Association weight matrix for the genetic dissection of puberty in beef cattle

Fortes, M.R.S., Reverter, A., Zhang, Y., Collis, E., Nagaraj, S.H., Jonsson, N.N. , Prayaga, K.C., Barris, W. and Hawken, R.J. (2010) Association weight matrix for the genetic dissection of puberty in beef cattle. Proceedings of the National Academy of Sciences of the United States of America, 107(31), pp. 13642-13647. (doi:10.1073/pnas.1002044107)

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Abstract

We describe a systems biology approach for the genetic dissection of complex traits based on applying gene network theory to the results from genome-wide associations. The associations of single-nucleotide polymorphisms (SNP) that were individually associated with a primary phenotype of interest, age at puberty in our study, were explored across 22 related traits. Genomic regions were surveyed for genes harboring the selected SNP. As a result, an association weight matrix (AWM) was constructed with as many rows as genes and as many columns as traits. Each {i, j} cell value in the AWM corresponds to the z-score normalized additive effect of the ith gene (via its neighboring SNP) on the jth trait. Columnwise, the AWM recovered the genetic correlations estimated via pedigree-based restricted maximum-likelihood methods. Rowwise, a combination of hierarchical clustering, gene network, and pathway analyses identified genetic drivers that would have been missed by standard genome-wide association studies. Finally, the promoter regions of the AWM-predicted targets of three key transcription factors (TFs), estrogen-related receptor. (ESRRG), Pal3 motif, bound by a PPAR-gamma homodimer, IR3 sites (PPARG), and Prophet of Pit 1, PROP paired-like homeobox 1 (PROP1), were surveyed to identify binding sites corresponding to those TFs. Applied to our case, the AWM results recapitulate the known biology of puberty, captured experimentally validated binding sites, and identified candidate genes and gene-gene interactions for further investigation.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jonsson, Professor Nicholas
Authors: Fortes, M.R.S., Reverter, A., Zhang, Y., Collis, E., Nagaraj, S.H., Jonsson, N.N., Prayaga, K.C., Barris, W., and Hawken, R.J.
College/School:College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Journal Abbr.:Proc. Natl. Acad. Sci.
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:18 July 2010

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