Redefining the Endophenotype Concept to Accommodate Transdiagnostic Vulnerabilities and Etiological Complexity

Abstract

In psychopathology research, endophenotypes are a subset of biomarkers that indicate genetic vulnerability independent of clinical state. To date, an explicit expectation is that endophenotypes be specific to single disorders. We evaluate this expectation considering recent advances in psychiatric genetics, recognition that transdiagnostic vulnerability traits are often more useful than clinical diagnoses in psychiatric genetics, and appreciation for etiological complexity across genetic, neural, hormonal and environmental levels of analysis. We suggest that the disorder-specificity requirement of endophenotypes be relaxed, that neural functions are preferable to behaviors as starting points in searches for endophenotypes, and that future research should focus on interactive effects of multiple endophenotypes on complex psychiatric disorders, some of which are ‘phenocopies’ with distinct etiologies.

Phenotypic features of central sensitization

“…Biomarkers can also be used to characterize a disorder and can be defined broadly as any interaction between a biological system and potential hazard that can be reproducibly measured (Strimbu & Tavel, 2010). Biomarkers can be functional, physiological, biochemical or molecular, but unlike phenotypes, may or may not have genetic influences and can tend to be state-dependent phenomena (Beauchaine & Constantino, 2017). Blood pressure is a good example of a biomarker associated with the clinical phenomena of hypertension.…”

Psychiatry and developmental psychopathology: Unifying themes and future directions

“…We focus on four interrelated principles, all of which acknowledge and embrace etiological complexity , an important theme in modern child, adolescent, and adult psychiatry [25,26]. These principles include calls for (1) multi disciplinary translational research [27,28], (2) specification of multi causal pathways to seemingly single diagnostic syndromes [26,29], (3) description of divergent multi final outcomes from common etiological starting points [29,30], and (4) research conducted across multiple levels of analysis spanning genes to environments [31,32]. After discussing these principles, we turn our attention to the importance of disrupted neuromaturational processes in developing psychopathology.…”

“…At the time, however, equifinality was not an influential concept in mainstream psychiatry. Instead, searches for distinct causes of mental disorders and associated pathognomonic signs predominated given how useful the approach had been in modern medicine [31,36,37]. …”

“…In merely 15 years since the human genome was sequenced [56], molecular geneticists have migrated away from conducting candidate gene studies with dozens to hundreds of participants toward large-scale genome-wide association studies (GWAS) that include tens of thousands of people [57]. As power of GWAS increases and methods such as genomewide complex trait analysis (GCTA) and approximate Bayesian polygenic analysis (ABPA) become mainstream, it is increasingly clear that hundreds and even thousands of genes affect complex behavioral traits, and that few if any particular genes are necessary or sufficient for psychiatric impairment [26,31]. Furthermore, epigenome-wide association studies (eGWAS) are providing insights into environmentally mediated gene regulation [58], and central roles for both de novo mutations and heritable copy number variants (CNVs) in the pathogeneses of psychiatric disorders have become clear [59].…”

“…Furthermore, epigenome-wide association studies (eGWAS) are providing insights into environmentally mediated gene regulation [58], and central roles for both de novo mutations and heritable copy number variants (CNVs) in the pathogeneses of psychiatric disorders have become clear [59]. Thus, in little more than a decade, oligogenic and polygenic theories have been largely abandoned in favor of complex, multifactorial models that include heritable, epigenetic, and stochastic effects [31,60]. Although the importance of genomewide significant single nucleotide polymorphisms (SNPs) in pathophysiologies of psychopathology should not be understated, they individually account for limited proportions of liability [61,62].…”