REVIEWS AND OVERVIEWS
Thinking About Schizophrenia in an Era of
Genomic Medicine
Daniel R. Weinberger, M.D.
Genetic discoveries about human brain development and
neuropsychiatric syndromes have changed the landscape of
psychiatric research. The genotyping of hundreds of thou-
sands of individuals has identified many hundreds of genomic
regions that are associated with psychiatric diagnoses, and
progress is being made in uncovering the specific genes that
underlie these statistical associations, although most are still
undetermined. While there are great expectations that such
genetic discoveries will lead to novel treatments based on
fundamental mechanisms of illness, there are important ca-
veats. Individual risk-associated common variants explain
only a tiny fraction of individual liability. The degree to which
common risk variants represent “core” pathogenic insights is
controversial. Individuals with rare and more penetrant risk
variants are often intellectually disabled, which raises
Why are genes important in psychiatry? The simple answer is
the same reason they are important in other areas of biology
and medicine—because most human traits and clinical dis-
orders have a substantial genetic component. Genes influence
and encode mechanisms of disease; they provide objective
insights into individual predisposition or risk; they may help
contextualize the interacting environment; and they are a
potential tool for the discovery of treatments based on cau-
sation and pathogenesis.
It has been clear for more than a century that psychiatric
syndromes run in families. Archival studies of concordance
differences between identical and fraternal twins and oc-
currence of schizophrenia in individuals who were adopted
away at birth and in their biological parents led to the con-
clusion that the main reason psychiatric diagnoses run in
families is because of inheritance rather than culture or
family dynamics. Psychiatry even before Freud has been
essentially a phenomenological discipline, based on differ-
ences that can be observed between individuals with a
particular diagnosis and those without one. Such phenom-
enology has been rich and compelling, with persuasive
inferences about mechanisms from various schools of de-
scriptive psychology and psychopathology and, more re-
cently, evidence for biological associations from molecular
studies of patient tissues and from neuroimaging studies.
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epistemological questions about classification. In clinical re-
search, the application of polygenic risk scores—the cumu-
lative sum of associated alleles in an individual genome—to
prediction models of environmental influences and outcome
is gaining enthusiasm because these scores explain more liability,
but predictions are small and not yet actionable for individuals.
Psychiatry is intertwined with genomic medicine, and our
understanding of what we call schizophrenia and the possi-
bilities of improving the lives of affected individuals have never
seemed more promising. Yet the research challenges are
daunting; psychiatric syndromes ultimately reflect how the
brain mishandles environmental information, which at the
systems level is far “downstream” of the effect of genes in cells.
Am J Psychiatry 2019; 176:12–20; doi: 10.1176/appi.ajp.2018.18111275
Causation, however, is not discernible from these phenom-
enological approaches. In contrast, genes are not merely
phenomenological observations. They are the proverbial
“egg” rather than the “chicken.” The study of gene func-
tion and genetic variation generates insights into etiolog-
ical mechanisms and into the root causes of psychiatric
syndromes.
Genes are also important because they make it possible
to begin to unravel the critical contributory role of the in-
teracting environment in complex disease. Genes are finite
and quantifiable biological entities; the environment, by con-
trast, is potentially far more complex, and without an under-
standing of an individual’s discrete biological background
(i.e., “genome”), the environment is a much more nebulous
and indefinable entity. If life is imagined as a game of Mo-
nopoly, genes will never determine how many railroads one
owns or where hotels will be built. But genes are the only
square on the board that can be known with certainty—they
are the “Go” square. Genes represent the biological tool box
with which one plays the game, the underlying basis of in-
dividual characteristics that interact with the environment
and lead to personal gain or resilience to loss. Daunting stress
to one individual may be an exciting opportunity to another.
As Paul Simon sang it, “one man’s ceiling is another man’s
floor.”
Am J Psychiatry 176:1, January 2019

There is abundant excitement in the research and phar-
maceutical industry communities about the prospect of ge-
netic discoveries leading to novel treatments based on
elucidation of fundamental mechanisms of illness. Finding a
disease-associated gene and translating that discovery into a
therapeutic agent is a daunting challenge, and so far, in all of
medicine, very few discoveries of disease-associated genes
have led to novel treatments. In psychiatry, the treatments
currently used, be it talk, electricity, magnetism, or phar-
macology, were discovered through understanding of cause
and pathogenesis; rather, nearly all were identified seren-
dipitously. Having insights into mechanisms of psychiatric
illness based on genetic information will surely be a more
successful approach to therapeutic discoveries.
DISCOVERY OF SCHIZOPHRENIA
RISK–ASSOCIATED GENETIC VARIANTS
The landscape of genetic research in psychiatry has changed
dramatically over the past decade. From family studies that
were state of the art during the closing decades of the
20th century, the current fashion in medical genetics is the
genome-wide association study (GWAS) comparing the DNA
“genotypes” of clinical case subjects with control subjects.
This approach is based on technological advances that allow
inexpensive and high-throughput analysis of sequence var-
iation across the human genome in DNA extracted from
blood or saliva. Genotyping millions of common sequence
variants, called single-nucleotide polymorphisms (SNPs),
across the 3 billion nucleotides of a person’s genome can
now be accomplished for little more than $100.
To facilitate discovery of genetic factors with rigorous
statistical objectivity, based on no a priori expectation that
any particular sequence variant will be associated with a
particular trait or clinical illness, large samples have been
acquired through collaborative consortia of investigators
around the world. Indeed, GWAS has been applied to hun-
dreds of traits and complex diseases to date, successfully
yielding statistically significant risk-associated genomic re-
gions for cancers, endocrinological disorders, and cardio-
vascular diseases, as well as for psychiatric illnesses, including
schizophrenia, autism, mood disorders, posttraumatic stress
disorder, and eating disorders.
The current state of the art in schizophrenia genetics is
the product of the schizophrenia working group of the Psy-
chiatric Genomics Consortium (PGC). In what is called
the PGC2 schizophrenia study (1, 2), which analyzed over
40,000 individuals with schizophrenia diagnoses and over
64,000 individuals identified as “controls” from over
50 centers in Europe and the United States, SNP allele fre-
quencies that significantly differ between the patient and
control samples have been identified in 145 regions (called
“loci”) across the genome. Because millions of SNPs were
surveyed for allele frequency differences between the sam-
ples, a statistical threshold for potential false positives was
set at a conservative p value of 531028. These regions are
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presumed to contain genes that increase susceptibility to
schizophrenia.
The finding of genome-wide statistically significant loci
for schizophrenia has transformed the landscape of research
in psychiatry, representing compelling evidence of the po-
tential biological underpinnings of schizophrenia at a basic
molecular level. The PGC2 study has recently been expanded
(“PGC3”), and, as reported at the 2018 World Congress of
Psychiatric Genetics in Glasgow, with 30,000 additional
subjects, the number of GWAS-significant loci is now 246.
As expected, most of the new loci were near statistical sig-
nificance in the PGC2 version, confirming that increasing
sample size will tend to elevate near statistically significant
loci into the rarefied range of GWAS significance.
SOME CAVEATS ABOUT COMMON VARIANTS
While increasing the size of study samples has successfully
provided increased power to identify loci that achieve sta-
tistical significance, larger samples do not increase the effect
size, as reflected by the odds ratio of an individual risk-
associated SNP. Even the SNPs with the greatest statistical
significance increase risk on an individual basis only to a
minuscule degree. Most of the SNPs increase risk less than
1.1-fold from general population risk (1, 2). Moreover, the
differences between patient and control samples in the fre-
quency of alleles associated with risk is typically no more than
2%. Thus, by themselves, individual GWAS-significant SNPs
have little or no role as predictors of a person’s clinical risk.
As sample sizes grow even further, the odds ratios of newly
significant GWAS loci will predictably be even smaller, and
it is conceivable that within a few years, we will have in our
gene quivers many hundreds of associations that increase risk
fractions of a fraction. This is an important caveat to overly
enthusiastic interpretations of existing data and promises of
future GWAS analyses. It also is important to realize that the
genetic analyses of this large case-control cohort charac-
terize primarily individuals of European ancestry. Compar-
isons with other populations will require similar large studies
of those populations, and preliminary evidence from Asian
samples, although consistent to a moderate degree in terms of
loci and effect sizes, has uncovered substantial divergences
(3). In African American samples, the attribution of pop-
ulation risk based on common alleles identified in European
ancestry samples is likely to be much less consistent.
It is also important to appreciate that the risk loci iden-
tified are not themselves susceptibility genes. They are rel-
atively low-resolution map points of regions of the genome
that enable more detailed analysis to identify the specific
genetic components accounting for the statistical associa-
tion between DNA variation and clinical status. Most of the
schizophrenia-associated loci contain more than one gene,
and often contain many genes. From the physical gene map
and the clinical statistics alone, it is impossible to conclusively
identify the causative gene in any locus. This task is further
complicated by the fact that most of the risk-associated SNPs
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THINKING ABOUT SCHIZOPHRENIA IN AN ERA OF GENOMIC MEDICINE
are not in the coding portion of any known genes, meaning
that they do not directly change the amino acids in the
protein. Rather, they may be located within regulatory do-
mains in the DNA that influence gene expression. While the
exons of most genes encode proteins, the vast majority of the
genome is noncoding. Recent work by the National Institute
of Health ENCODE and National Institute of Mental Health
PsychENCODE projects (4, 5) has demonstrated that much
of the noncoding genome is involved in regulating how genes
are expressed, and individual noncoding variants in “en-
hancers” can influence the processing of genes many thou-
sands of nucleotides from their physical location in the
genome. In other words, because a SNP of interest lies near or
even inside the physical boundaries of a gene does not
necessarily mean that it is a factor in the biology of that gene.
EARLY LESSONS FROM COMMON RISK
VARIANT DISCOVERY
Although the current data only scratch the surface of the
underlying biology of risk, the schizophrenia GWAS results
have arguably taught us a number of seminal lessons already.
First, there is no single schizophrenia gene, per se. Individual
SNPs indicate minor components of risk, not fate. Second,
there is no royal road to risk. The many loci that are high-
lighted span the entire genome, involving every chromosome,
and a schizophrenia-associated locus is likely to be found in
virtually any 5 million base pair section of the genome. In-
deed, there are many roads that potentially converge to
contribute to risk, a characteristic of most so-called polygenic
disorders. Third, the GWAS loci associated with schizo-
phrenia are not unique to schizophrenia. Many of the same
loci have been associated with other psychiatric diagnoses,
including bipolar disorder, autism, and attention deficit hy-
peractivity disorder (ADHD) (6, 7). It should come as no
surprise that the human genome did not evolve to validate
the DSM-5 or ICD-10 schema of psychiatric nosology. Fourth,
many SNPs associated with schizophrenia appear to influ-
ence the epigenetic state of the genome, that is, the molec-
ular machinery that regulates gene expression by changing
chromatin conformation and methylation of DNA (8–10).
Epigenetic factors respond to environmental events and
underlie gene-by-environment interactions that are critical
for development and aging, for learning, and for shaping
behavior patterns based on experience. These studies suggest
that many genetic variations related to risk for schizophre-
nia (and likely other psychiatric diagnoses) influence the
nature and sensitivity of the genomic response to environ-
mental events.
Fifth, most genes located within GWAS-significant loci are
not genes that confirm earlier hypotheses about the biology
of schizophrenia. Notwithstanding the aforementioned un-
certainty of which, if any, genes within a locus are actually
causative, there are a handful of genes in glutamate and GABA
signaling pathways in GWAS loci, and one GWAS-significant
locus contains the dopamine type 2 receptor gene (DRD2).
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Most of the genes within these loci, however, encode proteins
involved in biological and molecular processes not previ-
ously emphasized as potentially related to schizophrenia
or any psychiatric disorder. Many genes encode proteins in
intermediate metabolism and the core processes of cell sig-
naling and cell cycle biology, while many others reflect
cellular functions about which very little is known. In an
effort to reduce the potential biological complexity, if not
the opacity, of the diverse functions involved and find
common biological pathways of the sets of genes contained in
the GWAS loci, investigators have applied bioinformatic
tools, hoping to find some functional convergence. The as-
sumption here is that despite the apparent biological diver-
sity of the implicated genes, there may be common functions
that underlie core phenotypes. The bioinformatic tools
employed in these “in silico” studies give only crude ap-
proximations of biological reality, as they are based on the
available research literature and databases and often on
peripheral, but not CNS, biological data. Nevertheless, the
results have suggested that some of the gene sets within
schizophrenia GWAS-significant loci converge on several
quite general aspects of cell biology, including calcium
channel signaling, synaptic function, and basic neurodevel-
opmental processes (11–13). These results are consistent
with the general idea that genes associated with a behavioral
disorder influence the development of the brain and the
plasticity of cells, particularly how they “talk to each other”
and respond to environmental stimuli. However, as appealing
as these results are, the validity and utility of conclusions
about discrete pathogenesis or discrete pathophysiological
mechanisms derived from bioinformatic gene set and path-
way analyses should be interpreted with caution. The bi-
ological roles that genes play in brain function are highly
context dependent, spatially (cell and tissue dependent),
temporally (in terms of development and time of life), and
in terms of background (what other genes are doing in the
same cell).
Another lesson learned from the large-scale schizophrenia
GWAS is that the heritability of schizophrenia—that is, the
fraction of risk accounted for by common genetic variation as
analyzed under simple additive models—is not explained by
the cumulative associations reported to date, nor even by the
GWAS results expected over the next decade. Indeed, the
significant SNPs in the PGC2 study explain only a few percent
of heritability, and predictions are that less than 30% will be
explained by GWAS findings in the coming years (1, 2). The
reasons for this apparent “missing heritability” are unclear
and the subject of considerable debate. One view holds that
the model for calculating heritability is based on a simple
linear addition of risk factors and does not accurately rep-
resent how genes influence biology. In most nonhuman
contexts, including in yeast, worms, flies, and rodents (14–17),
and also in human cancer cells (18), genes interact in non-
additive ways—biological processes in living organisms tend
not to be linear. Whether this is a major factor in the ar-
chitecture of schizophrenia risk is unknown.
Am J Psychiatry 176:1, January 2019

A recent and provocative hypothesis, the “omnigenic
hypothesis” (19), opines that heritability related to common
genetic variation will eventually be more fully explained
when sample sizes are in the millions, based on the as-
sumption that variation in any gene expressed in a relevant
cell type will contribute to risk. The omnigenic hypothesis
argues in effect that any gene expressed in a neuron matters to
the biology of that neuron, and because cell function depends
on many layers of interacting protein networks, any gene
expressed in a relevant cell will exert at least a small influ-
ence on the function of multiple networks in that cell. While
some networks are presumed to contain more pathogenically
critical, or “core” genes, most of the genes in GWAS loci will
contribute to risk simply because they are expressed in the
relevant cell, even though they are relatively peripheral to
core pathogenesis. In other words, according to this hy-
pothesis, variations in most genes expressed in neurons will
contribute to the heritability of schizophrenia and eventually
be in GWAS-significant loci (each with a trivial effect size)
but will be of minimal biological relevance to understand-
ing the pathogenesis of schizophrenia. This also is a con-
troversial concept, in part because it is so challenging to the
prevailing GWAS zeitgeist.
RARE VARIANTS AND SCHIZOPHRENIA RISK
Genome-wide genotyping and, more recently, exome and
whole genome DNA sequencing studies have discovered that
approximately 2%23% of patients with schizophrenia di-
agnoses have rare variations in their genomes that have
deleterious effects on protein expression or sequence and in
general have a greater influence on risk—that is, are more
penetrant—than individual SNPs (20–22). These include
relatively large DNA segments that are deleted or duplicated,
called copy number variants (CNVs), and loss-of-function
mutations of individual coding nucleotides. When DNA is
copied, during meiosis or even during cell division, occa-
sional errors occur, and sections of DNA may be duplicated
or deleted, or single nucleotides may be mutated (single-
nucleotide variants, or SNVs). If the mutation alters a protein
or if the CNV is large enough, and typical risk-associated
CNVs are on the order of 100,000 bases or more, genes within
the altered region will be either deleted or duplicated. Be-
cause most of these more penetrant rare variants tend to arise
during gametogenesis, they are typically found on one pa-
rental chromosome, so affected individuals are heterozygotic
for the variation. It is thought that every person has at least
one large CNV in their genome and probably several hundred
protein-altering SNVs (23). Most of these do not “cause” a
clinical disorder. The most common CNV that consistently
does so is the 22q11 hemideletion of approximately 3 million
bases associated with the velocardiofacial syndrome, a con-
dition in which approximately 30% of individuals will meet
criteria for a diagnosis of schizophrenia in early adulthood.
Large-scale studies of patients with schizophrenia diagnoses
suggest that approximately 0.5% of individuals with this
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diagnosis have a 22q11 hemideletion (21). A dozen or so
other such recurrent CNVs have also been found to be
more frequent in individuals with schizophrenia diagnoses
than in control groups, but these CNVs have smaller effect
sizes on risk (21). Protein-altering SNVs that have been
observed in patients diagnosed with schizophrenia are
much rarer, and to date only one gene has been statistically
confirmed as being a schizophrenia risk factor based on rare
SNVs (24).
It is important to note that the CNVs and rare SNVs as-
sociated with schizophrenia are not specific to schizophrenia
but rather are also associated with other psychiatric and
medical illnesses, including autism, ADHD, seizure disor-
ders, and, in particular, intellectual disability. Indeed, in-
dividuals with schizophrenia-associated CNVs are more
intellectually disabled than patients without these genetic
variations (25). Moreover, in the few reported cases of in-
dividuals with schizophrenia diagnoses who have mutations
in SETD1A, which is the only gene so far statistically con-
firmed as a risk factor based on a protein-altering SNV, a
history of developmental disability (e.g., epilepsy and in-
tellectual disability) is typical (24). There is reason to
question whether the psychosis in these cases is a primary
phenomenon based directly on the genetic variant or a sec-
ondary associated feature often observed in individuals with
intellectual deficits. It is unclear whether loss-of-function
SNVs and large CNVs may be found in patients with
schizophrenia diagnoses who do not have intellectual defi-
cits, and claims to the contrary must be viewed with some
skepticism (25). Cognitive function is considered “normal”
across a broad range, but for any given individual, being
within that range does not mean that function is normal for
that individual. As twin and family studies have shown, in-
dividuals with seemingly normal cognition and a schizo-
phrenia diagnosis typically have poorer cognition than their
siblings and other family members, even before clinical di-
agnosis (26). The 22q11 hemideletion syndrome, the most
penetrant CNV associated with “schizophrenia,” highlights
the nosological ambiguity that underlies diagnosis of the
schizophrenia syndrome. Recall that CNS syphilis was di-
agnosed as “schizophrenia” at the turn of the 20th century
before the discovery of the spirochete. The velocardiofacial
syndrome is associated not only with intellectual deficits
but also with cardiac abnormalities, CNS malformations,
and facial dysmorphia. Studies of psychosis in individuals
with major intellectual disability, which used to be called
“pfropfschizophrenie,” have shown that the phenomenology is
highly similar to that of patients with schizophrenia whose
intellectual function is less impaired (27). We are once again
confronted with an epistemological conundrum because
of the inaccuracies of our phenomenologically based syn-
dromes. Furthermore, to the extent that many deleterious
CNVs and mutations arise during gamete differentiation
and are thus “de novo” and not inherited (i.e., not in the pa-
rental genome), it is unlikely that they contribute to missing
heritability.
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THINKING ABOUT SCHIZOPHRENIA IN AN ERA OF GENOMIC MEDICINE
As if de novo mutations and segmental duplications and
deletions in gamete formation did not add another non-
Mendelian level of genetic complexity to human develop-
ment, it has also become apparent that while every cell in a
human body is a daughter of the fertilized egg, not every cell
has the same genome. This is called somatic mosaicism. The
same mistakes that can be made in DNA replication during
meiosis can be made during cell division and perhaps even
during gene expression when DNA is replicated or repaired.
If these mosaic events occur early in development, they will
characterize many subsequent daughter cells, but if they
occur relatively late, for example, during the final stages of
neuronal migration in the brain, they will affect only a small
group of cells. The number of cells affected with a particular
mutation or CNV is in essence a lineage marker for the his-
tory of that assembly of cells. Facial hemangiomas are a classic
example of somatic mosaicism arising late in face maturation.
Single-cell DNA sequencing studies in brain neurons have
revealed that as many as 20%230% of such cells have vari-
ations in their genome, including SNVs and CNVs (28). While
rare variations in individual neuronal genomes are found in
the human brain, their role in CNS disorders, with rare ex-
ceptions (29), has yet to be determined.
BEYOND SCHIZOPHRENIA RISK VARIANT
DISCOVERY
The landmark discovery of common and rare variants as-
sociated with schizophrenia has initiated a tidal wave of
biological research to identify risk genes in the implicated
genomic regions and elucidate specific disease mechanisms
and disease pathways. Ongoing biological research, includ-
ing analyses of gene expression, epigenetics, proteomics,
and single cellular analyses, as well as animal modeling, has
intensified as a result of these recent genetic discoveries.
However, translating a GWAS positive locus into meaning-
ful or actionable biology or a clinical translation or even a
specific genetic entity is not straightforward and requires
extensive further research. It is not a simple task to discover
how a SNP identifying a GWAS locus relates to the biologi-
cal activity of genes within the tissue thought to be of
pathogenic relevance—the brain in the case of schizophre-
nia. Genetic variants that regulate expression can engage
many molecular mechanisms accounting for their regulatory
effects, such as transcription factor binding, small RNA in-
terference, epigenetic variation, transcript splicing, and so on,
but all these effects read out in the transcriptome. This is the
rationale behind brain RNA sequencing studies being carried
out in many centers around the world. As an illustration of the
complexity of this problem, recent work has shown that even
when association of the clinical risk SNP is made in brain to a
particular expressed gene, the transcript showing association
may not be the common, known form of the gene but rather an
isoform not previously characterized (30), or the classes of
putative risk isoforms may vary across different brain re-
gions (31, 32), or the association in brain may depend on a
16 ajp.psychiatryonline.org
particular time of life (33) or perhaps even a specific cell type.
Figure 1 illustrates this problem for a highly statistically sig-
nificant risk-associated locus, where many genes are mapped
to the region. RNA sequencing and molecular characterization
of transcripts in the region identified two genes underlying
the clinical association—BORCS7 and AS3MT—and for
AS3MT, the transcript was a previously unknown, human-
unique isoform of the gene (30). To understand the molecular
mechanisms of clinical association, precise characterization of
the transcript association is necessary. For most GWAS loci,
this degree of specification is not yet available.
In the meantime, while the biological research commu-
nity engages the tools of functional genomics to elucidate
the biological import of common and rare schizophrenia-
associated risk variants, the clinical psychiatry community
has begun to stratify patients by genetic risk and, in particular,
by a cumulative sum of risk-associated variants across the
genome, called the polygenic risk score. The clinical research
landscape is beginning to be transformed by the availability
of genetic risk factors in prediction models of risk, of envi-
ronmental influence, and of outcome.
POLYGENIC RISK SCORE
One of the principal goals of genetic counseling is to advise
about risk. As mentioned above for schizophrenia, rare ge-
nomic variants (CNVs) tend to be more penetrant compared
with common genomic variants. The velocardiofacial syn-
drome deletion may increase risk of a diagnosis of schizo-
phrenia up to 30-fold, and other identified rare variants
associated with schizophrenia increase risk on average 5- to
10-fold. While this is potentially of value in clinical coun-
seling, the odds are still much greater that schizophrenia will
not occur in the context of these rare variants than that it will.
Each common variant identified in GWAS, in contrast, in-
creases risk only a tiny amount and thus cannot be used to
predict risk. However, single variants are inherited on a
background of millions of other variants in the genome, and
genetic risk is presumably a cumulative manifestation of
“genome type.”
In an effort to achieve a more meaningful prediction of
genomic risk, a polygenic risk score (PRS) has been applied in
many areas of medicine (34, 35). The PRS is an approach to
assigning to an individual a numerical score that quanti-
tates his or her level of genomic risk for a particular trait. The
PRS is calculated by summing all the alleles (weighted by
their individual odds ratios) that have been associated with
an illness in the latest GWAS data set for that illness. For
example, for schizophrenia, considering SNPs in 145 inde-
pendent loci contributing to risk in the current schizo-
phrenia GWAS, a score can be assigned to an individual on
the basis of how many of those specific risk-associated al-
leles for those SNPs are found in that individual’s genome.
Scores can also be calculated from SNPs showing statisti-
cal association at varying p value thresholds (e.g., 531028,
131026, 0.05). In principle, two individuals could have the
Am J Psychiatry 176:1, January 2019
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FIGURE 1. Diagram of SNPs in a GWAS-significant locus for schizophrenia risk on chromosome 10a

1.0
18 0.8
0.6 a
16 0.4
0.2 3 1 2
14 0.1 4 5
12
Observed (–logP)

10

2
filter: p<0.04
0
GBF1 MIR1468 SUFU CYP17A1 NT5C2 USMG5

NFKB2LOC100505781 TRIM8 C10orf32 LOC729020 MIR1307

PSD C10art95 ARL3 C10orf32–AS3MT INA PDCD11

FBXL15 TMEM180 SFXN2 AS3MT PCGF6

CUEDC2 ACTR1A WBP1L CNNM2 TAF5

104100 104300 104600 104900 105100

Chromosome 10 (kb)
a
Each dot is a single-nucleotide polymorphism (SNP), and the y-axis shows the log of the p value for association of SNP genotype with diagnosis. The
SNPs are heat-scale colored according to the magnitude of genotype correlation (i.e., R2, as shown in the box) with the most significant SNP
(the diamond). The horizontal green line in the graph is the statistical threshold for genome-wide association study (GWAS) significance. Many SNPs
spanning a large block are GWAS significant, and because many genes are mapped to this 1-Mb region of the genome, as depicted in the lower
part of the figure, it is impossible to determine from these data alone which, if any, or how many, are causative. The x-axis shows the standard
physical coordinates in nucleotide numbers (in kb) for this section of chromosome 10. (See the text for more about this particular region.)

same score but actually share none of the same alleles that
make up their score. The PRS is thus a gross aggregate
measure of genomic risk, based on a simple additive model.
Nevertheless, current PRS explains more risk than individual
SNPs (on the order of 3%215%, depending on which p value
threshold is used [34]). Moreover, because it is a score that
can be calculated for any individual who has been genotyped,
it has generated considerable interest as an independent
measure for clinical research.
The PRS for schizophrenia has become a popular and
dependable variable in differentiating groups of patients
with schizophrenia diagnoses from control subjects, as pa-
tient samples have consistently higher scores than control
samples. The schizophrenia PRS also tends to be increased in
individuals with several other psychiatric disorders, partic-
ularly in the context of psychotic features (6, 7). Use of the
PRS has become a popular strategy in many studies as a
predictor of associated clinical characteristics, such as cog-
nitive deficits and treatment response, and it has also been
associated with an expanding catalog of diverse measures and
traits in unaffected people (e.g., adolescent cannabis use
[36] and body mass index [37]). Perhaps not surprisingly, as
a measure of overall genomic risk, the schizophrenia PRS
is associated with aspects of early child development, in-
cluding intellectual and emotional development and school
performance (6, 38–40), as well as aspects of brain physi-
ology associated with risk for schizophrenia (41, 42). It is
important to appreciate that associations and predictions in
clinical samples based on PRS, although at times statistically
strong, are still weakly predictive at the level of an individual
and are not clinically actionable. Furthermore, PRSs to date
are derived principally from samples of European ances-
try, and questions have been raised about the potential
confounding role of ancestral genetic components in medi-
ating some of the clinical associations (43).
The current incarnation of schizophrenia PRS has fo-
cused on index SNPs from the large GWAS study as an
omnibus measure of genomic risk for clinical illness, but the
concept can also be applied to basic biological data to identify
genomic profiles that represent that biology in the clinical
setting. For example, a PRS derived from a set of SNPs that
influence expression of a network of genes co-expressed in
brain with the dopamine D2 receptor (DRD2) has been shown
to predict response to antipsychotic drugs (44). A PRS de-
rived from a set of SNPs indexing genes in schizophrenia
GWAS loci expressed in the human placenta and dynami-
cally regulated in placenta from complicated pregnancies
predicts the interaction of genetic risk and obstetrical
complications on liability for schizophrenia (45). The devel-
opment of genomic profiles for specific biological processes

Am J Psychiatry 176:1, January 2019 ajp.psychiatryonline.org 17

THINKING ABOUT SCHIZOPHRENIA IN AN ERA OF GENOMIC MEDICINE
has considerable potential for parsing the role of genes in
biological processes that account for clinical variation. It is
reasonable to hypothesize that schizophrenia PRSs decon-
volved into “gene sets” reflecting specific molecular pathways
or networks will have differential and stronger effects on
specific clinical parameters than the whole-genome based PRS.
COMMENT
From a biological point of view, genetic research over the past
decade has led to an unprecedented level of raw information
about schizophrenia risk, as have genomic investigations of
other traits and complex diseases across medicine, including
in cancer, hypertension, diabetes mellitus, and cardiovascular
disease. But how far will genetic insights take psychiatry?
Will they change how patients are clinically diagnosed?
Will they predict outcome and personalize medicine? Will
they lead to novel therapies based on pathogenesis? My view
is that the latter is a good bet, and the others are much more
speculative. Given the substantial role of environmental
variables in the etiology and course of all complex disorders, it
is unlikely that even sequencing the DNA of everyone on the
planet would lead to a full understanding of schizophrenia.
It is important to continually emphasize that genes do not
encode for psychopathology. Genes associated with schizo-
phrenia implicate subtle malfunctions at the molecular and
cellular level, most likely within neurons, altering micro- and
macrocircuits in the developing brain. Cells process molec-
ular information, and circuits process environmental in-
formation (e.g., sensory information, cognitive information,
social information). Behavior is an emergent phenomenon of
circuit physiology, which may be aberrant because the cells
comprising the circuit are altered, for example, by not sig-
naling to each other in an appropriate manner for a given
context, based on the genetic and epigenetic programs that
entrain their development and function. Psychiatric dis-
orders ultimately reflect how the brain mishandles envi-
ronmental information, which at the systems level is far
“downstream” of the effect of genes in cells. Thus, given the
complexity of the development and function of the brain
and its emergent properties, determining what it means for
a brain to be at increased risk for schizophrenia is a far
more complex and challenging problem than finding sus-
ceptibility loci.
There is also reason to wonder to what degree GWAS
associations sharpen the focus on the core pathogenic
processes of schizophrenia. The omnigenic hypothesis men-
tioned above cautions that many GWAS associations are
likely to be relatively peripheral factors in causation, detected
because they play a role in the biological function of relevant
cells. This may account in part for the substantial overlap
between schizophrenia and not just other psychiatric di-
agnoses but even disorders as seemingly distant pathogeni-
cally as amyotrophic lateral sclerosis (46). Moreover, while
the loci that have been found seem not to respect our clinical
diagnoses, the drugs we use to treat patients generally do.
18 ajp.psychiatryonline.org
Lithium is not antipsychotic; clozapine does not benefit in-
dividuals with ADHD; and stimulants are not antimanic
drugs. From a clinical perspective, treatment is a litmus test
of biological relevance.
There is also concern that some of the genes within GWAS
loci may not substantially contribute to symptomatology in
adulthood. Studies of gene expression in adult postmortem
brain samples of patients with schizophrenia do not generally
find differential expression of genes within GWAS loci (47,
48). In contrast, in a consistent emergent literature, many of
the genes found in these loci have been found to be prefer-
entially expressed and dynamically regulated in fetal life (49),
consistent with the prevailing assumption that schizo-
phrenia, like most psychiatric syndromes, has early de-
velopmental origins (50). A recent study (45) found that a
substantial fraction of genes in the GWAS-significant loci are
abundantly expressed in the placenta and are dynamically
regulated in placenta from complicated pregnancies, possibly
explaining the link between schizophrenia risk and preg-
nancy complications. While this finding has potential im-
plications for primary prevention based on enhancing
placental health, it does not suggest specific treatment op-
tions for an affected adult.
These caveats notwithstanding, genes are critical and
valid entry points to the biology of cells, and genes related to
risk for schizophrenia are building blocks for model systems
that may lead to novel insights and novel therapeutic targets.
There is considerable enthusiasm in basic research labora-
tories for creating neuronal models based on human plu-
ripotent stem cells from patients with schizophrenia and
from cells with genomes that contain risk-associated variants
(51). In principle, such approaches may identify early de-
velopmental phenotypes that can be rescued experimentally.
While this work also may not translate simply to the adult
brain, it is worth remembering that the molecular programs
that build synapses are at least in part the same ones that
sustain them and modify them during adult life. Furthermore,
animal research has shown that some early developmental
abnormalities, even in brain structure, may be reversed
during adulthood (52). This is a new frontier, but it is not
science fiction.
For good reason, 21st-century medicine has become highly
intertwined with genomic-based medicine. Psychiatry is part
of this new age, and the opportunities to change our nosology
and our understanding of what we call mental illness and
to find new approaches to improve the lives of affected in-
dividuals have never seemed more promising. That being
said, as usual, the more we learn, the more we need to know,
and with such a complex task, it’s likely to be a bumpy ride.
AUTHOR AND ARTICLE INFORMATION
The Lieber Institute for Brain Development and Maltz Research Labora-
tories, Baltimore; and the Departments of Psychiatry, Neurology, and
Neuroscience and the McNusick Nathans Institute of Genomic Medi-
cine, Johns Hopkins School of Medicine, Baltimore.
Send correspondence to Dr. Weinberger (drweinberger@libd.org).
Am J Psychiatry 176:1, January 2019

The author thanks Richard Straub, Rebecca Birnbaum, and Michael
O’Donovan for their helpful suggestions and review of the manuscript.
The author reports no financial relationships with commercial interests.
Accepted November 15, 2018.
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