Integrating large-scale meta-GWAS and PigGTEx resources to decipher the genetic basis of 232 complex traits in pigs

Understanding the molecular and cellular mechanisms underlying complex traits in pigs is crucial for enhancing genetic gain via artificial selection and utilizing pigs as models for human disease and biology. Here, we conducted comprehensive genome-wide association studies (GWAS) followed by a cross-breed meta-analysis for 232 complex traits and a within-breed meta-analysis for 12 traits, using 28.3 million imputed sequence variants in 70 328 animals across 14 pig breeds. We identified 6878 quantitative trait loci (QTL) for 139 complex traits. Leveraging the Pig Genotype-Tissue Expression resource, we systematically investigated the biological context and regulatory mechanisms behind these trait-QTLs, ultimately prioritizing 14 829 variant-gene-tissue-trait regulatory circuits. For instance, rs344053754 regulates UGT2B31 expression in the liver and intestines, potentially by modulating enhancer activity, ultimately influencing litter weight at weaning in pigs. Furthermore, we observed conservation of certain genetic and regulatory mechanisms underlying complex traits between humans and pigs. Overall, our cross-breed meta-GWAS in pigs provides invaluable resources and novel insights into the genetic regulatory and evolutionary mechanisms of complex traits in mammals.

This work was supported by the National Key R&D Program of China (2022YFF1000900 to Zhe Zhang), the National Natural Science Foundation of China (32022078 to Zhe Zhang), the China Agriculture Research System (CARS-35 to Zhe Zhang, J.L., Y.C., X. Liu., S.M. and X.D.), the Local Innovative and Research Teams Project of Guangdong Province (2019BT02N630 to Zhe Zhang), the Agriculture and Food Research Initiative Competitive grants (2022-67015-36215 to L.F.) from the USDA National Institute of Food and Agriculture, the USDA NIFA AFRI grant (2019-67015-29321 and 2021-67015-33409 to G.E.L.), ‘Accelerating Genetic Improvement of Ruminants Through Enhanced Genome Assembly, Annotation, and Selection’ of the USDA Agricultural Research Service (ARS) (appropriated project 8042-31000-112-00-D to G.E.L.), the SCINet project of the USDA ARS project (0500-00093-001-00-D), the United States Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA) (in part by AFRI grant numbers 2020-67015-31398 and 2021-67015-33409 to L.M.), the Australian Research Council's Discovery Projects (DP200100499 to R.X.), the grant from the Danish Research Council for Independent Research (DFF 1335-00127 to M.F. and P.K.M.), PID2020-112677RB-C21 awarded by MCIN/AEI/https://doi.org/10.13039/501100011033 (to M.B.) and the European Union's Horizon 2020 research and innovation program (the GENE-SWitCH project under grant agreement no. 817998 to D.C.P.). Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the USDA. The USDA is an equal opportunity provider and employer. All the funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript.

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