Bernie and Tomas’ review of Massively Parallel Reporter Assays (MPRAs) as a method to identify noncoding functional genetic risk variants for neuropsychiatric disease was published in Biological Psychiatry!
Noncoding genomic sequences—for which molecular functions cannot usually be inferred—harbor a large portion of disease-associated variants, creating a substantial barrier to understanding higher-order molecular and biological systems of disease. Meanwhile, MPRAs are powerful molecular genetics tools that can be used to screen thousands of untranscribed or untranslated sequences and their variants for functional effects in a single experiment. This approach, though underutilized in psychiatric genetics, has several useful features for the field. In the publication, Tomas and Bernie review methods for assaying putatively functional genetic variants and regions, emphasizing MPRAs and the opportunities they hold for dissection of psychiatric polygenicity (inheritance from multiple genes). They also discuss literature applying functional assays in neurogenetics, highlighting strengths, caveats, and design considerations—especially regarding disease-relevant variables (cell type, neurodevelopment, and sex), and ultimately they propose applications of MPRA to both computational and experimental neurogenetics of polygenic disease risk.