The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions

Abstract

Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.

Impact of complex genetic variation in COMT on human brain function

“…Recently developed multilocus tests may offer advantages in power 34 that could be relevant for neuroimaging. 4 In any case, the sample size studied here, while very large for a neuroimaging study, is still small compared with those necessary for the study of clinical phenotypes, illustrating the potential advantage conferred by increased penetrance when studying biologically based quantitative phenotypes, 35 especially when potentially interacting variants are involved. Here, we have used haplotype imaging as a tool to study the functional impact of combinations of multiple loci within a gene.…”

The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

“…2009). Such electrophysiological measures can provide objective assessments and are potentially closely linked to neurobiological foundation of disease processes (Gottesman & Gould 2003). Consequently, pre‐attentive electrophysiological measures are also less likely to be biased by differences in behavioural states between species than more traditional behavioural measures.…”

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…The multiple related outcomes of the 5-HTTLPR G Â E pathogenic pathway could be due to either of the following mechanisms: (1) multiple effects of the same gene and environment (G Â E pleiotropy); (2) subsequent elements on one causal pathway: once depression or substance abuse is present in an individual carrying an s allele, this condition may act as a stressor, contributing to the development of comorbidity; (3) may be markers of a latent underlying feature, which is more directly linked with the genotype, that is an intermediate phenotype or 'endophenotype'. 160 Psychological and biological endophenotypes A discovery of intermediate phenotype that is more heritable or more strongly associate with a specific polymorphism than a diagnosed psychiatric disorder, would further our understanding of the mechanism of the observed G Â E. An obvious candidate is neuroticism, which in its essence is an enduring trait of exaggerated negative emotional reactivity to events. Neuroticism is highly heritable.…”