Meta-analysis of genome wide association studies for the stature of cattle reveals numerous common genes that regulate size in mammals

Authors: BOUWMAN, ANIEK - Wageningen Ur; DAETWYLER, HANS - Collaborator; CHAMBERLAIN, AMANDA - Collaborator; PONCE, CARLA - University Of Melbourne; SARGOLZAEI, MEHDI - University Of Guelph; SCHENKE, FLAVIO - University Of Guelph; SAHANA, GOUTAM - Aarhus University; GOVIGNON-GION, ARMELLE - Agro Paris Tech; BOITARD, SIMON - Agro Paris Tech; DOLEZAL, MARLIES - University Of Veterinary Medicine; PAUSCH, HUBERT - Technische Universitat Munchen; BRONDUM, RASMUS - Aarhus University; BOWMAN, PHIL - Collaborator; THOMSEN, BO - Aarhus University; GULDBRANDTSEN, BERNT - Aarhus University; LUND, MOGENS - Aarhus University; SERVIN, BERTRAND - University Of Toulouse; GARRICK, DORIAN - Iowa State University; REECY, JAMES - Iowa State University; VILKKI, JOHANNA - Natural Resources Institute Finland (LUKE); BAGNATO, ALESSANDRO - University Of Milan; WANG, MIN - La Trobe University; HOFF, JESSE - University Of Missouri; SCHNABEL, ROBERT - University Of Missouri; TAYLOR, JERRY - University Of Missouri; VINKHUYZEN, ANNA - University Of Queensland; PANITZ, FRANK - Aarhus University; BENDIXEN, CHRISTIAN - Aarhus University; HOLM, LARS-ERIK - Aarhus University; GREDLER, BIRGIT - Collaborator; HOZE, CHRIS - Agro Paris Tech; BOUSSAHA, MEKKI - Agro Paris Tech; SANCHEZ, MARIE-PIERRE - University Of Queensland; ROCHA, DOMINIQUE - Agro Paris Tech; CAPITAN, AURELIEN - Agro Paris Tech; TRIBOUT, THIERRY - Agro Paris Tech; BARBAT, ANNE - Agro Paris Tech; CROISEAU, PASCAL - Agro Paris Tech; DROGEMULLER, CORD - University Of Bern; JAGANNATHAN, VIDHYA - University Of Bern; JAGT, CHRISTY - Collaborator; CROWLEY, JOHN - Collaborator; INTERGENOMICS, CONSORTIUM - Collaborator; BIEBER, ANNA - Collaborator; PURFIELD, DEIRDRE - Collaborator; BERRY, DONAGH - Collaborator; EMMERLING, REINER - Collaborator; GOTZ, KAY-UWE - Collaborator; FRISCHKNECHT, MIRJAM - Collaborator; RUSS, INGOLF - Collaborator; SOLKNER, JOHANN - University Of Natural Resources & Applied Life Sciences - Austria; Van Tassell, Curtis - Curt; FRIES, RUEDI - Technische Universitat Munchen; STOTHARD, PAUL - University Of Alberta; VEERKAMP, ROEL - Wageningen Ur; BOICHARD, DIDIER - Agro Paris Tech; GODDARD, MIK - University Of Melbourne; HAYES, BEN - University Of Queensland

Submitted to: Nature Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/3/2018
Publication Date: 2/19/2018
Citation: Bouwman, A.C., Daetwyler, H.D., Chamberlain, A.J., Ponce, C.H., Sargolzaei, M., Schenke, F.S., Sahana, G., Govignon-Gion, A., Boitard, S., Dolezal, M., Pausch, H., Brondum, R., Bowman, P.J., Thomsen, B., Guldbrandtsen, B., Lund, M.S., Servin, B., Garrick, D.J., Reecy, J., Vilkki, J., Bagnato, A., Wang, M., Hoff, J.L., Schnabel, R.D., Taylor, J.F., Vinkhuyzen, A.A., Panitz, F., Bendixen, C., Holm, L., Gredler, B., Hoze, C., Boussaha, M., Sanchez, M., Rocha, D., Capitan, A., Tribout, T., Barbat, A., Croiseau, P., Drogemuller, C., Jagannathan, V., Jagt, C.V., Crowley, J.J., Intergenomics, C., Bieber, A., Purfield, D.C., Berry, D.P., Emmerling, R., Gotz, K., Frischknecht, M., Russ, I., Solkner, J., Van Tassell, C.P., Fries, R., Stothard, P., Veerkamp, R.F., Boichard, D., Goddard, M., Hayes, B.J. 2018. Meta-analysis of genome wide association studies for the stature of cattle reveals numerous common genes that regulate size in mammals. Nature Genetics. 50(3):362-367. https://doi.org/10.1038/s41588-018-0056-5.
DOI: https://doi.org/10.1038/s41588-018-0056-5

Interpretive Summary: A person’s height has been shown to be affected by a large number of genetic difference or polymorphisms, each having a small effect in height. In contrast, genetic variation for the analogous trait, stature, in dogs, even within breeds, is mostly influenced by differences in six genes. In this study, we used data from cattle to compare the genetic mechanisms of stature to that in humans and dogs. We conducted an across-experiment analysis, or meta-analysis, for stature using 58,265 cattle from 17 populations with 25.4 million inferred whole genome sequence variants. Results revealed that; genetic mechanism of stature in cattle is more similar to that in humans than dogs, as 163 statistically significant genomic regions (P<.0000005) explained at most 13.8% of the phenotypic variation. But, difference in stature between miniature cattle and standard cattle of the same breed can be predicted by the lead variants. Many of the differences likely arose prior to domestication as 23% were variable in an pre-domesticated cow, the Auroch, genome. Most of the regions associated with the biggest differences did not code for changes in protein sequence, including changes that were associated with gene expression differences. There were many genes that affected the stature in humans and other mammals. Differences in gene frequencies were strongly influenced by selection.

Technical Abstract: Stature is affected by many polymorphisms of small effect in humans but in contrast variation in dogs, even within breeds is largely due to variants in six genes. Here we use data from cattle to compare genetic architecture of stature to that in humans and dogs. We conducted a meta-analysis for stature using 58,265 cattle from 17 populations with 25.4 million imputed whole genome sequence variants. Results revealed that; genetic architecture of stature in cattle is more similar to that in humans than dogs, as lead variants in 163 significant genomic regions (p<5×10e^-8) explained at most 13.8% of the phenotypic variance; difference in stature between miniature cattle and standard cattle of the same breed can be predicted by the lead variants; many of the variants likely arose prior to domestication as 23% were heterozygous in an Auroch genome; most lead variants were non-coding, including variants that were also eQTL and in ChIP-seq peaks; significant overlap existed in loci for stature with humans and other mammals; and allele frequencies of these variants are strongly influenced by selection.