Gene expression and RNA splicing explain large proportions of the heritability for complex traits in cattle

Ruidong Xiang; Lingzhao Fang; Shuli Liu; Iona M Macleod; Zhiqian Liu; Edmond J Breen; Yahui Gao; George E Liu; Albert Tenesa; CattleGTEx Consortium; Brett A Mason; Amanda J Chamberlain; Naomi R Wray; Michael E Goddard

doi:10.1016/j.xgen.2023.100385

Gene expression and RNA splicing explain large proportions of the heritability for complex traits in cattle

Cell Genom. 2023 Aug 23;3(10):100385. doi: 10.1016/j.xgen.2023.100385. eCollection 2023 Oct 11.

Authors

Ruidong Xiang^{1

2

3}, Lingzhao Fang^{4

5}, Shuli Liu⁶, Iona M Macleod², Zhiqian Liu², Edmond J Breen², Yahui Gao⁷, George E Liu⁷, Albert Tenesa^{4

8}; CattleGTEx Consortium; Brett A Mason², Amanda J Chamberlain^{2

9}, Naomi R Wray^{10

11}, Michael E Goddard^{1

2}

Affiliations

¹ Faculty of Veterinary & Agricultural Science, the University of Melbourne, Parkville, VIC 3052, Australia.
² Agriculture Victoria, AgriBio, Centre for AgriBiosciences, Bundoora, VIC 3083, Australia.
³ Cambridge-Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
⁴ MRC Human Genetics Unit at the Institute of Genetics and Cancer, the University of Edinburgh, Edinburgh, UK.
⁵ Center for Quantitative Genetics and Genomics, Aarhus University, Aarhus, Denmark.
⁶ Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China.
⁷ Animal Genomics and Improvement Laboratory, Henry A. Wallace Beltsville Agricultural Research Center, Agricultural Research Service, USDA, Beltsville, MD 20705, USA.
⁸ The Roslin Institute, Royal (Dick) School of Veterinary Studies, the University of Edinburgh, Midlothian EH25 9RG, UK.
⁹ School of Applied Systems Biology, La Trobe University, Bundoora, VIC 3083, Australia.
¹⁰ Institute for Molecular Bioscience, the University of Queensland, Brisbane, QLD 4072, Australia.
¹¹ Queensland Brain Institute, the University of Queensland, Brisbane, QLD 4072, Australia.

Abstract

Many quantitative trait loci (QTLs) are in non-coding regions. Therefore, QTLs are assumed to affect gene regulation. Gene expression and RNA splicing are primary steps of transcription, so DNA variants changing gene expression (eVariants) or RNA splicing (sVariants) are expected to significantly affect phenotypes. We quantify the contribution of eVariants and sVariants detected from 16 tissues (n = 4,725) to 37 traits of ∼120,000 cattle (average magnitude of genetic correlation between traits = 0.13). Analyzed in Bayesian mixture models, averaged across 37 traits, cis and trans eVariants and sVariants detected from 16 tissues jointly explain 69.2% (SE = 0.5%) of heritability, 44% more than expected from the same number of random variants. This 69.2% includes an average of 24% from trans e-/sVariants (14% more than expected). Averaged across 56 lipidomic traits, multi-tissue cis and trans e-/sVariants also explain 71.5% (SE = 0.3%) of heritability, demonstrating the essential role of proximal and distal regulatory variants in shaping mammalian phenotypes.

Keywords: BayesR; BayesRC; RNA splicing; complex traits; eQTL; gene expression; heritability; sQTL.

Grants and funding

MR/P015514/1/MRC_/Medical Research Council/United Kingdom