Published March 2021 | Nature Communications

As part of an ongoing exploration of systemic lupus erythematosus (SLE), a 16-member research team has developed a new type of “massively parallel” genetic screening tool that could shed new light on many conditions.

“This study not only provides several critical new discoveries about lupus, it also provides a blueprint for dissecting the genetic mechanisms of many complex human diseases,” says Leah Kottyan, PhD, interim director of the Center for Autoimmune Genomics and Etiology.

Massively parallel reporter assays (MPRAs) help scientists quantify the regulatory capacity of thousands of pieces of DNA in a given cell type. Such DNA sequences control how much, when, and where particular gene products are made.

“More than 95% of the genome does not code for genes, but instead is involved in other processes, such as controlling gene expression levels,” Matthew Weirauch, PhD, says. “Understanding more about this information is vital because these regions of the genome also happen to be where genetic risk concentrates for complex diseases such as lupus.”

In this study, the authors used an MPRA to examine the effect of every known lupus genetic variant on gene expression levels. For people battling lupus, this study boiled down more than 3,000 potentially important genetic variants at 91 risk loci to just 51 of significant interest at 27 risk loci.

Many of the high-interest variants appear related to B cell function, which suggests some fresh ideas for preventing lupus-related complications that could be developed quickly, Kottyan says. Beyond lupus, the research team has begun using the MPRA technology to further explore atopic dermatitis, eosinophilic esophagitis, and multiple sclerosis.

Massively Parallel Reporter Assay Workflow

A schematic illustrating the process researchers used to conduct MRPA analysis of lupus-associated risk loci.

This schematic illustrates the process researchers used to conduct MRPA analysis of lupus-associated risk loci.