Arguments for the sake of endophenotypes: Examining common misconceptions about the use of endophenotypes in psychiatric genetics

Abstract

Endophenotypes are measurable biomarkers that are correlated with an illness, at least in part, because of shared underlying genetic influences. Endophenotypes may improve our power to detect genes influencing risk of illness by being genetically simpler, closer to the level of gene action, and with larger genetic effect sizes or by providing added statistical power through their ability to quantitatively rank people within diagnostic categories. Furthermore, they also provide insight into the mechanisms underlying illness and will be valuable in developing biologically-based nosologies, through efforts such as RDoC, that seek to explain both the heterogeneity within current diagnostic categories and the overlapping clinical features between them. While neuroimaging, electrophysiological, and cognitive measures are currently most used in psychiatric genetic studies, researchers currently are attempting to identify candidate endophenotypes that are less genetically complex and potentially closer to the level of gene action, such as transcriptomic and proteomic phenotypes. Sifting through tens of thousands of such measures requires automated, high-throughput ways of assessing and ranking potential endophenotypes, such as the Endophenotype Ranking Value. However, despite the potential utility of endophenotypes for gene characterization and discovery, there is considerable resistance to endophenotypic approaches in psychiatry. In this review, we address and clarify some of the common issues associated with the usage of endophenotypes in the psychiatric genetics community.

Targeting dynamic interplay among disordered domains or endophenotypes to understand complex neuropsychiatric disorders: Translational lessons from preclinical models

“…In the last decades, the endophenotype concept has emerged as a key paradigm in biological psychiatry (Braff, 2015;Cannon and Keller, 2006;Glahn et al, 2012Glahn et al, , 2014Hasler et al, 2006). Revealing both overlapping and unique candidate genes of various complex CNS disorders (Courtet et al, 2011;Crossley et al, 2014;Dick et al, 2006;Ikeda et al, 2013;Ivleva et al, 2010), this concept has also become an important part of computational psychiatry (Wang and Krystal, 2014).…”

Toward stratified treatments for bipolar disorders

“…The concept of endophenotypes assumes that there are fewer genes and less complex gene-environment interactions involved in the variation of endophenotypes than in psychological syndromes (Glahn et al, 2014;Gottesman and Gould, 2003).…”

Best behaviour? Ontologies and the formal description of animal behaviour

“…These measurable components are thought to be closer to the underlying biological basis of disease and therefore in principle might be genetically simpler and much more amenable to complex trait genetics and molecular and cellular analysis. Although there has been considerable resistance to the adoption of the endophenotype concept in clinical psychiatry (Glahn et al 2014), it is clear than any molecular or mechanistic nosology of psychiatric disease requires the objective approach offered using endophenotypes, and any mechanistic or genetic approaches to understanding their origins must benefit from the greater clarity offered. Importantly, the decomposition of complex human disease into component endophenotypes provides an opportunity to match disease manifestations in humans with those in non-human animals (Gould and Gottesman 2006) where it is not possible to use the same diagnostic approaches.…”