The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions
2003/03/31 by Irving I. Gottesman, Todd D. Gould · 5,654 citations
Biochemistry, Genetics and Molecular Biology · Medicine · Neuroscience · Psychology · #Clinical psychology #Cognition #Disease #Endophenotype #Genetic Associations and Epidemiology #Medicine #Neuropsychology #Neurotransmitter Receptor Influence on Behavior #Pathology #Psychiatry #Psychology #Receptor Mechanisms and Signaling
paper · doi:10.1176/appi.ajp.160.4.636
published in American Journal of Psychiatry 160(4), 636-645 (American Psychiatric Association)
openalex publication_date 2003/03/31 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/05
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.
Cited by
- The Primacy of Cognition in Schizophrenia.
- Increased Caudate Dopamine D2 Receptor Availability as a Genetic Marker for Schizophrenia
- Looping Genomes: Diagnostic Change and the Genetic Makeup of the Autism Population
- Sporadic adult onset primary torsion dystonia is a genetic disorder by the temporal discrimination test
- Effects of a novel schizophrenia risk variant rs7914558 atCNNM2on brain structure and attributional style
- Unity and diversity of executive functions: Individual differences as a window on cognitive structure
- Psychopathic, not psychopath: Taxometric evidence for the dimensional structure of psychopathy.
- Executive functioning and local‐global visual processing: candidate endophenotypes for autism spectrum disorder?
- Delayed reward discounting and addictive behavior: a meta-analysis
- The interaction between first-episode drug-naïve schizophrenia and age based on gray matter volume and its molecular analysis: a multimodal magnetic resonance imaging study
- The NIMH Research Domain Criteria Initiative: Background, Issues, and Pragmatics
- The oft‐neglected role of parietal EEG asymmetry and risk for major depressive disorder
- Are complex traits underpinned by polygenic molecular traits? A reflection on the complexity of gene expression
- Multimodal physiological responses evoked by emotional naturalistic stimuli facilitate classification of major depression and generalized anxiety
- Computational Psychiatry
- Meta-analysis of the P300 and P50 waveforms in schizophrenia
- Pragmatic Language and Theory of Mind Deficits in People with Schizophrenia and Their Relatives
- Psychological models of autism: an overview
- Are Executive Control Functions Related to Autism Symptoms in High-Functioning Children?
- The Relation Between ADHD Symptoms and Fine Motor Control: A Genetic Study
- The Cleveland Family Speech and Reading Study: A Review of Long-Term Outcomes Linking Phenotypes and Genotypes for Speech Sound Disorders
- Exposome and cognition in psychosis: an exploratory study in sex-specific patterns in patients and their unaffected siblings
- Extraversion but not depression predicts reward sensitivity: Revisiting the measurement of anhedonic phenotypes.
- Fast sleep spindle reduction in schizophrenia and healthy first-degree relatives: association with impaired cognitive function and potential intermediate phenotype
- Visibility predicts priming within but not between people: a cautionary tale for studies of cognitive individual differences
- The NeuroIMAGE study: a prospective phenotypic, cognitive, genetic and MRI study in children with attention-deficit/hyperactivity disorder. Design and descriptives
- Memory processes in schizophrenia: impact of comorbidity with substance use disorders
- Emotion Processing in Schizophrenia: Insights From a Brain Imaging Study Comparing Patients, Siblings, and Healthy Controls
- The changing impact of genes and environment on brain development during childhood and adolescence: Initial findings from a neuroimaging study of pediatric twins
- Test–retest reliability of P50, N100 and P200 auditory sensory gating in healthy subjects
- A novel functional brain imaging endophenotype of autism: the neural response to facial expression of emotion
- Treatment of anabolic–androgenic steroid dependence: Emerging evidence and its implications
- Disintegration: A reconceptualization of psychosis proneness as a personality trait separate from the Big Five
- The Effects of Alcohol and Cannabis Use on the Cortical Thickness of Cognitive Control and Salience Brain Networks in Emerging Adulthood: A Co-twin Control Study
- Interoceptive sensitivity in anxiety and anxiety disorders: An overview and integration of neurobiological findings
- Schizophrenia, “Just the Facts”: What we know in 2008
- Biomarkers for Psychiatric Disorders
- Sensory Impairments and Autism: A Re-Examination of Causal Modelling
- Brain perfusion mediates the relationship between miRNA levels and postural control
- Psychometric properties of neural responses to monetary and social rewards across development
- The Early Auditory Gamma-Band Response Is Heritable and a Putative Endophenotype of Schizophrenia
- ADHD and Genetics: A Consensus Reconsidered
- Twin Cities Metropolitan Area Summer Visitor Profile
- Pediatric Bipolar Disorder
- The genetics of early-onset bipolar disorder: A systematic review
- The genetics of bipolar disorder
- Moving towards ICD-11 and DSM-V: Concept and evolution of psychiatric classification
- Three Approaches to Understanding and Classifying Mental Disorder: ICD-11, DSM-5 , and the National Institute of Mental Health’s Research Domain Criteria (RDoC)
- Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene
- Hormones and the Evolution of Complex Traits: Insights from Artificial Selection on Behavior
- Introduction to the Special Section on Cognitive Abilities: 100 Years After Spearman's (1904) "'General Intelligence,' Objectively Determined and Measured".
- Continuity of genetic and environmental influences on cognition across the life span: A meta-analysis of longitudinal twin and adoption studies.
- Genetic foundations of human intelligence
- Genetics and Phenotyping of Urological Chronic Pelvic Pain Syndrome
- Discovering Endophenotypes for Major Depression
- The genetic epidemiology of personality disorders
- Molecular genetic approaches to understanding the comorbidity of psychiatric disorders
- Suicide attempts and psychological risk factors in patients with bipolar and unipolar affective disorder
- a neurobehavioral model of affiliative bonding: implications for conceptualizing a human trait of affiliation
- Biological insights from 108 schizophrenia-associated genetic loci
- Behavior Genetics
- Phenomics: the next challenge
- Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine
- Adult Hippocampal Neurogenesis, Fear Generalization, and Stress
- Causation in biology: stability, specificity, and the choice of levels of explanation
- Understanding Heritability: What it is and What it is Not
- The ascent of mouse: advances in modelling human depression and anxiety
- Gene-Environment Interplay Between Cannabis and Psychosis
- Beyond depression: Toward a process‐based approach to research, diagnosis, and treatment.
- Genetic, Environmental and Immunologic Factors in the Etiology of Autism Spectrum Disorders
- Lifetime course of eating disorders: design and validity testing of a new strategy to define the eating disorders phenotype
- The Epidemiology of Autism Spectrum Disorders
- Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders
- The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice
- Animal models of mood disorders: recent developments
- Is Autoimmune Thyroiditis Part of the Genetic Vulnerability (or an Endophenotype) for Bipolar Disorder?
- Future contributions on genetics
- The cognitive neuropsychology of obsessive-compulsive disorder: A critical review
- Obsessive–compulsive disorder: an integrative genetic and neurobiological perspective
- Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations. [europepmc]
- Toward an objective characterization of an anhedonic phenotype: a signal-detection approach. [europepmc]
- Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. [europepmc]
- Impaired cognitive flexibility and motor inhibition in unaffected first-degree relatives of patients with obsessive-compulsive disorder. [europepmc]
- Gene-environment correlations: a review of the evidence and implications for prevention of mental illness. [europepmc]
- Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. [europepmc]
- Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. [europepmc]
- Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task. [europepmc]
- Realistic expectations of prepulse inhibition in translational models for schizophrenia research. [europepmc]
- The error-related negativity (ERN) and psychopathology: toward an endophenotype. [europepmc]
- A cognitive neuroscience-based computerized battery for efficient measurement of individual differences: standardization and initial construct validation. [europepmc]
- Cortical thickness or grey matter volume? The importance of selecting the phenotype for imaging genetics studies. [europepmc]
- Neuropsychology of the prodrome to psychosis in the NAPLS consortium: relationship to family history and conversion to psychosis. [europepmc]
- Structural MRI of pediatric brain development: what have we learned and where are we going? [europepmc]
- Cognitive control deficits in schizophrenia: mechanisms and meaning. [europepmc]
- From reactive to proactive and selective control: developing a richer model for stopping inappropriate responses. [europepmc]
- Delayed reward discounting and addictive behavior: a meta-analysis. [europepmc]
- Animal models of schizophrenia. [europepmc]
- Depression, stress, and anhedonia: toward a synthesis and integrated model. [europepmc]
- The behavioral economics of substance use disorders: reinforcement pathologies and their repair. [europepmc]
- Biological insights from 108 schizophrenia-associated genetic loci. [europepmc]
- Neurobiology of rodent self-grooming and its value for translational neuroscience. [europepmc]
- Unity and diversity of executive functions: Individual differences as a window on cognitive structure. [europepmc]
- Painful Temporomandibular Disorder: Decade of Discovery from OPPERA Studies. [europepmc]
- ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries. [europepmc]
Related