Abstract
Recent studies have shown the ubiquity of pleiotropy for variants affecting human complex traits. These studies also show that rare variants tend to be less pleiotropic than common ones, suggesting that purifying natural selection acts against highly pleiotropic variants of large effect. Here, we investigate the mean frequency, effect size and recombination rate associated with pleiotropic variants, and focus particularly on whether highly pleiotropic variants are enriched in regions with putative strong background selection. We evaluate variants for 41 human traits using data from the NHGRI-EBI GWAS Catalog, as well as data from other three studies. Our results show that variants involving a higher degree of pleiotropy tend to be more common, have larger mean effect sizes, and contribute more to heritability than variants with a lower degree of pleiotropy. This is consistent with the fact that variants of large effect and frequency are more likely detected by GWAS. Using data from four different studies, we also show that more pleiotropic variants are enriched in genome regions with stronger background selection than less pleiotropic variants, suggesting that highly pleiotropic variants are subjected to strong purifying selection. From the above results, we hypothesized that a number of highly pleiotropic variants of low effect/frequency may pass undetected by GWAS.
Highlights
The analyses of thousands of genetic variants obtained in the last decades by Genome-Wide Association Studies (GWAS) have provided a great advance in the knowledge of the understanding of genetic variation, for human traits (Visscher et al 2017)
The mean effect size steadily increased with the pleiotropy degree (Fig. 1a, regression coefficient b = 0.035, p < 2 × 10−16), and the same was observed for the standard deviation of effect sizes (Fig. 1b) (b = 0.008, p = 0.04)
The rate of recombination was almost invariable across the different degrees of pleiotropy, with a tendency to be positively correlated with the pleiotropy level, and only slightly negative for the data of Shikov et al (2020) (Fig. 2)
Summary
The analyses of thousands of genetic variants obtained in the last decades by Genome-Wide Association Studies (GWAS) have provided a great advance in the knowledge of the understanding of genetic variation, for human traits (Visscher et al 2017). The latest meta-analysis on pleiotropic variants carried out by Shikov et al (2020), and based on more than 500 complex traits, concludes that about 180 Mbs of the human genome are covered by pleiotropic loci and about 50% of SNPs are associated with more than one phenotype. Another recent study (Watanabe et al 2019) suggests that this proportion is even larger (60%). Pleiotropic variants are generally associated with broadly expressed genes with ubiquitous functions, such as matrisome components, developmental and immunological system genes, and growth cell regulators (Shikov et al 2020)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
