Identification of genetic modifiers of vEDS mice using whole-genome SNP data

Aortic dissection or rupture is a major cause of mortality in vascular Ehlers Danlos Syndrome (vEDS), a connective tissue disorder caused by heterozygous mutations in the COL3A1 gene. C57BL6/J (BL6) mice carrying the Col3a1G938D/+ mutation recapitulate the vEDS vascular phenotype and die suddenly of aortic rupture/dissection. However, 129S6/SvEvTac (129) mice expressing the same Col3a1G938D/+ mutation show near-complete life-long protection from vascular rupture. To identify genetic modifiers of vascular risk in vEDS, we performed genome-wide genotyping of intercrossed BL6/129 vEDS mice stratified by survival and identified a significant protective locus encompassing a variant in Map2k6, encoding Mitogen-Activated Protein Kinase Kinase 6 (M2K6), a p38-activating kinase. We genotyped 91 mixed background vEDS mice with a mild phenotype (coded as controls, 62 females and 29 males) , and 96 mixed background vEDS mice with a severe phenotype (coded as cases, 29 females, 67 males). We used a linkage disequilibrium (LD) block-pruned set of 615 SNPs to perform logistic regression GWAS, using sex as a covariate.