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Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection.

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.

SUBMITTER: Novo I

PROVIDER: S-EPMC8338839 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Natural selection shapes the genetic architecture of many human traits. However, the prevalence of different modes of selection on genomic regions associated with variation in traits remains poorly understood. To address this, we developed an efficient computational framework to calculate positive and negative enrichment of different evolutionary measures among regions associated with complex traits. We applied the framework to summary statistics from >900 genome-wide association studies (GWASs) and 11 evolutionary measures of sequence constraint, population differentiation, and allele age while accounting for linkage disequilibrium, allele frequency, and other potential confounders. We demonstrate that this framework yields consistent results across GWASs with variable sample sizes, numbers of trait-associated SNPs, and analytical approaches. The resulting evolutionary atlas maps diverse signatures of selection on genomic regions associated with complex human traits on an unprecedented scale. We detected positive enrichment for sequence conservation among trait-associated regions for the majority of traits (>77% of 290 high power GWASs), which included reproductive traits. Many traits also exhibited substantial positive enrichment for population differentiation, especially among hair, skin, and pigmentation traits. In contrast, we detected widespread negative enrichment for signatures of balancing selection (51% of GWASs) and absence of enrichment for evolutionary signals in regions associated with late-onset Alzheimer's disease. These results support a pervasive role for negative selection on regions of the human genome that contribute to variation in complex traits, but also demonstrate that diverse modes of evolution are likely to have shaped trait-associated loci. This atlas of evolutionary signatures across the diversity of available GWASs will enable exploration of the relationship between the genetic architecture and evolutionary processes in the human genome.

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Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection.

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