In a paper appearing in Cell, researchers from the University of Chicago report that Mendelian variants likely also contribute to the development of complex diseases. The team scoured the medical records of more than 110 million patients in the US and Denmark, it found that there are thousand of connections between Mendelian variants and complex diseases. Each disease, the team adds, appears to have a unique Mendelian disease allelic architecture that forms a type of code for that disease. The group adds that genome-wide association signals often fall within this code. "[V]ariants underlying Mendelian disorders likely interact with one another to contribute to complex disease risk, highlighting the potential of clinical data for uncovering complicated genetic architectures," the team writes.
In mice, a mutation in the enzyme methionine synthase reductase, known as Mtrr, leads to changes in the in utero environment and affects the development of the mouse pups. Through the examining generations of mice, researchers from the University of Calgary found that Mtrr genotype the maternal grandparents had affects the developmental of their wild-type grandprogeny. "Therefore, the initial effect of Mtrr deficiency is likely transmitted through the germline via epigenetic factors, independent of physiological environment and genomic sequence," the researchers say.
Also in Cell, researchers led by Kenneth Smith from the University of Cambridge report that a noncoding polymorphism in FOXO3A is linked to a milder course of Crohn's disease and rheumatoid arthritis, but with more severe cases of malaria. To home in on that variant, the researchers drew upon an existing GWAS dataset and related phenotypic data. In addition, they report that this minor allele is associated with a limited inflammatory response through a FOXO3-driven pathway.