DEPRESSION AND ANXIETY 30:185–189 (2013)
The Cutting Edge
ENDOPHENOTYPE, INTERMEDIATE PHENOTYPE,
BIOMARKER: DEFINITIONS, CONCEPT COMPARISONS,
CLARIFICATIONS
Mark F. Lenzenweger, Ph.D., is currently Distinguished Professor of Psychology in clinical science, cognitive neuroscience, and behavioral neuroscience at the
State University of New York at Binghamton (Binghamton, NY), Adjunct Professor of Psychology in Psychiatry at the Weill Cornell Medical College (New York,
NY), and Senior Research Fellow at the Personality Disorders Institute of the
New York Presbyterian Hospital (White Plains, NY). He directs the Laboratory
of Experimental Psychopathology at SUNY-Binghamton, where he conducts his
research in several areas: (a) schizotypy and schizophrenia, (b) neurocognition in
borderline personality disorder, and (c) longitudinal research in personality disorders. Dr. Lenzenweger is internationally renowned for his research in schizotypy
and has long advocated the view that schizotypic psychopathology is a variant
of schizophrenia liability. His 2010 monograph, Schizotypy and schizophrenia: The
view from experimental psychopathology, provides an overview of this research within
the context of a discussion of psychopathology research methods. He also directs
the landmark NIMH-funded Longitudinal Study of Personality Disorders, which was
the first prospective multiwave study of personality disorders, personality, and temperament. He began his academic
career at Cornell (Ithaca, NY), where he remained for 11 years, before he moved on to Harvard. He is the author of
over 100 peer-reviewed scientific articles as well as six edited volumes and one monograph in psychopathology and
clinical science. A Fellow in both the Association for Psychological Science and the American Psychopathological
Association as well as a NARSAD Distinguished Investigator, he is also a licensed clinical psychologist who continues
to see patients in psychotherapy.
This Cutting Edge essay focuses on three concepts
enjoying increasing usage in contemporary psychopathology research, namely endophenotype, intermediate phenotype, and biomarker. These concepts are
likely to see a meteoric rise in use in studies of affective illness and anxiety disorders in the coming years.
This is true especially given the recently NIMH proposed research diagnostic criteria (RDoCs), a newly reconfigured nomenclature for psychopathology in the offing (e.g., DSM-5), and ever changing scene in genetics
∗ Correspondence
to: Mark F. Lenzenweger, Ph.D., Department
of Psychology, The State University of New York at Binghamton, Science IV, Binghamton, NY 13902–6000, E-mail:
[email protected]
Portions of this paper represent amended and extended versions of
prior discussions of these concepts by the author[1] and are used
here with permission of the author who holds copyright.
DOI 10.1002/da.22042
Published online 16 January 2013 in Wiley Online Library (wileyonlinelibrary.com).
C 2013 Wiley Periodicals, Inc.
research strategies (candidate gene, genome-wide association, epigenetic). These concepts, however, are not
fungible. A clear understanding of their specific meaning
and the implications of these meanings for psychopathology research, going forward, is essential.
THE ENDOPHENOTYPE
CONCEPT
The modern psychopathology research corpus supports the inference that most forms of mental illness
(e.g., bipolar illness, schizophrenia, unipolar depression,
anxiety disorders) possess an appreciable heritable substrate. This substrate contributes, in interaction with
other genetic assets and liabilities as well as environmental and epigenetic inputs, to the overall liability for
an illness. It is highly plausible to assume further that
the underlying liability for an illness will manifest itself
in some fashion before the emergence of its clinical signs
and symptoms. In the study of schizophrenia, as an example, this means the emergence of detectable pathological
processes before the appearance of psychotic symptoms,
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Lenzenweger
even before so-called prodromal features. In short, one
should be able to detect some internal manifestation of
a genetic liability for an illness within the at-risk person that (a) is not visible to common observation, (b)
exists in situ (i.e., in place, within (not outside) the person), and (c) predates observable signs or symptoms of
illness.
THE INTELLECTUAL HISTORY UNDERGIRDING
THE ENDOPHENOTYPE CONCEPT
The endophenotype model has long characterized I. I.
Gottesman’s thinking about the genetics of schizophrenia, and psychopathology more broadly. With James
Shields, he proposed the endophenotype concept in the
early 1970’s ([2, 3] , p. 172). The substantive background
and intended meaning of the endophenotype was explicated in Gottesman and Gould.[4] The endophenotype concept reflects the impact of two major intellectual currents in psychological science and genetics. One
current deriving from the insect genetics literature, that
advocated the term endophenotype to denote a feature
internal to an organism and visible upon microscopic
examination (i.e., not an obvious, external feature).[5]
The other current deriving from the theoretical and
methodological psychological science work on latent hypothetical constructs, inspired by the seminal substantive
distinction between “hypothetical constructs” and “intervening variables” made by MacCorquodale and
Meehl ([6] ; see also ref.[7] ). Well known to psychologists,
the “hypothetical construct” model advanced the core
idea that a theoretical concept (e.g., anxiety, depression,
pain, love, open mindedness) could (a) exist at a latent
level and (b) not be directly observable, but (c) be plausibly related via a nomological network to observable
and measurable characteristics (e.g., signs/symptoms,
test measurements, interview data). Using the example of
schizophrenia, Gottesman and Shields[2] argued that
endophenotypes should be considered internal phenotypes that might someday be detectable in families of
schizophrenics “ . . . either biological or behavioral (psychometric pattern), which will not only discriminate
schizophrenics from other psychotics, but will also be
found in all identical co-twins of schizophrenics whether
concordant or discordant” (p. 336). The endophenotype
is conceptualized as internal to or “within” the individual. Additionally, the endophenotype represents an unobservable latent entity (such as a hypothetical latent construct) that cannot be directly observed with the unaided
naked eye; rather, an appropriate technology would be
needed to “see” the endophenotype. Importantly, the
endophenotype is not “hidden,” rather it can be viewed
with the appropriate tools.
The endophenotype concept was prominently
positioned for psychopathology research writ large
by Gottesman and Gould.[4] However, it emerged
originally in schizophrenia research (e.g., [2, 8] ; see
also ref. [9, 10 ) and was subsequently imported into
research on other disorders, including anxiety and
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TABLE 1. Criteria for an endophenotype
(1) The endophenotype is associated with illness in the
population.
(2) The endophenotype is heritable.
(3) The endophenotype is primarily state-independent (manifests
in an individual whether or not the illness is active) but may
require a challenge to elicit the indicator.
(4) The endophenotype is more prevalent among the ill relatives
of ill probands compared with the well relatives of the ill
probands (i.e., within families, endophenotype and illness
co-segregate).
(5) The endophenotype found in affected family members is
found in nonaffected family members at a higher rate than in
the general population.
(6) The endophenotype should be a trait that can be measured
reliably, and ideally is more strongly associated with the
disease of interest than with other psychiatric conditions.
Adapted from Refs. [4] and [20]
affective disorders. The endophenotype concept
has clearly begun to gain traction in the study of
anxiety and affective disorders. Discussions of endophenotypes in the study of major depression
([11] ; see also the new major depression database—
http://mdd.psych.ac.cn/biomarkBrowser.do), bipolar
illness,[12] and anxiety-disorders[13] began in earnest in
recent years. Specific examples of potentially exciting
candidate endophenotypes in anxiety and affective
disorders research are (a) threat-related attentional
bias in anxiety;[14] (b) baseline activation and neural
response patterns in depression;[15] (c) cortical thinning
in depression;[16] (d) amygdala and medial prefrontal
cortex neural response configurations in PTSD;[17] and
(e) neurotrophic signal transduction pathways in mood
disorders.[18]
DEFINING THE ENDOPHENOTYPE: EXPLICIT
CRITERIA FOR VALIDITY
According to Gottesman and Gould,[4,19] an endophenotype is a measurable component, unseen by the unaided naked eye, that lies along (i.e., within) the pathway between disease (i.e., observable phenotype) and
distal genotype. An endophenotype is not a risk factor,
rather it is a manifestation of the underlying disease liability. Thus, an endophenotype is internal and not easily discerned without some technological assistance with
appropriate sensitivity. An endophenotype may be
neurophysiological, endocrinological, neuroanatomical,
cognitive, or neuropsychological in nature and it can include configured self-report (e.g., inventory) data. The
utility of an endophenotype is that it represents, in principle, a relatively simpler clue to genetic underpinnings
than the disease syndrome (i.e., symptom constellations).
Gottesman and colleagues ([4] , p. 639; [20] , p. 964) proposed six explicit criteria defining an endophenotype (see
Table 1). Gottesman and Gould[4] articulated the benefits of the endophenotype for research.
The Cutting Edge: Endophenotype, Intermediate Phenotype, and Biomarker
THE BIOMARKER CONCEPT
In biomedical research, a biomarker (occasionally
termed “bioindicator”) could be any measurable indicator of a disease. An elevated blood concentration of one
or another substance in the blood that would be taken as
indicative of the presence of illness, thus a “biomarker”
(e.g., high cholesterol is a biomarker of cardiovascular ill-health). In other words, such a biomarker could
be correlated with an aspect of the disease process, but
not fall within the genotype to phenotype pathway and,
therefore, may not be specifically embedded in the causal
chain for the disease. A biomarker could also reflect a biologically detectable impact of an outside agent upon
the organism. The National Institute of Environmental
Health[21] defined biomarkers as “key molecular or cellular events that link a specific environmental exposure
to a health outcome.”[22] Consider blood or urine lead
(Pb) levels as examples of biomarkers of environmental lead exposure. Finally, perhaps casting the broadest
net in the biomarker dialogue, the Biomarkers Working
Group (2001) defined a biomarker as “a characteristic
that is objectively measured and evaluated as an indicator
of normal biological processes, pathogenic processes, or
pharmacologic responses to a therapeutic intervention”
(p. 91). In all of these descriptions, it is evident that a genetic basis for the biomarker is not a necessary criterion.
However, in comparison, an essential component of the
endophenotype concept is that it is heritable. In short, a
biomarker may or may not be subject to genetic influences.
The easiest way to remember the distinction between
these two terms is that all endophenotypes are, by definition, biomarkers, but not all biomarkers are endophenotypes.
Whereas an endophenotype must meet all the criteria
presented in Table 1, a biomarker need only reflect some
measurable deviation in the organism, reflective of either internal factors operating in either health/illness or
the impact of an external agent. Thus, for example, a
biomarker that is reflective of an environmental exposure will necessarily fail to satisfy those criteria of validity
for an endophenotype that concern patterns of familial
aggregation (e.g., elevated ammonia levels due to some
forms of drug abuse). Thus, the term biomarker is not fungible with (or equivalent to) endophenotype.
THE INTERMEDIATE
PHENOTYPE CONCEPT
The term “intermediate phenotype” has also seen
increased use in some discussions related to liability
for psychopathology. However, not unlike the term
“biomarker,” the concept “intermediate phenotype” is
also not fungible with endophenotype. This is because
the term intermediate phenotype can be used in multiple ways, but only one of them approximates the intended meaning of an endophenotype. Weinberger and
colleagues[23, 24] clearly state a preference for the term
intermediate phenotype in their work. They argue it
“implies a biological [italics added] trait that is in a pre-
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dictable path from gene to behavior and because the phenotypes and mechanisms are not secondary, but probably
primary” ([23] , p. 820). This definition, which does not
specify heritability as a necessary feature, suggests that
the biological trait in question could be a biomarker.
More recently, however, Rasetti and Weinberger[24]
state, “An intermediate phenotype related to mental illness is a heritable [italics added] trait that is located in the
path of pathogenesis from genetic predisposition to psychopathology” (p. 340) and in defining the intermediate
phenotype they explicitly reference[4] “endophenotype.”
Weinberger and colleagues buttress their preference for
the intermediate phenotype concept as they see their intended usage of the term as “analogous to its usage in
other areas of complex medical genetics” ([23] , p. 820).
As discussed elsewhere ([1] ), the term intermediate
phenotype can denote a number of meanings, all of
which are plausible and all of which would differently
impact research. First, the term intermediate phenotype
has an established meaning in genetics related to “incomplete dominance” (also known as “partial dominance,”
when known a priori that a true autosomal dominant gene
is causal) or a form of intermediate genetic inheritance in
which heterozygous alleles are both expressed to varying degrees, resulting in an intermediate phenotype that
represents a combination of the parent phenotypes. Examples of intermediate phenotypes are a white flower
and a red flower gives rise to a pink flower; in shorthorn cattle, coat color may be red, white, or roan (roan
is an intermediate phenotype expressed as a mixture of
red and white hairs); and in humans, one form of familial hypercholesterolemia (in humans) represents an
intermediate phenotype reflective of incomplete dominance. This technical definition of intermediate phenotype in the genetics field predates all discussions in the
psychopathology literature.
Intermediate phenotype, using schizophrenia as an
illustrative referent, could also be taken to mean any
of the following: (a) “not quite or almost a recognized/established phenotype” (e.g., schizotypal personality disorder; prodromal schizophrenia states); (b)
“lying between two established phenotypes” (e.g.,
schizoaffective disorder lying between schizophrenia and
affective illness); (c) “a phenotype precisely halfway (i.e.,
Latin intermedia) between a genotype and phentotype”
(plausible, but no known example); and (d) “a measureable, but unobservable phenotype falling somewhere
between an illness genotype and phenotype” (e.g., eye
tracking dysfunction in schizophrenia; this is a Gottesman and Gould[4] endophenotype). The intended meaning of intermediate phenotype as used by Weinberger
and colleagues is essentially that concept defined by endophenotype. As can be readily seen, the concept intermediate phenotype has several plausible interpretations in addition to its longstanding technical meaning
genetics. This variability in interpretation of the meaning of intermediate phenotype has sown some confusion
already. For example, Insel and Cuthbert[25] suggested
that endophenotype is appropriate to situations where
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Figure 1. Hypothetical relations among biomarker, intermediate
phenotype, and endophenotype concepts.
This diagram reveals that all endophenotypes and intermediate
phenotypes are subsets within a greater domain of biomarkers.
However, not all biomarkers are necessarily either intermediate
phenotypes or endophenotypes. Importantly, only a subset of
intermediate phenotypes can be regarded as endophenotypes.
C 2010 Mark F. Lenzenweger. Used by permission of
Copyright the author.
a specific process is studied (e.g., prepulse inhibition),
whereas intermediate phenotype should be used for constructs such as “personality or clinical constellations” (p.
988). Insel and Cuthbert clearly recommend usage of
“intermediate phenotype” quite different from that espoused by Weinberger et al.
CONCLUSION
The biomarker and intermediate phenotype concepts are not fungible with the endophenotype concept
and should not be confused with the latter (see Figure 1). The concept/term endophenotype enjoys freedom
from the terminological ambiguity necessarily associated
with the term intermediate phenotype. The semantic
and substantive considerations reviewed here favor endophenotype as a concept for psychiatric genetics and
psychopathology research (including RDoC efforts).[31]
The biomarker and intermediate phenotype concepts do
have utility, however. The biomarker term captures the
domain of any biologically influenced factor or deviation
in relation to psychopathology (including endophenotypes). It may be useful in distinguishing between biological factors that occur secondary to an illness, but fall
outside the realm of endophenotypes (e.g., state markers). Biomarker may have utility when discussing the
biological impact of environmental or exogenous factors on the emergence of psychopathology. Intermediate phenotype may be best used to describe a subclinical
variant of a form of major psychopathology—such as
schizotypic psychopathology vis-a-vis schizophrenia—
the phenotype is visible to the unaided eye and it bears
some resemblance to the classic phenotype of interest.
Intermediate phenotype, in this usage, describes a dilute
form of an established phenotype (or unit of analysis).
Depression and Anxiety
More conservatively, the term intermediate phenotype
might be best reserved for describing incomplete or partial dominance as it has been used in genetics for decades.
The endophenotype approach may aid in parsing heterogeneity in all manner of laboratory data in future
psychopathology studies, including affective and anxiety
disorders. One could easily argue that heterogeneity represents the Achilles’ heel of psychopathology research,
especially in genetic work. Going forward, endophenotypes (when carefully chosen, see ref. [26] ) can be put
to use maximally in efforts to reduce heterogeneity[27]
in laboratory data relevant to RDoC processes relevant
to affective illness. Such heterogeneity reduction might
also advance efforts seeking to develop diagnostic biological tests in psychiatry.[28] One can clearly imagine
that reliable and valid endophenotypes may eventually
constitute the core of a biological diagnostic test battery. Consider, as an example, the potential utility that
a measure of cortical thinning (a putative endophenotype of major depression)[16] might have in the diagnosis
of major depression or assessment for major depression
risk. Such a ratio scale-based measure of a biological
substrate would be welcome indeed as a diagnostic tool.
Finally, communication, research strategies, and the scientific unit of analysis all hinge on the meaning attached
to our theoretical concepts such as those discussed here
(biomarker, endophenotype, intermediate phenotype).
In science, we must seek clarity and precision in language and psychopathology research discourse continues to evolve in this manner, pulling itself up by its bootstraps to achieve the precision one finds in the more
mature sciences, such as chemistry or physics.[29, 30]
Acknowledgments. I thank several colleagues for
their helpful comments regarding candidate endophenotypes in major affective and anxiety-based illness, including David J. Miklowitz, Lauren B. Alloy, Ian H.
Gotlib, and Richard J. McNally. I am also grateful to Irving I. Gottesman for discussions of the endophenotype
concept.
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