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Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size

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Abstract

Heart size is an important factor in cardiac health and disease. In particular, increased heart weight is predictive of adverse cardiovascular outcomes in multiple large community-based studies. We use two cohorts of Diversity Outbred (DO) mice to investigate the role of genetics, sex, age, and diet on heart size. DO mice (n = 289) of both sexes from generation 10 were fed a standard chow diet, and analyzed at 12–15 weeks of age. Another cohort of female DO mice (n = 258) from generation 11 were fed either a high-fat, cholesterol-containing (HFC) diet or a low-fat, high-protein diet, and analyzed at 24–25 weeks. We did not observe an effect of diet on body or heart weight in generation 11 mice, although we previously reported an effect on other cardiovascular risk factors, including cholesterol, triglycerides, and insulin. We do observe a significant genetic effect on heart weight in this population. We identified two quantitative trait loci for heart weight, one (Hwtf1) at a genome-wide significance level of p ≤ 0.05 on MMU15 and one (Hwtf2) at a genome-wide suggestive level of p ≤ 0.1 on MMU10, that together explain 13.3% of the phenotypic variance. Hwtf1 contained collagen type XXII alpha 1 chain (Col22a1), and the NZO/HlLtJ and WSB/EiJ haplotypes were associated with larger hearts. This is consistent with heart tissue Col22a1 expression in DO founders and SNP patterns within Hwtf1 for Col22a1. Col22a1 has been previously associated with cardiac fibrosis in mice, suggesting that Col22a1 may be involved in pathological cardiac hypertrophy.

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  • 04 December 2018

    The original article has been published with an incorrect text in Materials and Methods section. The corrected text should read as.

  • 04 December 2018

    The original article has been published with an incorrect text in Materials and Methods section. The corrected text should read as.

  • 04 December 2018

    The original article has been published with an incorrect text in Materials and Methods section. The corrected text should read as.

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Acknowledgements

This work was supported in part by NIH Grants DK076050 and DK087346 (DP) and the UAI Research Foundation (BCJ). Phenotypes were collected using the Animal Metabolism Phenotyping core facility within UNC’s Nutrition and Obesity Research Center funded by NIH DK056350. We also acknowledge George Weinstock and The Genome Institute (Washington University) for partial funding of the mouse purchase and husbandry costs for cohort 2 of the DO mice used in these studies. We thank Liyang Zhao and Kuo-Chen Jung for assistance with all mouse experiments, and Brian Bennett and Tangi Smallwood for assistance with the cohort 2 experiments. We thank Martin Ferris for analysis support. Charles Farber is gratefully acknowledged for performing the femur length phenotyping and providing those data for use in these studies.

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Authors and Affiliations

  1. Department of Genetics, University of North Carolina, CB# 7264, Chapel Hill, NC, 27599, USA

    John R. Shorter, Kunjie Hua, Fernando Pardo-Manuel de Villena & Daniel Pomp

  2. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA

    Fernando Pardo-Manuel de Villena

  3. Division of Cardiology, Department of Medicine, University of North Carolina, 6012 Burnett-Womack Building, Chapel Hill, NC, 27599, USA

    Brian C. Jensen

  4. The Jackson Laboratory, Bar Harbor, ME, 04609, USA

    Daniel M. Gatti

  5. Department of Pharmacology, University of North Carolina, Chapel Hill, NC, 27599, USA

    Brian C. Jensen

  6. McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, 27599, USA

    Wei Huang, Ju Youn Beak & Brian C. Jensen

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  1. John R. Shorter
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335_2017_9730_MOESM1_ESM.tif

Fig. S1 Mapping heart weight as a function of other characteristics. A) QTL mapping of 547 DO mice for heart weight without an adjustment for total body size. B) QTL mapping of 547 DO mice for heart weight as a function of total body weight. C) QTL mapping of 547 DO mice for heart weight as a function of femur length, which is represented in Figure 1. Horizontal lines represent significance threshold from permutation testing (dashed line at p value =0.05, dotted line at p value =0.1). (TIF 17716 KB)

335_2017_9730_MOESM2_ESM.tif

Fig. S2 Mapping heart weight as a function of femur length across each generation. A) QTL mapping of 289 male and female DO G10 mice for heart weight as a function of femur length. B) QTL mapping of 258 female DO G11 mice for heart weight as a function of femur length. C) QTL mapping of 547 DO mice across both generations for heart weight as a function of femur length, which is represented in Figure 1. (TIF 18693 KB)

335_2017_9730_MOESM3_ESM.tif

Fig. S3 Transcription expression patterns of QTL candidate genes. Blue circles represent male mice, pink circles represent female mice. A) Expression profiles of 4 candidate genes selected near the QTL peak identified on chromosome 10. B) Expression profiles of eight candidate genes selected near the QTL peak identified on chromosome 15. (TIF 15028 KB)

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Shorter, J.R., Huang, W., Beak, J.Y. et al. Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size. Mamm Genome 29, 80–89 (2018). https://doi.org/10.1007/s00335-017-9730-7

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