Table 1.
Expression Traits Corresponding to Genes Implicated in the T1D WTCCC Study [14,15] or Close to Genes Associated with Either SNPs That Were Associated with T1D in the WTCCC Study or with SNPs Close the T1D-Associated SNPs
Table 2.
Significant Associations Detected in the HLC for 11 of the 14 HLA Class II Gene Expression Traits Represented on the Microarray Used in This Study
Figure 1.
Local Networks for Rps26 and Erbb3 Derived from Causal, Probabilistic Whole-Gene Networks Constructed from the Liver, Adipose, Muscle, and Brain Gene Expression Data Generated from the BXH/wt and BXC Mouse Crosses
(A) The Rps26 subnetwork includes a number of known T1D associated genes (green nodes), and RPS26 in this subnetwork is directly linked to H2-Eb1, a mouse ortholog of HLA-DRB1, a previously identified T1D susceptibility gene that is also strongly associated with a cis eSNP in the HLC (Table 2). The known T1D genes annotated by the Gene Ontology are significantly enriched in this subnetwork (Table 3).
(B) The Erbb3 subnetwork is not associated with any pathways known or predicted to be involved in T1D.
Table 3.
GO Biological Process Categories Enriched in the RPS26 Subnetwork Depicted in Figure 1A
Figure 2.
PSRC1, CELSR2, and SORT1 Liver Expression Is Associated with a CAD Risk Allele and Plasma LDL Cholesterol Levels
The CAD risk allele for SNP rs599839 was established in a previous WTCCC study [16] (lilac panel). In the HLC, this same SNP is strongly associated with PSRC1, CELSR2, and SORT1 expression, with the CAD risk allele associated with lower relative expression (pink panel). In the BXH/wt cross designed to study metabolic traits that increase cardiovascular risk (green panel), all three of these expression traits were strongly correlated with plasma LDL cholesterol levels, a major CAD risk factor (scatter plots associated with the green panel). Given the association of these genes to plasma LDL-cholesterol levels, we examined whether rs599839 was associated with LDL cholesterol in a previously published GWAS [35] and found this SNP was significantly associated with LDL cholesterol levels, where the CAD risk allele was associated with higher LDL cholesterol levels in this cohort. Lower levels of CELSR2 and SORT1 expression were associated with the risk allele in humans, and with higher LDL cholesterol levels in mouse, making them ideal candidate susceptibility genes for the CAD and LDL cholesterol associations to this locus. On the other hand, lower levels of PSRC1 expression were associated with the risk allele in humans, but with lower LDL cholesterol levels in mouse, suggesting that PSRC1 is not the gene increasing CAD risk, but instead may be acting to protect against it.
Table 4.
Significant Associations Detected between Liver Expression Traits in the HLC and the CAD-Associated SNP, rs599839, on Chromosome 1p13.3
Figure 3.
Local Networks for PSRC1, CELSR2, and SORT1 Derived from Causal, Probabilistic Whole-Gene Networks in Mouse and Human
(A) Mouse network for Psrc1, Celsr2, and Sort1 derived from the liver, adipose, muscle, and brain gene expression data generated from the BXH/wt and BXC mouse crosses.
(B) Human network for PSRC1, CELSR2, and SORT1 derived from the HLC and from a previously published adipose and blood tissue cohort [21].