The ubiquity of pleiotropy in human disease

Abstract

Pleiotropy has long been thought to be a common phenomenon in the human genome; however, until recently appropriate data was unavailable to test this hypothesis. Prior studies focused on assessing the prevalence of pleiotropy in only small subsets of phenotypes (≤ 53 phenotypes), without a truly comprehensive assessment of pleiotropy in the human genome. In this study, we determined the prevalence of pleiotropy, using the entire GWAS catalog (1094 disease phenotypes, 14,459 genes), as well as investigate the relationship between the degree of pleiotropy and the average effect size for each associating gene. The number of associating phenotypes per gene ranged from 1 to 53, with 44% of genes reported in the GWAS catalog associating with more than one phenotype. The proportion of genes shown to be pleiotropic has continued to increase as more studies are added to the catalog. We also found the degree of pleiotropy scales positively with a gene's average effect size (r = 0.04, p value = 0.0003) and negatively with the variance of effect sizes in genes with a given number of associating phenotypes (r = − 0.590, p value = 0.0019). Based on this and prior work, it is becoming evident that pleiotropy is a common, if not ubiquitous, phenomenon. These results have implications in understanding disease etiologies, potentially common biology underlying even disparate diseases, and in elucidating the genotype-phenotype map.

HOPS: a quantitative score reveals pervasive horizontal pleiotropy in human genetic variation is driven by extreme polygenicity of human traits and diseases

“…Our findings are in keeping with several recent studies that have found abundant pleiotropy in the genome (26,27,8,2,9). HOPS goes a step further than many of these studies by explicitly removing vertical pleiotropy between traits, which are indicative of fundamental biological relationships between traits (8,24,28).…”

“…The term "pleiotropy" refers to a single genetic variant having multiple distinct phenotypic effects. In general terms, the existence and extent of pleiotropy has far-reaching implications on our understanding of how genotypes map to phenotypes (1), of the genetic architectures of traits (2,3), of the biology underlying common diseases (4) and of the dynamics of natural selection (5). However, beyond this general idea of the importance of pleiotropy, it quickly becomes difficult to discuss in specifics, because of the difficulty in defining what counts as a direct causal effect and what counts as a separate phenotypic effect.…”

“…In principle, we might imagine selecting a variant and counting how many phenotypes are associated with it. Indeed, several versions of this analysis have been performed for different lists of traits (8,2,3,9).…”

Pleiotropy or linkage? Their relative contributions to the genetic correlation of quantitative traits and detection by multi-trait GWA studies

“…Moving from one trait to two or more trait associations can lead to discovering pleiotropic loci (Saltz et al, 2017). One GWAS using 1094 traits and 14,459 genes, found that 44% of genes were "pleiotropic", but this was determined by assigning genetic variants to the closest gene and even to both flanking genes when the genetic variant was intergenic (Chesmore et al, 2018). This conflates linkage and pleiotropy, and the chain of causality (Platt et al, 2010).…”

“…Distinguishing between the two types of genetic architectures is important for understanding the underlying molecular functions of the traits, and determining how the traits may be deferentially affected by selection (Lynch et al, 1998;Barrett and Hoekstra, 2011;Saltz et al, 2017). This is salient at a time when an increasing number of traits of interest (e.g., human diseases) appear to be affected by loci that affect other traits, and especially when targeted gene therapy clinical trials are more widespread than ever (Edelstein et al, 2007;Cai et al, 2016;Pickrell et al, 2016;Visscher and Yang, 2016;Chesmore et al, 2018;Ginn et al, 2018). There are potentially negative implications for gene therapy because fixing a gene underlying one disease might increase risk for another disease.…”