Opinion
EDITORIAL
Endophenotype Research in Psychiatry—
The Grasshopper Grows Up
Joshua L. Roffman, MD, MMSc
Although Irving Gottesman, PhD, and his colleagues first
brought it to psychiatry research in 1987 (in McGuffin et al1),
the term endophenotype originated 21 years earlier, in ento-
mology. In their studies of grasshoppers, John and Lewis2 noted
that the insects’ external ap-
Related article
pearance (or exophenotype)
provided few clues to under-
stand their geographic affinities; rather, they speculated that
the insects’ internal, microscopic constitution (or endophe-
notype) would reveal more answers. But while the term may
have arisen outside of psychiatry, there is no question that, with
respect to health research, psychiatry now owns it. For ex-
ample, a PubMed search reveals that, of more than 4100 pub-
lished articles linked to the term endophenotype, more than
90% focus on psychiatric conditions and their underlying
neural constructs.
McGuffin et al1 (and later Gottesman and Gould3) estab-
lished a forward-thinking, remarkably precise, and persis-
tent rubric for endophenotypes, as reflected in the article
in this issue of JAMA Psychiatry by Greenwood et al. 4
While much of biological psychiatry research focuses on
measurable intermediate phenotypes or biomarkers that
putatively link clinical phenomena with their root biological
causes, endophenotypes specifically require heritability
(cosegregating with illness across populations and also
within families) and state independence (manifesting
whether illness is active or in remission). These require-
ments respect the tenet that genes are the biological bedrock
of mental illness and an important starting point to delineate
pathophysiology.
Over the last 30 years, biological psychiatry investigators
have built up a number of assumptions based on but not re-
quired by this framework. For example, many posit that en-
dophenotypes have a simpler genetic architecture than clini-
cal syndromes and thus provide better signal-to-noise ratios
and greater statistical power (that is to say, they are detect-
ible in smaller sample sizes). Endophenotype studies have also
been described as an opportunity to connect different levels
of biology in a vectorized way (in that discrete genes code for
proteins, which discretely influence brain structure, circuit
function, cognitive and behavioral patterns, and ultimately risk
for clinical diagnoses).
However, endophenotype research has yet to deliver
hoped-for clinical innovation in psychiatry, while over the
same 3 decades, other areas of medicine have seen greater
success in leveraging biological insights, including genetic
ones, into better treatments. There are of course many
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unique challenges in translational psychiatry research, but
publication of this latest large-scale investigation4 provides a
good moment to consider what more it might take for endo-
phenotype studies to realize their clinical potential. To wit,
while the original endophenotype framework retains
its promise, some of the prevalent underlying assumptions
may be unfounded and should be reconsidered. Particular
examples are described here.
Linearity and Parsimony
An intrinsic limitation to clinical gene association studies is
the biological distance between genes and disorders. But as
is now known from large-scale genome-wide association
studies (GWAS), there exists substantial overlap in genetic
liability across numerous psychiatric illnesses.5 This pattern
suggests that intermediate biology is far more entangled
than previously imagined (ie, multiple combinations of
genes underlie multiple categories of diagnosis).6 As such,
variation in intermediate biology is likely to be equally non-
specific with respect to both its genetic origins and its con-
nection to discrete disease.
Genetic Complexity
Because endophenotypes can be measured more precisely and
reliably than psychiatric diagnoses, it follows that their un-
derlying biology may be less noisy. But the notion that endo-
phenotypes are genetically less complex than psychiatric dis-
orders is controversial and potentially “oversold.”7(p115) By
analogy, although height measurements are simple and reli-
able and height is strongly heritable, it has taken sample sizes
in the hundreds of thousands (as in GWAS of psychiatric dis-
orders) to account for significant genetic signal.8
Validity
Anchoring specific endophenotypes to specific genes that have
been implicated through GWAS provides biological triangu-
lation, particularly if these links emerge through unbiased
analyses. However, putting aside long-standing questions
about the biological validity of some DSM diagnoses, it is im-
portant to recall that the contributions of individual GWAS vari-
ants to disease risk are quite small.5 Furthermore, it remains
to be seen whether identification of new genes will reach an
asymptote with ever-increasing sample sizes. It would be sur-
prising if genes that represent all essential pathways in the brain
are not picked up at some point, regardless of their relevance
to disease or existing drugs that may or may not affect core
pathophysiology.
(Reprinted) JAMA Psychiatry Published online October 9, 2019 E1
 Opinion Editorial

Neurodevelopmental Context analyses) rather than specific genetic markers. As mentioned

An assumption built into these studies, particularly studies of
adults, is that the relevance of endophenotypes to causal genes
is constant, because DNA does not change over the life span.
But gene expression clearly does change, including in ways that
are relevant to the suspected neurodevelopmental origins of
numerous psychiatric illnesses.9 This also points to a broader
(but inevitable) limitation of endophenotype studies: what we
can measure (be it through genotype, brain structure and physi-
ology, and perhaps even behavior and cognition) does not nec-
essarily capture biological processes that are most salient to
illness.
How, then, can endophenotype studies in psychiatry
evolve in ways that stay true to Gottesman’s seminal
framework1 but have greater potential for clinical benefits?
In several respects, the new article from the Consortium on the
Genetics of Schizophrenia,4 a long-standing champion of the
endophenotype approach, shows a way forward.
First, especially in light of what is now known about
genomic overlap across traditional diagnostic boundaries,
endophenotype studies should provide a roadmap for the
next generation of genomic studies in psychiatry by identify-
ing specific patterns of cognition and behavior that can be
measured in standardized and feasible ways and track with
appreciable genetic signal. Binary, DSM-based diagnoses
may be reaching the limit of their utility as primary end
points for GWAS for the reasons outlined. Instead, dimen-
sional measures that capture a range of psychopathology are
relevant across a range of disorders and show initial promise
for a discernable (even if still complex) genetic architecture
can be vetted through endophenotype studies before larger
scale implementation in GWAS.
Second, endophenotype investigators should prioritize
linkage to biological pathways (eg, through gene ontology
by Greenwood et al, “Such convergence at the pathway level
may be more likely to be observed and more meaningful than
concordance at the level of an individual gene or SNP [single-
nucleotide polymorphism] in illuminating…underlying neu-
robiological dysfunction….”4 Gene ontology algorithms are
gaining sophistication (including a recent example focused on
synapse biology10) and will facilitate mapping of endopheno-
types to more discrete and potentially targetable biological
pathways.
Third, a neurodevelopmental emphasis and associated
development-specific gene expression patterns should be
brought more prominently into endophenotype studies. As
with psychosis, numerous psychiatric disorders are thought
to reflect biological process that occur years before the onset
of an illness. Harnessing cell-type and development-specific
data on gene expression as it emerges in coming years, endo-
phenotype investigators should also consider studying younger
cohorts, including perinatal studies to capture critical neu-
rodevelopmental periods.11
A final thread that perhaps reflects the greatest contribu-
tion of endophenotype studies to psychiatry research to date
also warrants explicit mention: endophenotype studies should
continue to focus expertise from interdisciplinary domains to
address knowledge gaps that are clearly more complex than
can be resolved by any one of them alone. The Consortium on
the Genetics of Schizophrenia team, which includes investi-
gators across 7 sites who specialize in psychiatry, psychology,
neurocognition, brain imaging, biostatistics, and clinical
genetics, typifies this approach. Expanding these teams to
include expertise in molecular biology and epigenetics, big-
data analytics, and developmental neurobiology may help
endophenotype studies mature to their full potential and
deliver clinically actionable insights.

ARTICLE INFORMATION
Author Affiliation: Department of Psychiatry,
Massachusetts General Hospital, Harvard Medical
School, Charlestown.
Corresponding Author: Joshua L. Roffman, MD,
MMSc, Department of Psychiatry, Massachusetts
General Hospital, Harvard Medical School, 149 13th
St, Room 2616, Charlestown, MA 02129 (jroffman@
partners.org).
Published Online: October 9, 2019.
doi:10.1001/jamapsychiatry.2019.2194
Conflict of Interest Disclosures: None reported.
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