Research

JAMA Psychiatry | Original Investigation

Role of the Gut-Brain Axis in the Shared Genetic Etiology

Between Gastrointestinal Tract Diseases and Psychiatric Disorders
A Genome-Wide Pleiotropic Analysis
Weiming Gong, MM; Ping Guo, MM; Yuanming Li, BM; Lu Liu, PhD; Ran Yan, PhD; Shuai Liu, MM;
Shukang Wang, MD, PhD; Fuzhong Xue, PhD; Xiang Zhou, PhD; Zhongshang Yuan, PhD

Supplemental content
IMPORTANCE Comorbidities and genetic correlations between gastrointestinal tract diseases
and psychiatric disorders have been widely reported, with the gut-brain axis (GBA)
hypothesized as a potential biological basis. However, the degree to which the shared genetic
determinants are involved in these associations underlying the GBA is unclear.

OBJECTIVE To investigate the shared genetic etiology between gastrointestinal tract diseases
and psychiatric disorders and to identify shared genomic loci, genes, and pathways.

DESIGN, SETTING, AND PARTICIPANTS This genome-wide pleiotropic association study using
genome-wide association summary statistics from publicly available data sources was
performed with various statistical genetic approaches to sequentially investigate the
pleiotropic associations from genome-wide single-nucleotide variation (SNV; formerly
single-nucleotide polymorphism [SNP]), and gene levels and biological pathways to
disentangle the underlying shared genetic etiology between 4 gastrointestinal tract
diseases (inflammatory bowel disease, irritable bowel syndrome, peptic ulcer disease, and
gastroesophageal reflux disease) and 6 psychiatric disorders (schizophrenia, bipolar disorder,
major depressive disorder, attention-deficit/hyperactivity disorder, posttraumatic stress
disorder, and anorexia nervosa). Data were collected from March 10, 2021, to August 25,
2021, and analysis was performed from January 8 through May 30, 2022.

MAIN OUTCOMES AND MEASURES The primary outcomes consisted of a list of genetic loci,
genes, and pathways shared between gastrointestinal tract diseases and psychiatric
disorders.

RESULTS Extensive genetic correlations and genetic overlaps were found among 22 of 24 trait
pairs. Pleiotropic analysis under a composite null hypothesis identified 2910 significant
potential pleiotropic SNVs in 19 trait pairs, with 83 pleiotropic loci and 24 colocalized loci
detected. Gene-based analysis found 158 unique candidate pleiotropic genes, which were
highly enriched in certain GBA-related phenotypes and tissues, whereas pathway enrichment
analysis further highlighted biological pathways primarily involving cell adhesion, synaptic
Author Affiliations: Department of
structure and function, and immune cell differentiation. Several identified pleiotropic loci Biostatistics, School of Public Health,
also shared causal variants with gut microbiomes. Mendelian randomization analysis further Cheeloo College of Medicine,
illustrated vertical pleiotropy across 8 pairwise traits. Notably, many pleiotropic loci were Shandong University, Jinan,
Shandong, China (Gong, Guo, L. Liu,
identified for multiple pairwise traits, such as 1q32.1 (INAVA), 19q13.33 (FUT2), 11q23.2 Yan, S. Liu, Wang, Xue, Yuan);
(NCAM1), and 1p32.3 (LRP8). Institute for Medical Dataology,
Shandong University, Jinan, China
CONCLUSIONS AND RELEVANCE These findings suggest that the pleiotropic genetic (Gong, Guo, L. Liu, Yan, S. Liu, Wang,
determinants between gastrointestinal tract diseases and psychiatric disorders are Xue, Yuan); School of Medicine,
extensively distributed across the genome. These findings not only support the shared Cheeloo College of Medicine,
Shandong University Jinan, China
genetic basis underlying the GBA but also have important implications for intervention (Li); Department of Biostatistics,
and treatment targets of these diseases simultaneously. University of Michigan, Ann Arbor
(Zhou); Center for Statistical
Genetics, University of Michigan,
Ann Arbor (Zhou).
Corresponding Author: Zhongshang
Yuan, PhD, Department of
Biostatistics, School of Public Health,
Cheeloo College of Medicine,
Shandong University, 44,
Wenhua West Road, Jinan, Shandong
JAMA Psychiatry. doi:10.1001/jamapsychiatry.2022.4974 250012, China (yuanzhongshang@
Published online February 8, 2023. sdu.edu.cn).

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 Research Original Investigation Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders
T
he comorbidities and associations between gastroin-
testinal tract diseases and psychiatric disorders have
been widely reported,1-3 which was likely to be regu-
lated by the gut-brain axis (GBA). The GBA is characterized
by bidirectional interactions between the gastrointestinal tract
and the central nervous system (CNS) and would link intesti-
nal dysfunction and inflammation with brain function and psy-
chiatric disorders.4,5 Various biological mechanisms were in-
volved in the GBA, such as inflammatory immune responses,
the autonomic nervous system, and enteric nervous system,
where the role of the composition of gut microbiota and re-
lated metabolites has been particularly highlighted.4-7 Under-
lying the conceptual framework of the GBA, the shared ge-
netic etiology might be involved in the associations between
gastrointestinal tract diseases and psychiatric disorders.
Genome-wide association studies (GWAS) have identi-
fied multiple genetic variants (ie, single-nucleotide varia-
tions [SNVs]; formerly single-nucleotide polymorphisms
[SNPs]) associated with gastrointestinal tract diseases and
psychiatric disorders. 8-10 Genetic correlations have been
suggested between these 2 types of diseases using linkage
disequilibrium (LD) score regression (LDSC).10-14 However,
it remains unclear whether the overall genetic correlation
would be attributed to a few loci or across the genome.15 In-
deed, there would be genetic overlap even without any ge-
netic correlation. Although previous studies have investi-
gated genetic overlap,16 shared susceptibility genes,17,18 and
causal relationships19-21 between these 2 types of diseases, they
mainly focused on inflammatory bowel disease (IBD) and
psychiatric disorders with limited sample sizes. Recently,
2 studies10,22 have conducted GWAS of specific gastrointesti-
nal tract diseases as well as systematic post-GWAS analyses and
pointed out the necessity to explore the shared genetic risk
across traits to improve the understanding of the disordered
brain-gut interactions. Therefore, it is of great importance to
further seek out the specific genomic variants or loci account-
ing for genome-wide genetic correlation and to deeply probe
into the shared genetic etiology between these 2 types of dis-
eases. Shared genetic etiology also indicates the potential
pleiotropy, which often acts as genetic confounding of the as-
sociations between trait pairs.23-25 Cross-trait analysis has been
proposed to investigate the pleiotropic genetic variants or loci
among multiple traits by leveraging the correlation of GWAS
signals,23,26-29 where the pleiotropic loci could serve as inter-
vention targets with the potential to simultaneously prevent
or treat these diseases.
In this genome-wide pleiotropic association study, using
large-scale GWAS summary data, we performed a genome-
wide pairwise trait pleiotropic analysis between 4 gastroin-
testinal tract diseases (IBD, irritable bowel syndrome [IBS],
peptic ulcer disease [PUD], and gastroesophageal reflux dis-
ease [GERD]) and 6 psychiatric disorders (schizophrenia,
bipolar disorder [BIP], major depressive disorder [MDD],
attention-deficit/hyperactivity disorder [ADHD], posttrau-
matic stress disorder [PTSD], and anorexia nervosa [AN])
through various statistical genetic approaches to sequentially
investigate the pleiotropic associations from genome-wide,
SNV, and gene levels and biological pathways to disentangle
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Key Points
Question To what extent are shared genetic determinants in
the comorbidities and associations between gastrointestinal tract
diseases and psychiatry disorders involved in the gut-brain axis?
Findings In this genome-wide pleiotropic association study
using genome-wide association summary statistics from publicly
available data sources, pervasive genetic correlations and genetic
overlaps between gastrointestinal tract diseases and psychiatric
disorders were found. The pleiotropic genetic determinants
between them were extensively distributed across the genome.
Meaning These findings not only support the shared genetic basis
underlying the gut-brain axis but also have important implications
for intervention and treatment targets of these 2 types of diseases
simultaneously.
the underlying shared genetic etiology. Of note, under
the framework of pleiotropic analysis, we first performed
the SNV-level analysis to detect pleiotropic variants and loci,
followed by pairwise colocalization analysis to determine
colocalized loci and gene-level analysis to identify candidate
pleiotropic genes, based on which we further performed par-
allel phenotype and tissue-specific enrichment analysis
to characterize the phenotype and tissue specificity as well
as additional gene-level analysis to identify the tissue-
specific and cell type-specific pleiotropic genes. We also
highlighted the role of gut microbiomes in interpreting
the shared genetic etiology, followed by mendelian random-
ization analysis to evaluate pairwise causal associations
and partly characterize different types of pleiotropy (vertical
pleiotropy or horizontal pleiotropy).
Methods
GWAS Data Sets
We sought GWAS summary statistics from publicly available
data sources with European ancestry, owing to the limited
availability of well-powered GWAS with other ancestries, and
selected GWAS with sample sizes larger than 50 000 to en-
sure statistical power. GWAS for GERD, IBD, and PUD were ob-
tained from the same gastrointestinal tract GWAS based on
456 327 individuals from UK Biobank (UKB).10 GWAS for IBS
were obtained from a larger meta-analysis with 486 601 indi-
viduals (53 400 cases and 433 201 controls).22 GWAS for the
6 psychiatric disorders were from the Psychiatric Genomics
Consortium, including schizophrenia,30 BIP,31 MDD,32 ADHD,33
PTSD,34 and AN.35 In addition, GWAS for early age-related
macular degeneration (AMD)36 and cataract37 were obtained
to serve as a common set of negative controls for both gastro-
intestinal tract diseases and psychiatric disorders, given these
2 disorders are relatively limited to the pathological lesions of
intraocular contents, and previous studies also showed no sig-
nificant genetic correlations between AMD and MDD38 as well
as among cataract, GERD, and psychiatric symptoms.39 All
GWAS were approved by relevant ethic committees, and writ-
ten informed consent was obtained from all participants, with
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 Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders
details provided in the eTable 1 in Supplement 1. Data were col-
lected from March 10, 2021, to August 25, 2021, and analyzed
from January 8 through May 30, 2022. This genome-wide pleio-
tropic association study followed the Strengthening the
Reporting of Genetic Association Studies (STREGA) reporting
guideline.
Statistical Analysis
All analyses were performed after excluding SNVs in the
major histocompatibility complex region (chromosome 6:
25-35 megabase [Mb]) due to its complex LD structure and
restricted to biallelic SNVs with minor allele frequency larger
than 0.01. Details of these methods are provided in Figure 1
and eMethods in Supplement 1.
Both LDSC40 and high-definition likelihood41 were used
to assess genome-wide genetic correlations for 24 pairwise
traits. The intercept from LDSC could also indicate potential
sample overlap between 2 GWAS. Given that genetic correla-
tion only reflects the overall correlation across the genome, we
further applied genetic analysis incorporating pleiotropy and
annotation (GPA)29 to explore the overall genetic overlap be-
tween traits. The Bonferroni-corrected significant threshold
was set at P < 2.08 × 10−3 (.05/24). In addition, negative con-
trol analysis was performed through LDSC between AMD and
cataract and the 4 gastrointestinal tract diseases as well as the
6 psychiatric disorders, with Bonferroni-corrected significant
threshold set at P < 2.5 × 10−3 (.05/20).
For the union set of pairwise traits with significant
genetic correlation or genetic overlap, we used pleiotropic
analysis under composite null hypothesis (PLACO) to identify
potential pleiotropic SNVs.26 Single-nucleotide variations
with P < 5 × 10 −8 for PLACO were considered significant
pleiotropic variants. Functional mapping and annotation of
genetic associations (FUMA)42 was applied to characterize
potential pleiotropic loci, based on which a bayesian colocal-
ization analysis43 was performed to further identify shared
causal variants in each pleiotropic locus. We declared a colo-
calized locus with posterior probability of H4 (PP.H4) larger
than 0.7.
Based on PLACO results, we further explored the shared
biological mechanisms of these pleiotropic loci. We per-
formed gene-level multimarker analysis of GenoMic annota-
tion (MAGMA)44 analysis on the genes located in or over-
lapped with the pleiotropic loci based on both PLACO outputs
and single-trait GWAS to identify candidate pleiotropic genes,
with the significance declared at the locus-specific Bonferroni-
corrected 2-sided P < .05 for MAGMA analysis on PLACO re-
sults and 2-sided P < .05 for MAGMA analyses based on origi-
nal single-trait GWAS. Further, we performed phenotype
enrichment analysis based on the Mouse Genome Informat-
ics platform45 to characterize the phenotype specificity of these
pleiotropic genes against that of nonpleotropic genes by ex-
amining the differences in the proportions of genes associ-
ated with certain phenotypes in the pleiotropic gene group
against that in the nonpleotropic gene group using the Fisher
exact test. Then, we performed tissue-specific enrichment
analyses to illustrate the tissue specificity of these pleiotro-
pic genes using the deTS tissue-specific enrichment method46
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Original Investigation Research
based on 2 different reference panels, Genotype-Tissue
Expression project (GTEx)47 and the Encyclopedia of DNA
Elements project (ENCODE).48 We declared the significance
with a nominal threshold (2-sided P < .05) for these 2 parallel
enrichment analyses. In addition, we used E-MAGMA (expres-
sion quantitative trait loci [eQTL]–informed MAGMA)49 and
transcriptome-wide association study analysis using joint-
tissue imputation50 to further investigate the tissue-specific
genes, parallelized with H-MAGMA (Hi-C–coupled MAGMA)51
to indicate the cell-type specificity, in which we declared the
significance with locus-specific Bonferroni correction. Gene
set enrichment analysis was also performed to identify poten-
tial biological pathways using the clusterProfiler package.52
Significantly enriched pathways were declared with normal-
ized enrichment score greater than 2 and adjusted P < .05.
Multitrait colocalization analysis with HyPrColoc (hypoth-
esis prioritization for multi-trait colocalization)53 incorporat-
ing host-microbiome GWAS was performed to highlight the
critical role of gut microbiome.
Last, we conducted bidirectional mendelian randomiza-
tion analysis for 24 pairwise traits between gastrointestinal
tract diseases and psychiatric disorders to investigate the po-
tential causal trait pairs (ie, vertical pleiotropy), along with
negative control analysis using AMD and cataract. We used the
inverse-variance weighted method54 as main analysis and in
total 6 alternative mendelian randomization methods with dif-
ferent model assumptions as additional analyses for further
validation. For main analysis, we chose a false discovery rate
approach for multiple testing correction with the signifi-
cance threshold being false discovery rate–adjusted P < .05,
given that the commonly used Bonferroni correction is often
too stringent for multiple nonindependent tests. The nomi-
nally significant threshold (P < .05) was used for alternative
mendelian randomization methods. The Latent Heritable
Confounder Mendelian Randomization (LHC-MR) method,
which could account for sample overlap, was used for pair-
wise traits with potential sample overlap to further validate
the mendelian randomization results.55
Genomic Loci Characterization
and Functional Annotation
For significant pleiotropic SNVs from PLACO, we applied FUMA
to identify independent variants, characterize genomic risk
loci, and annotate the functions of variants using LD informa-
tion from the 1000 Genome Project phase 3 reference panel
of European population.42 We characterized independent
SNVs with r2 less than 0.6000 and lead SNVs with r2 less than
0.1000 within 1 Mb. Genomic risk loci were defined by merg-
ing genomic regions if the physical distance between lead
SNVs was less than 250 kilobase.42
Functional annotations, including ANNOVAR software
tool categories (Bioinformatics), combined annotation-
dependent depletion (CADD) scores, and RegulomeDB scores,
were also provided by FUMA. Single-nucleotide variations with
a CADD score larger than 12.37 were considered a potentially
deleterious variant. 42 Single-nucleotide variations with
P < 5 × 10−8 in each single-trait GWAS were also annotated by
FUMA for comparison.
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 Research Original Investigation Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders

Figure 1. Study Workflow

A Genetic correlation and overlap

..
Trait 1 Trait 2

..
E[z1*z2] .. PM10 PM11 PM01

LD score Pleiotropic variants

Genetic correlation
Genetic overlap

B Identification of pleiotropic variants and loci

20 14 20

12
15 15
10
-log10 P value

8
10 10
6

4
5 5
2

0 0 0
Chr 1 2 3 4 5 6 7 8 9 10 11 12 13 15 17 19 22 Chr 1 2 3 4 5 6 7 8 9 10 11 12 13 15 17 19 22 Chr 1 2 3 4 5 6 7 8 9 10 11 12 13 15 17 19 22
GWAS of GIT disease PLACO GWAS of PSY disorder

C Exploration of shared biological mechanisms

P .adjust
Asymmetric synapse .0067
Dendritic spine .0159
Running enrichment score

6 SNVs Gene 0.4 Neuron to neuron synapse .0159

Postsynaptic density
P value P value .0052
–log10 P for GWAS of PSY disorder

0.3 Postsynaptic specialization .007

MAGMA 0.2 GIT disease

4
0.1
0
PSY disorder
2
Ranked list metric

Phenotype and tissue enrichment

5.0 Gut microbiome
2.5
0 QTL 0 Locus
-2.5
0 2 4
5000 10 000 15 000
–log10 P for GWAS of GIT disease
Rank in ordered data set

COLOC E-MAGMA TWAS-JTI H-MAGMA GSEA HyPrColoc

D Bidirectional associations

Confounder

Instrumental variable GIT disease PSY disorder Instrumental variable

Mendelian randomization

We conducted the comprehensive pleiotropic analysis between of GenoMic annotation (MAGMA); H-MAGMA, Hi-C–coupled MAGMA;
4 gastrointestinal tract (GIT) diseases and 6 psychiatric (PSY) disorders HyPrColoc, hypothesis prioritization for multi-trait colocalization; LD, linkage
from different perspectives. COLOC indicates colocalization; GSEA, gene disequilibrium; PLACO, pleiotropic analysis under composite null hypothesis;
set enrichment analysis; GWAS genome-wide association study; SNV, single-nucleotide variation; and TWAS-JTI, transcriptome-wide association
E-MAGMA, expression quantitative trait loci–informed multi-marker analysis study analysis using joint-tissue imputation.

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 Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders Original Investigation Research

Table 1. Genetic Correlation and Genetic Overlap Estimations Between 24 Pairwise Traitsa

Genetic correlation Genetic overlap

Genetic P value P value P value
Trait pair correlation (SE) for LDSC Intercept (SE) for intercept PM 11 PARb for GPA
IBD-MDDc,d 0.1706 (0.0407) 2.82 × 10−5 0.0003 (0.0055) 9.57 × 10−1 0.0116 0.0473 1.41 × 10−3
IBD-PTSD 0.1742 (0.0377) 7.39 × 10−2 0.0049 (0.0051) 3.37 × 10−1 0.0038 0.0189 2.27 × 10−1
IBD-SCZd 0.0359 (0.0403) 3.73 × 10−1 0.0004 (0.0062) 9.49 × 10−1 0.0167 0.0605 6.07 × 10−15
IBD-ADHD –0.0045 (0.0599) 9.40 × 10−1 0.0121 (0.0057) 3.38 × 10−2 0.0121 0.0512 5.16 × 10−2
IBD-BIPd 0.0221 (0.0478) 6.45 × 10−1 0.0064 (0.0063) 3.10 × 10−1 0.0194 0.0828 3.80 × 10−28
IBD-ANd –0.0296 (0.0630) 6.38 × 10−1 0.0019 (0.0063) 7.63 × 10−1 0.0206 0.0851 8.85 × 10−11
IBS-MDDc,d,e 0.5705 (0.0256) 1.14 × 10−109 0.0795 (0.0066) 2.05 × 10−33 0.1571 0.7791 <1 × 10−300
IBS-PTSDc,d,e 0.4720 (0.0795) 2.87 × 10−9 0.0275 (0.0049) 2.00 × 10−8 0.0422 0.1504 1.27 × 10−5
IBS-SCZc,d 0.1711 (0.0285) 1.85 × 10−9 –0.0025 (0.006) 6.77 × 10−1 0.1246 0.4130 <1 × 10−300
IBS-ADHDc,d 0.2060 (0.0405) 3.73 × 10−7 0.0138 (0.0059) 1.93 × 10−2 0.1155 0.3895 1.67 × 10−87
c,d,e −5 −4
IBS-BIP 0.1269 (0.0305) 3.12 × 10 0.0219 (0.0058) 1.59 × 10 0.1183 0.4579 3.54 × 10−268
c,d −4 −1
IBS-AN 0.1536 (0.0413) 2.00 × 10 0.0003 (0.0064) 9.63 × 10 0.1207 0.4059 3.98 × 10−86
c,d,e −24 −8
PUD-MDD 0.4438 (0.0437) 3.31 × 10 0.0333 (0.0059) 1.66 × 10 0.0987 0.4011 1.04 × 10−102
c −6 −1
PUD-PTSD 0.5448 (0.1120) 1.15 × 10 0.0074 (0.0046) 1.08 × 10 0.0274 0.1052 3.65 × 10−2
c,d −3 −1
PUD-SCZ 0.1306 (0.0402) 1.20 × 10 –0.0007 (0.006) 9.07 × 10 0.0832 0.2713 7.89 × 10−55
c,d −16 −1
PUD-ADHD 0.4771 (0.0579) 1.63 × 10 0.0072 (0.0058) 2.14 × 10 0.0886 0.3409 1.27 × 10−37
d −1 −1
PUD-BIP 0.0691 (0.0437) 1.14 × 10 0.0023 (0.0054) 6.70 × 10 0.0679 0.2491 1.31 × 10−34
d −1 −1
PUD-AN 0.0366 (0.0539) 4.97 × 10 0.0014 (0.0056) 8.03 × 10 0.0448 0.1441 8.03 × 10−4
c,d,e −66 −39
GERD–MDD 0.4596 (0.0267) 3.50 × 10 0.0692 (0.0053) 5.83 × 10 0.1762 0.6824 <1 × 10−300
c,d −9 −3
GERD-PTSD 0.4193 (0.0690) 1.24 × 10 0.0156 (0.0051) 2.22 × 10 0.0538 0.1567 3.43 × 10−4
d −1 −2
GERD-SCZ 0.0313 (0.0273) 2.51 × 10 0.0107 (0.0062) 8.44 × 10 0.1299 0.3596 1.07 × 10−189
c,d −40 −1
GERD-ADHD 0.4919 (0.0371) 3.32 × 10 –0.0003 (0.0063) 9.62 × 10 0.1543 0.4844 6.81 × 10−132
d −01 −1
GERD-BIP 0.0332 (0.0308) 2.81 × 10 0.0048 (0.0059) 4.16 × 10 0.1279 0.4050 1.27 × 10−174
d −1 −1
GERD-AN 0.0179 (0.0386) 6.43 × 10 0.0038 (0.0063) 5.46 × 10 0.1265 0.3597 1.24 × 10−61
−3
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AN, anorexia P < 2.83 × 10 (.05/24), producing a final union set of 22 pairwise traits with
nervosa; BIP, bipolar disorder; GERD, gastroesophageal reflux disease; significant genetic correlation or genetic overlap for subsequent analysis.
GPA, genetic analysis incorporating pleiotropy and annotation method; b
We introduced PAR as PM 11/(PM 10 + PM 01 + PM 11) to represent the
IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; LDSC, linkage proportion of pleiotropic single-nucleotide variations (SNVs) associated with
disequilibrium score regression; MDD, major depressive disorder; both traits against the proportion of SNVs associated with at least 1 trait.
PAR, pleiotropy association ratio; PM 11, proportion of genetic variants c
Pairwise trait with significant genetic correlation.
associated with both traits; PTSD, posttraumatic stress disorder; PUD, peptic
d
ulcer disease; SCZ, schizophrenia. Pairwise trait with significant genetic overlap.
e
a
Genetic correlation and genetic overlap were estimated by LDSC and GPA Genome-wide association study summary data with potentially significant
methods, respectively. Bonferroni-corrected significance threshold was set at sample overlap.

Shared Loci Between Gastrointestinal Tract Diseases

Results
Genetic Correlations and Genetic Overlaps Between
Gastrointestinal Tract Diseases and Psychiatric Disorders
Using genome-wide association summary statistics from pub-
licly available data sources, pervasive significant genome-
wide genetic correlations and genetic overlaps were found
across 24 pairwise traits, among which 14 were identified from
LDSC and 21 were identified from GPA (Table 1). Notably, 8 trait
pairs were identified with nonsignificant genetic correlation
but with significant genetic overlap, producing a final union
set of 22 pairwise traits for subsequent analysis. In addition,
the results from the LDSC were highly consistent with those
from high-definition likelihood (eTable 2 and eFigure 1 in
Supplement 1) and suggested significant sample overlap for
5 trait pairs (Table 1). For negative control analysis, no signifi-
cant genetic correlations were detected as expected (eTable 3
in Supplement 1).
and Psychiatric Disorders
A total of 2910 SNVs (2284 unique) were identified as poten-
tial pleiotropic variants by PLACO in 19 trait pairs (eFigure 2
in Supplement 1). FUMA identified 83 independent genomic
risk loci as pleiotropic loci, involving 54 unique chromo-
somal regions (Figure 2 and eTables 4 and 5 in Supplement 1).
Some pleiotropic regions were identified in multiple pair-
wise traits, such as 11q23.2 (mapped gene: NCAM1 [OMIM
116930]) and 1q32.1 (mapped gene: INAVA [OMIM 618051]),
suggesting the extensive pleiotropic effects of these loci. The
top SNVs in 83 FUMA-annotated pleiotropic loci showed mixed
directions of allelic associations (eTable 6 in Supplement 1).
Overall, 53 of 83 top SNVs (64%) showed concordant associa-
tions with a certain pair of traits, indicating these variants could
simultaneously decrease or increase the risk of gastrointesti-
nal tract diseases and psychiatric disorders. The remaining
30 of 83 top SNVs (36%) showed discordant associations,
suggesting the possibly distinct biological mechanisms.

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 Research Original Investigation Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders

Figure 2. The Overall Landscape of the Pleiotropic Associations Across 4 Gastrointestinal Tract Diseases and 6 Psychiatric Disorders

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A circular dendrogram included 4 gastrointestinal tract diseases (inner circle,
including gastroesophageal reflux disease [GERD], inflammatory bowel disease
[IBD], irritable bowel syndrome [IBS], and peptic ulcers disease [PUD]) and
6 psychiatric disorders (second circle; attention-deficit/hyperactivity disorder
[ADHD], anorexia nervosa [AN], bipolar disorder [BIP], major depressive
disorder [MDD], posttraumatic stress disorder [PTSD], and schizophrenia
[SCZ]), resulting in 24 trait pairs. A total of 83 pleiotropic loci were identified
across 19 trait pairs (third circle; no pleiotropic loci were identified for IBS-PTSD,
PUD-MDD, and PUD-PTSD), in which 53 of 83 top single nucleotide variations
(SNVs) showed concordant associations (marked by a plus sign) with a certain
pair of traits while the remaining top SNVs showed discordant associations
(marked by a minus sign); 24 pleiotropic loci were colocalized for pairwise traits
(orange dots, posterior probability of H4 [PP.H4]>0.7); and 11 were colocalized
for certain gastrointestinal tract diseases, psychiatric disorders, and gut
microorganisms (gray dots, PP>0.7, with the specific microorganism annotated
on the lines). A total of 196 significant pleiotropic genes (158 unique) were
further identified by multimarker analysis of GenoMic annotation (MAGMA).
For the trait pairs with more than 3 pleiotropic genes, we only showed the top
3 pleiotropic genes according to the prioritization of candidate pleiotropic
genes, which were shown with the statistical prioritization attenuation
manifested by clockwise direction (fourth circle), the genes with the tissue
specificity in at least one of gastrointestinal tract or brain tissues and in other
tissues identified by E-MAGMA were also highlighted (dark blue dots). Detailed
information for 83 pleiotropic loci (eTable 6 in Supplement 1), colocalization
results (Table 2), multitrait colocalization results (eTable 17 Supplement 1),
significant pleiotropic genes with annotations of tissue specificity (eTable 15 in
Supplement 1) was also provided.

ANNOVAR category annotation illustrated that 34 of 83 in- in Supplement 1). Of note, 5 mRNA exonic variants (4 unique)
dex SNVs (41%) were intronic variants and 27 of 83 (33%) were were located in 3 loci and mapped to 3 genes. Specifically, the
intergenic variants. Only 7 of 83 index SNVs (8%) (6 unique) index SNV rs20551 at 22q13.2 locus (PLACO P = 5.07 × 10−11 for
were exonic variants, including 5 messenger RNA (mRNA) ex- IBS-schizophrenia) was a significant eQTL for EP300 (OMIM
onic variants and 2 noncoding RNA exonic variants (eTable 5 602700) encoding p300 protein, which plays an important role

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 Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders Original Investigation Research

Table 2. 24 Colocalized Loci Identified by Colocalization Analysis Performed on 83 Pleiotropic Loci

Trait pair Top SNV Locus boundarya Region Nearest gene PP.H3 PP.H4 Best causal SNV.PP.H4
IBD-MDD rs12118513 1:197342380–197781198 1q31.3 DENND1B 0.0395 0.7372 rs12118513b 0.2022
IBD-MDD rs60689680 5:158827769–158856513 5q33.3 AC008703.1 0.0614 0.7034 rs60689680b 0.1184
IBD-SCZ rs905634 1:200874229–201027055 1q32.1 INAVA 0.0813 0.9139 rs905634b 0.4835
IBD-SCZ rs492430 7:100219167–100523241 7q22.1 EPO 0.0801 0.9116 rs492430b 0.1452
IBD-BIP rs56073120 8:59800835–59925249 8q12.1 TOX 0.0435 0.9044 rs56073120b 0.0632
IBD-BIP rs7090073 10:64387108–64441247 10q21.2 ZNF365 0.0257 0.9719 rs7090073b 0.1992
IBD-BIP rs196001 16:23892887–23962504 16p12.2 PRKCB 0.0656 0.8724 rs196001b 0.0811
IBS-MDD rs3099439 5:87514778–87822672 5q14.3 TMEM161B 0.0536 0.9428 rs3099439b 0.2131
IBS-MDD rs4937872 11:112826867–112912811 11q23.2 RP11-629G13.1 0.0845 0.9030 rs4937872b 0.1163
IBS-MDD rs1862743 16:60665658–60743834 16p12.2 GNPATP 0.0108 0.9578 rs1862743b 0.4157
IBS-SCZ rs12031155 1:53658317–53752134 1p32.3 LRP8 0.0518 0.9368 rs12031155b 0.1577
IBS-SCZ rs7542202 1:163616199–163766672 1q23.3 RP4-640E24.1 0.0550 0.9299 rs7542202b 0.0691
IBS-SCZ rs1280622 3:135807609–136673157 3q22.3 RP11-731C17.1 0.1145 0.8386 rs7432375 0.0965
IBS-SCZ rs11604175 11:124619407–124624854 11q24.2 VSIG2 0.0011 0.7717 rs11604175b 0.5730
IBS-SCZ rs12277680 11:134576216–134595774 11q25 RP11-469N6.2 0.0106 0.7331 rs12277680b 0.4057
IBS-BIP rs5177 1:53658317–53752134 1p32.3 LRP8 0.0553 0.8665 rs5177b 0.1081
IBS-BIP rs2345964 1:163582980–163768927 1q23.3 RP4-640E24.1 0.0254 0.9684 rs2345964b 0.1043
IBS-BIP rs13239217 7:82387493–82583609 7q21.11 PCLO 0.0939 0.8493 rs13239217b 0.1919
PUD-SCZ rs681343 19:49103447–49254955 19q13.33 FUT2 0.0951 0.8927 rs681343b 0.2834
GERD-MDD rs1263674 2:208017033–208088987 2q33.3 AC007879.1:AC007879.2 0.0567 0.8596 rs62188630 0.0638
GERD-PTSD rs13107325 4:102938709–103438709 4q24 SLC39A8 0.0111 0.7904 rs13107325b 0.7793
GERD-SCZ rs1892346 1:66304167–66333877 1p31.3 PDE4B 0.0210 0.8141 rs1892346b 0.0854
GERD-SCZ rs13107325 4:102702364–103387161 4q24 SLC39A8 0.0020 0.9966 rs13107325b 0.8466
GERD-AN rs1873914 12:56368708–56478658 12q13.2 RAB5B 0.0484 0.8134 rs1873914b 0.1042
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AN, anorexia SCZ, schizophrenia; SNV.PP.H4, posterior probability of the best causal variant.
nervosa; Best causal, the candidate causal single-nucleotide variation (SNV); a
Locus boundary of each pleiotropic genomic risk locus was denoted as
BIP, bipolar disorder; GERD, gastroesophageal reflux disease; IBD, inflammatory “chromosome: start-end” defined by FUMA for the corresponding trait
bowel disease; IBS, irritable bowel syndrome; MDD, major depressive disorder; pair.
PP.H3, posterior probability of H3; PP.H4, posterior probability of H4; b
The top SNV in this locus was also identified as a candidate causal SNV.
PTSD, posttraumatic stress disorder; PUD, peptic ulcer disease;

in cell proliferation and differentiation. The index SNVs
rs681343 (PLACO P = 1.36 × 10−12 for PUD-schizophrenia) and
rs601338 (PLACO P = 5.07 × 10−11 for PUD-ADHD) at 22q13.2
were in high LD (r2 = 0.996) and had almost identical eQTL
regulation information (eTable 7 in Supplement 1), regulating
the expression of FUT2 (OMIM 182100). The index SNV
rs13107325 at 4q24 locus (PLACO P = 1.78 × 10−14 for GERD-
schizophrenia; PLACO P = 4.19 × 10−8 for GERD-PTSD) was a
significant eQTL for SLC39A8 (OMIM 608732), which en-
codes ZIP8 metal cation transporter. In addition, 7 index SNVs
(6 unique) were identified with CADD scores larger than 12.37,
in which 2 mRNA exonic variants had higher CADD scores, in-
cluding rs601338 (CADD score: 52; mapped gene: FUT2 [OMIM
182100]) and rs13107325 (CADD score: 34; mapped gene:
SLC39A8).
Further colocalization analysis identified 24 of 83 poten-
tial pleiotropic loci (29%) with PP.H4 larger than 0.7, in which
22 top SNVs of corresponding loci were identified as candi-
date shared causal variants (Table 2, Figure 2, and eFigure 3
in Supplement 1). Interestingly, the 19q13.33 locus, which was
identified as pleiotropic loci for 2 pairs of traits, was only co-
localized between PUD and schizophrenia (PP.H4 = 0.8927)
rather than PUD and ADHD (PP.H4 = 0.3552), with the same
potential shared causal variant rs681343 identified (mapped
gene: FUT2). In addition, 7 pleiotropic loci were identified with
PP.H3 larger than 0.7000, indicating there might be different
causal variants in these loci (eTable 8 in Supplement 1).
Prioritization of Candidate Pleiotropic Genes
and Characterization of Phenotype and Tissue Specificity
MAGMA analysis based on 295 potential pleiotropic genes that
located in or overlapped with 83 pleiotropic loci identified 196
significant pleiotropic genes (158 unique), in which 38 genes
were detected in 2 or more trait pairs (eTable 9 in Supple-
ment 1). For example, NCAM1 was identified as a significant
pleiotropic gene in 5 pairs of traits, followed by INAVA,
CACNA1S (OMIM 114208), and KIF21B (OMIM 608322) in 4 pairs
of traits and BANK1 (OMIM 610292), CAMKV (OMIM 614993),
DPYD (OMIM 612779), MON1A (OMIM 611464), MST1R (OMIM
600168), PSCA (OMIM 602470), RBM5 (OMIM 606884), RBM6
(OMIM 606886), and SLC39A8 in 3 pairs of traits.
Further parallel phenotype and tissue-specific enrich-
ment analysis suggested both higher phenotype and tissue
specificity (Figure 3). Specifically, we obtained in total 19 326
genes with available phenotype annotations resorting to Mouse
Genome Informatics platform, in which 144 of 158 unique pleio-
tropic genes were included. These pleiotropic genes were as-
sociated with several GBA-related phenotypes with the analy-
ses performed on each phenotype (Figure 3A) and were
associated with the 2 phenotypes simultaneously (behavior-

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 Research Original Investigation
Figure 3. Phenotype and Tissue Specificity for Candidate Pleiotropic Genes
A Enrichment of pleiotropic genes
Phenotype
MP:0005381 digestive/alimentary
MP:0010768 mortality/aging
MP:0005384 cellular
MP:0005387 immune system
MP:0005386 behavior neurological
MP:0003631 nervous system
MP:0005380 embryo
0 10
B Gene associations with phenotypes
Pleiotropic
MP:0005386 or MP:0005381
MP:0005386 and MP:0005381 P = 1.8×10–2
Nonpleiotropic
MP:0005386 or MP:0005381
MP:0005386 and MP:0005381 P = 1.8×10–2
0 0.1
C Tissue-specific enrichment analysis using GTEx reference panel
GTEx tissue
Adrenal gland
Stomach
Colon-transverse
Small intestine-terminal ileum
0 5
D Tissue-specific enrichment analysis using ENCODE reference panel
ENCODE tissue
Stomach
Diencephalon
Adrenal gland
Peyer's patch
Liver
0 5
neurological phenotype and digestive-alimentary pheno-
type), contrasting with that of nonpleotropic genes with
less association with these phenotypes (7.64% vs 3.61%;
P = 1.80 × 10−2) (Figure 3B). Details of these genes were pro-
vided in eTable 10 in Supplement 1. Tissue-specific enrich-
ment analysis using deTS based on GTEx and ENCODE refer-
ence panels suggested higher tissue specificity (Figure 3)
in several gastrointestinal tract and brain tissues, such as
stomach, transverse colon, terminal ileum of small intestine,
Peyer’s patch, and diencephalon. The hypothalamic-pituitary-
adrenal axis is an important component of the GBA and could
provide primary biological response to stressful stimuli, with
adrenal gland especially highlighted. Details of these tissue-
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Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders
P = 1.88×10–4
P = 3.4×10–3
P = 4.91×10–3
P = 1.04×10–2
P = 1.28×10–2
P = 1.75×10–2
P = 2.32×10–2
20 30 40 50 60 70
No. of genes
P = 2.04×10–4
Phenotype enrichment analysis
based on existing mouse/human
orthology with phenotype
P = 2.04×10–4 annotations from the Mouse Genome
Informatics platform suggested
7 phenotypes in which the significant
0.2 0.3 0.4 0.5 0.6 pleiotropic genes were enriched (A)
Proportion
and both the proportions of the
genes associated with at least 1 of
2 gut-brain axis–related phenotypes
or associated with both phenotypes
(behavior-neurological phenotype
P = 6.95×10–4 and digestive-alimentary phenotype)
in the pleiotropic gene group were
P = 6.95×10–4
higher (B). Detailed information of
P = 8×10–3 phenotype annotations for these
P = 3.11×10–2 genes was provided in eTable 10
in Supplement 1. Tissue-specific
10 15 20 25 enrichment analysis using the deTS
No. of genes method based on 2 reference panels
showed higher tissue specificity,
4 significantly enriched tissues were
identified when using the
Genotype-Tissue Expression project
P = 6.26×10–3 (GTEx) reference panel (C), and
P = 1.29×10–2 5 were identified when using the
Encyclopedia of DNA Elements
P = 1.30×10–2
project (ENCODE) reference panel
P = 2.57×10–2 (D). Detailed information of
P = 4.77×10–2 tissue-specific genes was provided
in eTables 11 and 12 in Supplement 1.
10 15 20 25 We declared the nominally
No. of genes significant threshold (2-sided P < .05)
in both analyses.
specific genes were also provided (eFigure 4 and eTables 11 and
12 in Supplement 1).
In addition, E-MAGMA and joint-tissue imputation analy-
sis also confirmed the tissue specificity not only in gastroin-
testinal tract and brain tissues but also in other GBA-related
tissues. In total, 52 pleiotropic genes (22 unique) across 8
pleiotropic loci were significantly detected in multiple
GBA-related tissues in at least 2 trait pairs, for example, PSCA
(8q24.3) for 3 pairwise traits (PUD-schizophrenia, PUD-BIP, and
schizophrenia-AN), LPR8 (1p32.3) for 2 pairwise traits (IBS-
schizophrenia and IBS-BIP), and FUT2 (19q13.33) for 2 pair-
wise traits (PUD-schizophrenia and PUD-ADHD). H-MAGMA
analysis further suggested the cell-type specificity of these
jamapsychiatry.com
 Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders
pleiotropic genes. Details of these gene-level analyses were also
provided (eTables 13-15 in Supplement 1).
Synaptic and Immune-Related Mechanisms Shared Between
Gastrointestinal Tract Diseases and Psychiatric Disorders
Gene set enrichment analysis identified 127 significantly
enriched pathways (normalized enrichment score >2 and ad-
justed P < .05), including 99 Gene Ontology (GO) terms and
28 Kyoto Encyclopedia of Genes and Genomes (KEGG) path-
ways (eTable 16 in Supplement 1). These enriched pathways
are mainly involved in cell adhesion, synaptic structure and
function, and immune cell differentiation. For example,
homophilic cell adhesion via plasma membrane adhesion mol-
ecules (GO:0007156), which plays important roles in neural
and immune mechanisms, was identified in 5 pairs of traits.
A γ-aminobutyric acid (GABA)–modifying synapse (GO:
0098982), which typically functions as an inhibitory syn-
apse using GABA as neurotransmitter, was significantly en-
riched in 3 pairs of traits. Notably, both T helper 1 (TH1) and
TH2 cell differentiation (KEGG has04658) and TH17 cell differ-
entiation (KEGG has04659), which involve in immunoinflam-
matory responses, were highlighted in 2 pairs of traits.
Multitrait Colocalization Analysis to Pinpoint
Critical Gut Microbiomes
Multitrait colocalization analysis from HyPrColoc high-
lighted 15 pleiotropic loci (11 unique) that were colocalized to
share a causal variant, supporting the significant role of gut
microorganisms (Figure 2 and eTable 17 in Supplement 1).
Seven of 11 unique loci were identified to be colocalized among
schizophrenia, gastrointestinal tract diseases, and gut micro-
organisms. For example, 19q13.33 was particularly colocal-
ized between PUD and schizophrenia not only with the preva-
lence of Ruminococcaceae species but with the abundance of
Bacteroides species, where the index SNV rs681343 (mapped
gene: FUT2) was also identified as shared causal variant.
Mendelian Randomization and Associations Between
Gastrointestinal Tract Diseases and Psychiatric Disorders
Bidirectional mendelian randomization analyses using inverse-
variance weighted method showed 11 significant positive
associations (eFigure 5 and eTable 18 in Supplement 1).
In addition, no significant bidirectional associations were
detected in negative control analysis (eTable 19 in Supple-
ment 1). The results from several alternative mendelian ran-
domization methods were largely consistent with that from
main analysis (eTables 18 and 19 in Supplement 1). Notably,
among 5 pairwise traits with potential sample overlap, LHC-MR
further validated the results (eTable 20 in Supplement 1).
Discussion
In this genome-wide pleiotropic association study, we found
extensive genome-wide genetic correlations and genetic over-
laps between gastrointestinal tract diseases and psychiatric
disorders. Further comprehensive analyses highlighted the
pleiotropic genetic variants and loci, potential shared causal
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Original Investigation Research
variants, pleiotropic genes, biological pathways, and a poten-
tial genetic basis associated with gut microbiome. All these
findings supported the role of GBA in the shared genetic eti-
ology underlying these 2 types of diseases.
Using multiple methods with different model assump-
tions could provide complementary evidence and allow deep
investigation of the underlying pleiotropic associations from
different perspectives. The GPA identified substantial ge-
netic overlap between several trait pairs even without any
significant genetic correlation. The mixed directions across the
genomic risk loci, which indicate the existence of concordant
and discordant pleiotropy, also help explain the polygenic over-
lap despite nonsignificant genetic correlation. PLACO analy-
sis further determines the pleiotropic variants, followed by
colocalization analysis to identify potential shared causal
variants in each pleiotropic locus. Mendelian randomization
analysis could detect causal trait pairs and partially reflect
vertical pleiotropy. Of note, we conducted LDSC to examine
potential sample overlap and performed pleiotropic analysis
using PLACO as well as mendelian randomization analysis using
LHC-MR to alleviate sample overlap issue. The LDSC and men-
delian randomization analyses were of comparable consis-
tency with previous studies, with detailed comparisons pro-
vided (eTables 21-23 in Supplement 1).
Overall, pleiotropic variants between gastrointestinal tract
diseases and psychiatric disorders were extensively distrib-
uted, with several loci especially highlighted between cer-
tain trait pairs, such as 1q32.1 (INAVA), 19q13.33 (FUT2), 11q23.2
(NCAM1), and 1p32.3 (LRP8). Several loci previously identi-
fied to be associated with gastrointestinal tract diseases were
illustrated to be potential pleiotropic loci shared with psychi-
atric disorders and vice versa (eDiscussion in Supplement 1).
The pleiotropic genes were more likely to be enriched in
GBA-related phenotypes, such as behavioral, neurological, and
digestive phenotypes, as well as GBA-related tissues, espe-
cially gastrointestinal and brain tissues.
Shared genetic determinants also reflect common biologi-
cal pathways, among which the TH1, TH2, and TH17 cell differ-
entiation pathways were highlighted between IBD and schizo-
phrenia, BIP, and AN. The TH17 cells play important roles in the
development of inflammatory responses and autoimmune
diseases.56-58 Previous studies suggested the significant role of
dysfunction of TH17 cell differentiation and the accumulation
of TH17-related cytokines in the pathological process of IBD.59,60
In addition, TH17 cells and related cytokines would provoke
CNS neuroinflammation and neurotoxicity under pathologi-
cal status and disrupt the blood-brain barrier and thus alter the
permeability of the blood-brain barrier.61,62 Bacterially pro-
duced bile acid metabolites have been shown to inhibit TH17 cell
differentiation, which may be related to the pathophysiology
of IBD.63 Therefore, TH17 cell differentiation and function play
a vital role in the regulation of brain-gut-microbiome axis.
Limitations
Our study is not without limitations. First, we were unable to
assess the causal effects of gut microbiome on gastrointesti-
nal tract diseases or psychiatric disorders through mendelian
randomization analyses since SNVs with associated gut mi-
(Reprinted) JAMA Psychiatry Published online February 8, 2023 E9
 Research Original Investigation Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders

croorganisms were hard to obtain due to the limited sample
size of gut microbiome GWAS. Therefore, caution should be
used on the interpretation of the role of gut microorganisms.
Second, our study was restricted to European ancestry and may
not generalize to other ancestries.
Conclusions
Given strong evidence of genetic correlation and genetic over-
lap between gastrointestinal tract diseases and psychiatric
disorders, we found that pleiotropic genetic variants, loci, and
genes were extensively distributed across the genome, with
higher phenotype and tissue specificity. We highlighted some
genetic determinants previously associated with gastrointes-
tinal tract diseases that were shared with psychiatric disor-
ders and vice versa. More importantly, shared biological mecha-
nisms concerning immune response, synaptic structure and
function, and potential gut microbiome were identified. Our
findings not only support the shared genetic basis underly-
ing GBA but provide novel insight into the intervention and
treatment targets of these diseases.

ARTICLE INFORMATION REFERENCES Consortium. Cross-disorder analysis of

Accepted for Publication: December 4, 2022.
Published Online: February 8, 2023.
doi:10.1001/jamapsychiatry.2022.4974
Open Access: This is an open access article
distributed under the terms of the CC-BY License.
© 2023 Gong W et al. JAMA Psychiatry.
Author Contributions: Dr Yuan had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis. Mr Gong and Ms Guo contributed
equally.
Concept and design: Yuan.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: Gong, Guo.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Gong, Guo, Li, L. Liu, Yan, S. Liu,
Zhou.
Obtained funding: Yuan.
Administrative, technical, or material support:
Wang, Xue, Yuan.
Supervision: Yuan.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by
grants 82173624 and 81872712 from the National
Natural Science Foundation of China (Dr Yuan),
grant ZR2019ZD02 from the Natural Science
Foundation of Shandong Province (Dr Yuan),
the Taishan Scholar Project of Shandong Province
(Dr Yuan), and Cheeloo Young Talent Program
of Shandong University (Dr Yuan).
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review,
or approval of the manuscript; and decision to
submit the manuscript for publication.
Additional Contributions: The Program in
Complex Trait Genomics (https://cnsgenomics.com/
content/data), GWAS Catalog (https://www.ebi.ac.
uk/gwas/), the Psychiatric Genomics Consortium
(https://www.med.unc.edu/pgc/), Regensburg GEM
Platform (https://www.uni-regensburg.de/medizin/
epidemiologie-praeventivmedizin/genetische-
epidemiologie/gwas-summary-statistics/index.
html), and GWAS Atlas (https://atlas.ctglab.nl/
traitDB) provided access to genome-wide
association study data. We thank all research
participants who provided DNA samples for these
studies.
Data Sharing Statement: See Supplement 2.
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