From Common Variant to Function: State-of-the-Art Approaches

Excerpt

Genome-wide association studies (GWASs) have been integral to our understanding of the polygenic architecture of psychiatric disorders, yet distilling disease biology from GWAS remains a challenge because GWAS-identified genomic regions often contain dozens of variants with highly correlated structure. The majority of variants within these loci are located within the noncoding genome, so their functional consequences are not immediately apparent. Moreover, to characterize thousands of such variants requires a highly scalable experimental approach. Such systematic interrogation of the functional consequences of variants is enabled by population-scale molecular assays (e.g., quantitative trait loci) or scalable genomic perturbation assays (e.g., massively parallel reporter assays or CRISPR screens). This review describes available genomic resources and cutting-edge experimental approaches that have been adopted to infer functional consequences of risk variants. Additionally, it outlines gaps in defining causal variants, linking variants to target genes, interrogating combinatorial effects of variants within the polygenic background, and considering the context-specific nature of variants. Extended efforts to fill these gaps will enable more comprehensive interpretation of GWAS and ultimately reveal the fundamental biological context behind polygenic psychiatric disorders.