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This Week in PLOS: Apr 8, 2019

In PLOS Genetics, researchers from the University of California, San Francisco, outline a 'reverse genome-wide association study,' or RGWAS, method for uncovering disease subtypes that might explain individuals' phenotypes, treatment responses, or environmental exposures. "[W]hile GWAS seeks the genetic basis of a given trait, RGWAS seeks to define trait subtypes with distinct genetic bases," the authors note, adding that the approach makes it possible to "simultaneously split samples into homogeneous subtypes and to learn differences in genetic or treatment effects between subtypes." The team validated the RGWAS strategy with data for 9,300 deeply-phenotyped Han Chinese women with major depression, picking up a known 'stress' subtype of the disease, before using it to find several new metabolic subtypes.

A team based in Australia, Turkey, and Iran describes apparent genetic ties between the autosomal recessive autoinflammatory disease Familial Mediterranean Fever, and an immune-related form of arthritis called ankylosing spondylitis in Turkey and Iran for another PLOS Genetics paper. With a genome-wide association studies that included 1,001 ankylosing spondylitis patients from Turkey and 1,011 Turkish controls, along with 479 cases and 830 controls from Iran, the researchers tracked down a rare coding variant in the inflammation-related gene MEFV, which coincides with ankylosing spondylitis risk and with serum interleukin-1-beta levels in the Turkish population, where cytokine levels were measured. The authors suggest the MEFV risk SNP "markedly increases the risk of [ankylosing spondylitis] even in patients not suffering from FMF, and is associated with increased serum [interleuken-1-beta] levels in these patients."

For a study in PLOS Pathogens, Yale University researchers share findings from a genome-wide screen for mechanisms in human cells that Salmonella Typhi takes advantage of to transport typhoid toxins. Using a CRISPR-Cas9 gene editing-based screen, typhoid toxin labeling, immunofluorescence microscopy, and other approaches, the team saw signs that typhoid toxins hitchhike into host cell targets via retrograde transport machinery and endoplasmic reticulum machinery. From there, authors compared this transport method to that used by other bacterial toxins to find shared and distinct transport features. "By comparing typhoid toxin's transport pathway with the transport mechanisms utilized by other toxins, we have defined unique common components that transport these toxins to their cellular destinations," they write.