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

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.

Developmental constraint through negative pleiotropy in the zygomatic arch

“…Our primary sample consisted of mice raised at the University of North Carolina (UNC), and at JAX. The 287 adult specimens raised at UNC were male and female sibling pairs from outbreeding generation 10 that were raised in previously described conditions [ 19 , 29 ] under approval and conduced in accordance with the guidelines set forth by the Institutional Animal Care and Use Committee (IACUC) at the University of North Carolina at Chapel Hill. The 277 adult specimens raised at Jackson Labs (JAX IACUC #99066) were females of outbreeding generations 9, 10, and 15.…”

High-Diversity Mouse Populations for Complex Traits

“…DO mice have been successfully used for mapping multiple complex traits including cardiovascular phenotypes [68,69], metabolic syndrome related traits [70], environmental toxicity [71], cancer modifier traits [72], behavioral traits [73,74], and meiotic drive [40]. Early large-scale studies in incipient CC strains successfully mapped many traits [32] and CC lines were used to map motor performance and body weight [75], energy balance traits [76], exercise physiology [67], toxicology [77], perinatal nutrition in CC RIX lines [78], kidney phenotypes [79], and hematological phenotypes [80].…”

The Collaborative Cross: A Systems Genetics Resource for Studying Host-Pathogen Interactions

“…Extinction of CC strains during the inbreeding process inspired the creation of the Diversity Outbred (DO) panel, an outbred population derived from a set of incipient CC strains ( Churchill et al., 2012 ). The DO now serves as its own important genetic resource that has proven useful for high-resolution genetic mapping as well as exploration of phenotypic diversity ( Chick et al., 2016 , Gatti et al., 2014 , Smallwood et al., 2014 , Shorter et al., 2018 ). While the DO has only been used in a limited number of infectious disease studies ( McHugh et al., 2013 , Niazi et al., 2015 ), the DO and CC should be viewed as complementary resources for studying how genetic variation affects pathogen susceptibility and immunity.…”