EDITORIALS
Do Polygenic Scores Inform Psychiatric Disease Risk
After Considering Family History?
Joanna M. Biernacka, Ph.D.
Psychiatric disorders are heritable, and thus both family
history and an individual’s genetic makeup are related to their
risk of illness. It has long been known that family history can
help predict psychiatric outcomes (1), yet individual pre-
diction of risk has remained challenging. In some circum-
stances, family history can predict substantial increase in risk;
for example, the risk of schizophrenia is increased about
eightfold for those who have a first-degree relative with the
illness (2). However, most people do not have a first-degree
relative with any given illness, and for them family history
is not very informative. Even among those with a family
history, most people will remain unaffected.
Recently, leveraging the results of large genome-wide as-
sociation studies of psychiatric traits has enabled the com-
putation of individual polygenic scores (PGSs) for those traits
from a person’s genome (3). PGSs, often referred to as poly-
genic risk scores when they are used to quantify risk of a
particular disorder, are currently not predictive enough to be
used in most clinical settings (3), but show consistent asso-
ciations with the target traits in research studies. Given suf-
ficient knowledge about effects of specific genetic variants on
disease risk, a direct measurement of an individual’s genome
should be more informative than family history (which ig-
nores which parental alleles were transmitted to the off-
spring) regarding the genetic contribution to a person’s
phenotype. Thus, it is pertinent to ask, Do current PGSs
provide information on disease risk beyond what can be
inferred from family history?
In this issue, Zwicker et al. (4) report on a study that
explored this question in the context of onset of major mood
and psychotic disorders (major depressive disorder, bipolar
disorder, and schizophrenia). The outcome was measured pro-
spectively in a cohort ranging in age from 6 to 36 years at most
recent follow-up. To predict the outcome, the authors considered
a binary family history variable representing parental his-
tory of major mood and psychotic disorders, as well as PGSs
for depression, bipolar disorder, anxiety, attention deficit
hyperactivity disorder, schizophrenia, “p factor” (an index of
general genetic liability to psychopathology), neuroticism, and
subjective well-being. They observed that family history as well
as many of the PGSs were associated with onset of major mood
and psychotic disorders, but only the PGSs for neuroticism
and subjective well-being remained statistically significant
predictors of the outcome after accounting for family history.
256 ajp.psychiatryonline.org
As the authors remarked, this may be partly due to the
transdiagnostic nature of these phenotypes. In fact, of all the
considered PGSs, the neuroticism PGS showed the strongest
association with the clinical outcome, even before adjustment for
family history. It is also worth noting that (unsurprisingly) the
family history measure reflected major mood and psychotic
disorders, rather than neuroticism or subjective well-being. It
may not be feasible, or constructive, to measure family history of
more general psychological or personality traits, but subclinical
psychopathology and related measures can be directly assessed in
patients and can be important predictors of subsequent devel-
opment of psychiatric disorders (5). Thus, it would be interesting
to evaluate whether, for example, a neuroticism PGS would be a
significant predictor of psychiatric disorder outcomes after ac-
counting for measured neuroticism in at-risk young people.
Zwicker et al. used a simple binary definition of family
history based on the presence of a major mood or psychotic
disorder in a biological
parent, which does not Although some studies have
account for disease status already demonstrated
of other relatives. This statistical significance of
single family-history var- PGSs as predictors of
iable also made no dis- psychiatric outcomes after
tinction between different accounting for family
mood or psychotic dis- history, statistical
orders, meaning that, for significance does not imply
example, parental history
clinical significance.
of major depressive dis-
order, was treated equally with parental history of schizo-
phrenia. While a more nuanced or even quantitative measure
of family history could be an even better predictor of risk,
possibly further reducing the relative importance of PGSs,
it is difficult to collect more extensive family history accu-
rately. Moreover, reduction of family sizes has made extended
family history measures less informative. Furthermore, the
direct measurement of family history in the Zwicker et al.
study, which was largely through diagnostic interviews of
parents, likely provided a much more accurate predictor
of risk than could be achieved in clinical practice, where
family history collection usually relies on patient self-report.
Thus, it is reasonable to expect that in clinical settings, family
history would contribute less to prediction of risk, and
therefore the relative contribution of PGSs after accounting
for family history would be greater.
Am J Psychiatry 180:4, April 2023

In the analysis presented by Zwicker et al., aside from the
PGS for subjective well-being, all PGS effects were attenu-
ated after accounting for family history, but not fully. For
example, the hazard ratio for the schizophrenia PGS effect
was 1.10 (95% CI51.00–1.22) with family history adjustment,
as opposed to 1.15 (95% CI51.04–1.26) without family history
adjustment. Given the observed PGS effects and their con-
fidence intervals, it is reasonable to expect that in an analysis
of a larger sample, family-history-adjusted PGS effects would
remain statistically significant, even for current PGSs with
their limited predictive value. In fact, other psychiatric studies
have already found that specific-disorder PGSs are significant
predictors over and above family history, or within cohorts
with family history (6, 7). Outside of psychiatry, a recent large
study of 24 common diseases in the FinnGen sample found
that family history and PGSs provide complementary infor-
mation on inherited disease susceptibility, with both making
independent contributions to risk prediction (8).
Although some studies have already demonstrated sta-
tistical significance of PGSs as predictors of psychiatric out-
comes after accounting for family history, statistical significance
does not imply clinical significance. In the Zwicker et al. study,
neither family history nor the different PGSs contributed greatly
to overall risk prediction, with each explaining less than 5% of
the variance in time until diagnosis, which again emphasizes
the limited clinical utility of current PGSs. More importantly,
given the poor performance of current PGSs in populations
underrepresented in research, until genetic research becomes
more representative of ancestral diversity of patients, appli-
cation of PGSs in clinical settings would only exacerbate
current health disparities (9). Finally, to be useful in clinical
settings, PGSs must be converted to absolute or relative risks.
Although methods were recently proposed to achieve this
(10), they also rely on input parameters that are represen-
tative of the population in which the method is applied. Thus,
as the research community works toward more predictive
PGSs and develops tools for using them in clinical settings, we
must ensure that this research is conducted in diverse re-
search cohorts to allow for equitable application of research
findings across populations.
Psychiatric disorders are only partially heritable. There-
fore, ultimately PGSs—and for some conditions, specific genetic
risk factors, such as copy number variants—will need to be
combined with other relevant information, including environ-
mental factors and social determinants of health, to enable more
precise risk prediction. Because family history reflects not only
shared genetics but typically also shared environment, it will
remain a relevant risk predictor for many outcomes even as
PGSs become more predictive. Some studies have begun ex-
ploring the contribution of PGSs to risk prediction based on
multiple predictors; for example, in a high-risk population,
Perkins et al. (11) found that a schizophrenia PGS showed
promise in improving risk prediction of a psychosis risk
calculator that included certain environmental and clinical
risk factors in addition to family history of psychosis. Stud-
ies have also shown that incorporating multiple PGSs
Am J Psychiatry 180:4, April 2023
EDITORIALS
simultaneously can improve prediction of psychiatric outcomes
(12). More research should be directed toward development of
improved predictive models that capture the full range of
environmental and genetic risk factors, include multiple PGSs,
and consider potential interactions among risk factors.
It is also important to consider prediction of outcomes
beyond broad diagnostic categories or their groupings. In the
Zwicker et al. study, which aimed to identify stable predictors
across diagnostic categories, little was gained from consid-
ering PGSs after accounting for family history. However,
many studies have demonstrated that beyond diagnostic cat-
egories, PGSs are often associated with specific subphenotypes
within diagnostic groups (13). Thus, PGSs may ultimately prove
helpful for prediction of more nuanced clinical outcomes,
including illness trajectories, predominant symptoms, and
treatment outcomes, where it becomes increasingly difficult
to collect relevant family history.
The relative value of family history data and PGSs as pre-
dictors of risk depends on several factors, including the ge-
netic architecture of the outcome being predicted, the ease
and feasibility of collecting precise family history data, the
availability of genetic data, and the precision of PGSs derived
from these data. Critically, PGSs need to be developed using
data from more diverse patient populations to ensure that
they provide valuable information for all patients. Other risk
factors, including environmental and social determinants of
health, and in some cases specific genetic variants, will have to be
incorporated in the predictive models (14). As genetic data con-
tinue to become more readily available and the precision of PGSs
further improves, the relative contribution of PGSs will increase,
but optimal prediction will always require a holistic approach.
AUTHOR AND ARTICLE INFORMATION
Department of Psychiatry and Psychology and Department of Quanti-
tative Health Sciences, Mayo Clinic, Rochester, Minn.
Send correspondence to Dr. Biernacka (biernacka.joanna@mayo.edu).
Dr. Biernacka receives funding from NIMH, NIAAA, the Milken Institute
(Baszucki Brain Research Fund), the J. Willard and Alice S. Marriott Foun-
dation, and the Thomas and Elizabeth Grainger Fund in Bipolar Disorder
Novel Therapeutics and Advanced Diagnostics.
Accepted February 10, 2023.
Am J Psychiatry 2023; 180:256–258; doi: 10.1176/appi.ajp.20230116
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