Opinion

VIEWPOINT
The Exposome Paradigm and the Complexities
of Environmental Research in Psychiatry
Sinan Guloksuz, MD, “But a great advantage of possession of the habit of reflec-
PhD tive activity is that failure is not mere failure. It is instruc- Box. Domains in Preparation for the Next Phase
Department of tive. The person who really thinks learns quite as much from of Environmental Research
Psychiatry and his failures as from his successes.” in Large Population Cohorts
Psychology, School for
John Dewey
Mental Health and Concept
Neuroscience, • Adopt a multidisciplinary framework for better
Maastricht University Decades of epidemiologic research into environmen- integration of psychiatry, epidemiology, data
Medical Centre,
tal factors in psychiatry have yielded consistent find- sciences, genetics, social sciences, and
Maastricht, the
ings and identified several (proxy) environmental risk fac- neuroscience.
Netherlands; and
Department of • Embrace agnostic data-driven approaches over
tors associated with mental disorders. These risk factors
Psychiatry, Yale hypothesis-driven, selective 1-exposure to
include childhood adversities, immigration and minor- 1-phenotype matching.
University School of
Medicine, New Haven, ity status, urbanicity, cannabis use, and obstetric and • Prioritize large population-based cohort designs
Connecticut. pregnancy complications.1 Although the effects of these over case-control samples.
risk factors may be genetically confounded to a degree • Integrate with systems biology and -omics
Jim van Os, MD, PhD (ie, gene-environment correlation), evidence from (eg, epigenomics) approaches to incorporate
Department of biological knowledge.
controlled studies1,2 suggests that a substantial part is
Psychiatry and
Psychology, School for environmental. Measurement
Mental Health and Most research has thus far focused on investigat- • Increase communication to develop a common
Neuroscience, ing the effects of a single environmental exposure on a language and standards for definition of
Maastricht University environmental factors.
Medical Centre,
single outcome (termed caseness), aiming for a deter-
• Refine conventional tools by leveraging existing
Maastricht, the ministic specificity of cause and effect with an etiologic data sets to reduce measurement error and
Netherlands; and precision. However, we may reasonably think that the increase precision.
Department of
environment, akin to genetics, consists of conjoint net- • Use novel measurement techniques (eg, wearable
Psychiatry, Brain
Centre Rudolf Magnus, works involving many interacting elements that may be and mobile devices for collecting person-level
University Medical pinned down to shared biological and mental processes information, geographic information system for
Centre Utrecht, in the causal pathways to mental illness.3,4 Accumulat- collecting group-level information).
Utrecht, the • Aim for multimodal, multilevel, and
Netherlands.
ing evidence indicates that the effects of most environ-
multidimensional measurement to capture the
mental factors are (1) pleiotropic, when the same type dynamic nature of environment.
Bart P. F. Rutten, MD, of environmental exposure (eg, childhood adversity) • Develop assessment tools for the psychological
PhD confers risk for a diverse set of mental disorders meaning and cultural context of exposure and their
Department of (eg, psychosis and affective spectrum disorders) 5 ; mechanistic effect.
Psychiatry and • Extend the scope of environmental exposures
Psychology, School for
(2) ubiquitous but not universal, when low-grade expo-
beyond the traditional list of risk factors by novel
Mental Health and sure is highly prevalent and not associated with mental
candidates.
Neuroscience, disorders (eg, cannabis use and psychological stress);
Maastricht University • Develop follow-up experimental approaches for
(3) redundant, when a variety of exposures is associ- controlled replication and translational mechanistic
Medical Centre,
Maastricht, the ated with the same phenotype (eg, childhood adversity research.
Netherlands. and cannabis use confer risk for psychosis spectrum
Data Analytics
disorder) and none of them are necessary components • Embrace advanced statistical learning methods
for developing mental disorders1; (4) not independent, (machine learning) to handle high-dimensional
when correlation, confounding, mediation, and mod- “big data.”
eration are commonly observed; (5) time sensitive, • Identify data standards for exposomic approach.
Corresponding
Author: Sinan when individuals are more prone to the effects of envi- • Emphasize causal inference.
Guloksuz, MD, PhD, • Develop models to accommodate heterogeneity
ronmental factors at exposure-specific and -sensitive
Department of arising from merging data sets.
time windows (eg, cannabis use during adolescence)2;
Psychiatry and
(6) dose dependent, when a higher degree of exposure Reproducibility
Psychology, School for
• Incentivize independent replication.
Mental Health and (concerning the magnitude and duration) results in a
Neuroscience, • Encourage data and code sharing.
higher likelihood of mental illness5; (7) yielding small
Maastricht University Organization
Medical Centre, effect sizes when adjusted for each other; (8) operating
• Introduce consortia model to meet sample size
PO Box 616, 6200 MD, across a spectrum of severity of mental disorders2;
requirements and access to upcoming research
Maastricht, the (9) subject to genetic (reverse causality) and contex-
Netherlands endeavors.
tual confounds; and (10) intrinsically connected with • Develop infrastructure and research capacity for
(sinan.guloksuz
@maastrichtuniversity the individual or a cultural-specific attribution of multidisciplinary work.
.nl). meaning, which etiologically may be as important as

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 Opinion Viewpoint

any underlying biological changes associated with the onset of
symptoms.
In this regard, we propose that investigating the entirety of
environmental exposures (ie, the totality of the nongenetic com-
ponent) from conception onward—along with the lines of the con-
temporary exposome paradigm,6 the effects of which accumulate
over time—may offer opportunities for a deeper understanding of
the interaction of polygene and polyenvironment in mental health.
The exposome paradigm promises a holistic view of environmen-
tal exposures—an agnostic alternative to the current hypothesis-
driven candidate environment approach in psychiatry—and
complements the genome to provide a more realistic perspective
of the complex and dynamic interaction between environmental
factors that may give rise to mental illness over time. The expo-
some consists of dynamic, interactive, and intertwined domains
that include the internal (eg, gut microflora), the specific external
(eg, drug use), and the general external (eg, urban environment).
The overambitious goal of the exposome paradigm, capturing the
hypothesized totality of environmental exposure at a granular
level with repeated time-sensitive collections of environmental
exposures, is difficult to achieve at this stage. In addition, the mea-
surement of psychological meaning attributed to an exposure and
the corresponding experience, as well as its etiologic significance,
remains a great scientific challenge. However, the field is advanc-
ing rapidly, tied to the goals of precision medicine, with a growing
investment in large population cohort studies that are designed to
collect massive amounts of multimodal, multilevel, multidimen-
sional data. Recent examples include the recent National Institutes
of Health initiative, the All of US research program7 designed
to collect data for many years from 1 million people in the United
States, and emerging exposomic research endeavors across
the world.
Although the task of precisely capturing the dynamic expo-
some may be more difficult than measuring the genome, much
can be learned from failures and successes of psychiatric genetics.
The field of genetics—learning from past mistakes of overstated
findings that appeared to be largely false-positive—has gone
through a major restructuring by embracing the complexity of the
genome with an agnostic genome-wide approach. Alongside this
paradigm shift, psychiatric genetics has recently taken various pre-
cautionary measures to minimize the false-positive rate, including
replication requirement, strict correction for multiple testing,
accurate sample size estimation, and careful consideration of
population stratification. Primed by significant financial endorse-
ment and collaborative international consortium model (the Psy-
chiatric Genetics Consortium), genetics research leveraged access
to high-throughput techniques and large populations to recon-
struct the molecular genetic architecture of mental disorders—
perhaps a bit slower than anticipated but in a more down-to-earth
agenda.8
Exposome research is still in its infancy and needs larger
samples with more comprehensive environmental measurement
than the existing data sets to take full advantage of agnostic
exposure-wide analytic approaches in the capacity of embracing
the complexity of the environment, with early environment-wide
research leveraging the National Health and Nutrition Examination
Survey database.9 In view of the current practice, a general agree-
ment that adhering to more stringent research standards and
increasing large-scale collaborative efforts, including standardized
measurement methods, multiplicity consideration, embracing the
interconnected nature of exposures, and comprehensive report-
ing, will produce immediate benefit.10 However, several chal-
lenges need to be addressed to go beyond the current state of the
art and start implementing the exposome framework. To this end,
we propose several action points that are categorized into the
major domains of concept, measurement, data analytics, repro-
ducibility, and organization (Box).
The steady growth of the genetics knowledge base in the field
of mental health is encouraging, and this growth should be accom-
panied by significant progress of research into the role of environ-
ment, which may provide clues for potentially modifiable factors in-
fluencing individual genetic vulnerability to transform the prevention
and treatment of mental disorders and contribute to precision medi-
cine. To move forward and emulate the pace of progress in the ge-
netics field, environmental research in psychiatry is now in a phase
to optimize its methodologically sound and reproducible path that
would enable seamless integration with projected collections of large
general population cohorts.

ARTICLE INFORMATION
Published Online: June 6, 2018.
doi:10.1001/jamapsychiatry.2018.1211
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by
the European Community’s Seventh Framework
Program under grant No. HEALTH-F2-2009-
241909 (Project EU-GEI: European Network of
National Schizophrenia Networks Studying
Gene-Environment Interactions).
Role of the Sponsor: The funding sources had no
role in the preparation, review, or approval of the
manuscript and decision to submit the manuscript
for publication.
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