Research Review: Polygenic methods and their application to psychiatric traits

Despite evidence from twin and family studies for an important contribution of genetic factors to both childhood and adult onset psychiatric disorders, identifying robustly associated specific DNA variants has proved challenging. In the pregenomics era the genetic architecture (number, frequency and effect size of risk variants) of complex genetic disorders was unknown. Empirical evidence for the genetic architecture of psychiatric disorders is emerging from the genetic studies of the last 5 years. METHODS AND SCOPE: We review the methods investigating the polygenic nature of complex disorders. We provide mini-guides to genomic profile (or polygenic) risk scoring and to estimation of variance (or heritability) from common SNPs; a glossary of key terms is also provided. We review results of applications of the methods to psychiatric disorders and related traits and consider how these methods inform on missing heritability, hidden heritability and still-missing heritability.

Genome-wide genotyping and sequencing studies are providing evidence that psychiatric disorders are truly polygenic, that is they have a genetic architecture of many genetic variants, including risk variants that are both common and rare in the population. Sample sizes published to date are mostly underpowered to detect effect sizes of the magnitude presented by nature, and these effect sizes may be constrained by the biological validity of the diagnostic constructs.