted.Functional annotationConveniently, the GWAS Catalog database, and data downloaded from it, includes information about the functional status of each SNP (in the CONTEXT column). Specifically, it categorizes each SNP (with exceptions detailed in the inconsistent reporting section below) into exactly one of the following categories: