bioRxiv Science⌕ Search

Biology subjects

Pomp, D.

Publications and source records attributed to Pomp, D..

2 recordsLinked to original sources
bioRxiv2026

Primary-Level Meta-Analysis of Diversity Outbred Mice Identifies a Fasting Plasma Trimethylamine N-Oxide (TMAO) Locus Modified by Sex and Diet

Trimethylamine n-oxide (TMAO) is a plasma metabolite linked to adverse cardiometabolic health with complex regulation involving diet, sex, and host genetics. We explored the role of these factors in the genetic regulation of TMAO by performing a primary-level meta-analysis in 1,482 female and male Diversity Outbred (DO) mice from five distinct studies conducted in various regions of the United States. We identified a quantitative trait locus (QTL) associated with TMAO concentration at [~]86 megabase pairs on mouse chromosome 12 with a highly significant LOD score of 67.67. Alleles at the chromosome 12 QTL inherited from the Cast/EiJ (CAST) and PWK/PhJ (PWK) mouse strains primarily drove the association with reduced TMAO concentrations. The chromosome 12 QTL remained significant in sex-stratified analyses and the mode of inheritance appeared additive; furthermore, the QTL was regulated by sex-by-genotype and sex-by-diet interactions. Using a CAST/EiJ X C57BL/6J F2 cross, positional candidates were prioritized by eQTL analysis. Further analysis in a study utilizing the eight DO founding strains identified that Acyp1 was differentially expressed in hepatic tissue from CAST mice, prompting investigation into its genetic regulation. Acyp1 demonstrated relevant cis- and trans-regulation and was significantly correlated with TMAO and hepatic Fmo3. However, no significant relationships between Acyp1 and TMAO were identified in mice inactivated for Acyp1 or with AAV overexpression of Acyp1 in the liver. Genes within the chromosome 12 QTL have synteny with humans and may translate to the genetic regulation of human plasma TMAO concentrations and atherosclerosis. Author SummaryWe explored the roles of diet, sex, and genetics on the regulation of fasting plasma trimethylamine n-oxide (TMAO) concentration by performing a meta-analysis in 1,482 female and male Diversity Outbred (DO) mice from five unique studies. We identified a QTL associated with TMAO concentration on chromosome 12 at [~]86 mega base pair (Mb) with a highly significant LOD score of 67.67. The locus is modified by both sex and diet.

genetics↗
bioRxiv2020

Systems genetics analyses in Diversity Outbred mice inform human bone mineral density GWAS and identify Qsox1 as a novel determinant of bone strength

Genome-wide association studies (GWASs) for osteoporotic traits have identified over 1000 associations; however, their impact has been limited by the difficulties of causal gene identification and a strict focus on bone mineral density (BMD). Here, we used Diversity Outbred (DO) mice to directly address these limitations by performing the first systems genetics analysis of 55 complex skeletal phenotypes. We applied a network approach to cortical bone RNA-seq data to discover 72 genes likely to be causal for human BMD GWAS associations, including the novel genes SERTAD4 and GLT8D2. We also performed GWAS in the DO for a wide-range of bone traits and identified Qsox1 as a novel gene influencing cortical bone accrual and bone strength. Our results provide a new perspective on the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics.

genetics↗