Just a SNP away: The future of massively parallel reporter assay.

The human genome is largely noncoding, yet the field is still grasping to understand how noncoding variants impact transcription and contribute to disease etiology. The massively parallel reporter assay (MPRA) has been employed to characterize the function of noncoding variants at unprecedented scales, but its application has been largely limited by the context. The field will benefit from establishing a systemic platform to study noncoding variant function across multiple tissue types under physiologically relevant conditions.

The association of GNB5 with Alzheimer disease revealed by genomic analysis restricted to variants impacting gene function.

Disease-associated variants identified from genome-wide association studies (GWASs) frequently map to non-coding areas of the genome such as introns and intergenic regions. An exclusive reliance on gene-agnostic methods of genomic investigation could limit the identification of relevant genes associated with polygenic diseases such as Alzheimer disease (AD). To overcome such potential restriction, we developed a gene-constrained analytical method that considers only moderate- and high-risk variants that affect gene coding sequences.

Specific regulation of mechanical nociception by Gβ5 involves GABA-B receptors.

Mechanical, thermal, and chemical pain sensation is conveyed by primary nociceptors, a subset of sensory afferent neurons. The intracellular regulation of the primary nociceptive signal is an area of active study. We report here the discovery of a Gβ5-dependent regulatory pathway within mechanical nociceptors that restrains antinociceptive input from metabotropic GABA-B receptors.

Ancestry-specific high-risk gene variant profiling unmasks diabetes-associated genes.

How ancestry-associated genetic variance affects disparities in the risk of polygenic diseases and influences the identification of disease-associated genes warrants a deeper understanding. We hypothesized that the discovery of genes associated with polygenic diseases may be limited by the overreliance on single-nucleotide polymorphism (SNP)-based genomic investigation, as most significant variants identified in genome-wide SNP association studies map to introns and intergenic regions of the genome. To overcome such potential limitations, we developed a gene-constrained, function-based analytical method centered on high-risk variants (hrV) that encode frameshifts, stopgains or splice site disruption.