European Neuropsychopharmacology 86 (2024) 49–54

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European Neuropsychopharmacology
journal homepage: www.sciencedirect.com/journal/european-neuropsychopharmacology

SHORT COMMUNICATION

Shared vulnerability and sex-dependent polygenic burden in

psychotic disorders
Marina Mitjans a, b, o, p, 1, * , Sergi Papiol c, d, p, 1 , Mar Fatjó-Vilas e, f, p , Javier González-Peñas g ,
Miriam Acosta-Díez f , Marina Zafrilla-López f , Javier Costas h , Celso Arango g, p ,
Elisabet Vilella i, p , Lourdes Martorell i, p , M Dolores Moltó j, k, p , Julio Bobes l, p ,
Benedicto Crespo-Facorro m, p , Ana González-Pinto n, p , Lourdes Fañanás f, o, p , Araceli Rosa f, o, p, 1 ,
Bárbara Arias f, o, p, 1
a
Departament Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
b
Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues de Llobregat, Spain
c
Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany
d
Max Planck Institute of Psychiatry, Munich, Germany
e
FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain
f
Departament Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
g
Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, School of Medicine,
Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
h
Psychiatric Genetics group, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela
(CHUS), Santiago de Compostela, Galicia, Spain
i
Hospital Universitari Institut Pere Mata, Institut d’Investigació Sanitària Pere Virgili-CERCA, Universitat Rovira i Virgili, Reus, Spain
j
INCLIVA Biomedical Research Institute, Fundación Investigación Hospital Clínico de Valencia
k
Department of Genetics, Universitat de València, Valencia, Spain
l
Department of Psychiatry, Universidad de Oviedo, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Neurociencias del
Principado de Asturias (INEUROPA), Servicio de Salud del Principado de Asturias (SESPA) Oviedo, Spain
m
University Hospital Virgen del Rocio/IBiS/CSIC-Department of Psychiatry, School of Medicine, University of Sevilla, Sevilla, Spain
n
BIOARABA Health Research Institute, OSI Araba, University Hospital, University of the Basque Country, Vitoria, Spain
o
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
p
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

A R T I C L E I N F O A B S T R A C T

Keywords: Evidence suggests a remarkable shared genetic susceptibility between psychiatric disorders. However, sex-
Psychotic disorders dependent differences have been less studied. We explored the contribution of schizophrenia (SCZ), bipolar
Polygenic scores disorder (BD) and major depressive disorder (MDD) polygenic scores (PGSs) on the risk for psychotic disorders
Shared genetics
and whether sex-dependent differences exist (CIBERSAM sample: 1826 patients and 1372 controls). All PGSs
Sex differences
were significantly associated with psychosis. Sex-stratified analyses showed that the variance explained in
psychotic disorders risk was significantly higher in males than in females for all PGSs. Our results confirm the
shared genetic architecture across psychotic disorders and demonstrate sex-dependent differences in the
vulnerability to psychotic disorders.

1. Introduction worldwide affecting approximately 3 % of the general population

(Perälä et al., 2007). Epidemiological and genetic studies show both
Psychotic disorders rank among the leading causes of disability high heritability and a complex genetic architecture, with a significant

* Corresponding author at: Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Av. Diagonal 645, 08028 Barcelona,
Spain.
E-mail address: marina.mitjans@ub.edu (M. Mitjans).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.euroneuro.2024.04.017
Received 29 January 2024; Received in revised form 21 April 2024; Accepted 27 April 2024
Available online 27 June 2024
0924-977X/© 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
M. Mitjans et al. European Neuropsychopharmacology 86 (2024) 49–54

proportion of heritability contributed by common variants (Gratten 2.3. Statistical analysis

et al., 2014).
Recent genome-wide association studies (GWAS) have identified a The statistical power of our sample was estimated with AVENGEME
large number of risk loci that only convey modest increases in risk (Palla and Dudbridge, 2015).Our study had more than 90 % power
individually. The combination of these genetic variants into a polygenic (α = 0.05) to detect effects of PGSs with an R2 ≥ 2.21 % (SCZ-PGS), R2
score (PGS) constitutes a robust disease risk index. GWAS have also ≥ 0.90 % (BD-PGS), and R2 ≥ 0.37 % (MDD-PGS) on the risk of broadly
provided molecular evidence for a common genetic architecture among defined psychosis.
psychiatric disorders, clustering schizophrenia (SCZ), bipolar disorder Statistical analyses were performed with R program 4.1.3 (https://
(BD) and major depressive disorder (MDD) in the mood and psychotic www.R-project.org/). Logistic regression models were used to associate
disorders group, with the largest genetic correlation (rg) between SCZ psychotic disorder diagnosis with SCZ-PGS, BD-PGS and MDD-PGS,
and BD (rg=0.70) (Lee et al., 2021). Polygenic analyses in pilot studies including sex, CIBERSAM group and the first ten PCs as covariates.
within the psychotic disorder spectrum have already shown a substan­ For each PGS, two models were built: 1) baseline model including only
tial SCZ polygenic risk overlap between some of the diagnostic groups covariates and 2) full model including PGS plus covariates. The pro­
defined under this category (Smigielski et al., 2021). portion of variance explained by the PGS was calculated by the differ­
The analysis of sex-dependent differential genomic load still repre­ ence between the Nagelkerke’s pseudo-R2 values of the full model and
sents an under-explored area in large-scale genomics of mental disorder. the baseline model. Nagelkerke’s pseudo-R2 were converted to liability
However, it has been long reported the existence of sex differences in scale as proposed by Lee et al. (Lee et al., 2012) and assuming a prev­
psychotic disorders (Riecher-Rössler et al., 2018). To our knowledge, alence of 1 % in the general population. Following the same afore­
sex-stratified PGS analyses examining the genetic contribution to psy­ mentioned procedure, we assessed PGS contribution to psychotic
chotic disorders risk among males and females have not been previously disorders risk in males and females separately, including CIBERSAM
investigated. group and the first ten PCs as covariates. In order to statistically compare
The aim of this study was to evaluate whether PGSs for SCZ, BD and the variances explained between males and females we performed
MDD are associated with psychotic disorders in a large sample of pa­ bootstrap resampling (5000 permutations) of 400 psychotic disorder
tients with broadly defined psychosis and healthy subjects. In addition, and 400 control subjects across males and females separately, and
we also explored whether genetic sex differences exist in those calculated explained variance predictions by logistic regression and R2
associations. estimations on the liability scale for all PGSs (SCZ, BD and MDD). For
each PGS, we statistically compared the differences between the distri­
2. Experimental procedures bution of liability R2 in males and females with two-sided t-tests.
In secondary analyses, subjects were ranked from lower to higher
2.1. Sample description according to each PGS (SCZ, BD and MDD) adjusted for sex, CIBERSAM
group and the first ten PCs (sex was excluded in sex-stratified analyses)
The sample consisted of 3198 unrelated individuals of European and divided into quartiles. Odds ratios (ORs) were calculated based on
ancestry: 1826 patients (33.23 % females) with a range of psychotic the case-control ratio in each quartile using the lowest quartile as
disorders (Supplementary Table 1) and 1372 healthy controls (45.70 % reference. Bonferroni correction was applied to correct for multiple
females). Participants were recruited as part of the Spanish sample testing. The criterion for significance was set at p < 0.0056 (0.05/9).
collection of CIBERSAM (Mental Health Networking Biomedical
Research Centre) (Andreu-Bernabeu et al., 2022; Sada-Fuente et al., 3. Results
2023). All patients met the DSM-IV diagnostic criteria for psychotic
disorders. Healthy controls were recruited after being screened for We found an association between all PGSs and broadly defined
psychiatric illness. All participants provided written informed consent, psychosis in our sample. SCZ-PGS explained the highest percentage of
and the study was approved by the different ethical committees at the the variance of psychotic disorders in the liability scale (R2 = 8.274 %; p
hospitals involved in the recruitment. < 2 × 10− 16), followed by BD-PGS (R2 = 2.414 %; p < 2 × 10− 16) and
MDD-PGS (R2 = 0.268 %; p = 6.60 × 10− 04) (Fig. 1A and Supplementary
2.2. Genetic analysis Table 2). Sensitivity analyses showed that only using SCZ/schizo­
affective samples (91.8 % of patients) yielded very similar results to
Samples were genotyped with the Infinium PsychArray from Illu­ those obtained with the whole sample (Supplementary Table 3). Despite
mina. Data quality control was done following standard quality control the small sample size, the analyses of the remaining sample with other
procedures (Trubetskoy et al., 2022). Imputation was conducted in the psychotic diagnoses (8.2 % of patients), also showed similar results to
Michigan Imputation Server (www.imputationserver.sph.umich.edu) those observed for the full sample (Supplementary Table 3).
and only SNPs with an rsq > 0.3 and MAF > 0.01 were retained for In the analyses of sex-specific genetic load in psychotic disorders, the
subsequent analyses. variance explained was higher in males than in females for all PGS
Ancestry principal components (PCs) on the 3198 individuals who (Fig. 1A, Supplementary Table 2). When we statistically compared these
passed QC were calculated using PLINK v.1.9 (Chang et al., 2015). For sex-based differences, all PGS explained significantly more variance in
the sex-stratified and sensitivity analyses, PCs were recalculated in the psychotic disorders risk in males than in females (SCZ-PGS: t = 96.704,
respective groups. df = 9458.4, p < 2.2 × 10− 16; BD-PGS: t = 12.895, df = 9997.8, p < 2.2
PGSs were calculated from best-guess genotypes after imputation × 10− 16; MDD-PGS: t = 23.472, df = 9479.7, p < 2.2 × 10− 16) (Fig. 1B).
based on the following GWAS summary statistics: SCZ (Trubetskoy et al., Lastly, quartile analyses (all, males, and females) based on SCZ-PGS,
2022) (leave-one-out analyses excluding the CIBERSAM sample), BD BD-PGS and MDD-PGS showed a significant progressive increase in the
(Mullins et al., 2021) and MDD (Wray et al., 2018). PRS continuous case-control ratio in all higher quartile categories for SCZ and BD-PGS,
shrinkage (PRS-CS) tool was used to infer posterior SNP effect sizes and, to a lesser extent, MDD-PGS (Fig. 1C and Supplementary
under continuous shrinkage priors and to estimate the global shrinkage Table 4). Compared with individuals in the first quartile, those at the
parameter (φ) using a fully Bayesian approach (Ge et al., 2019). The highest quartile had an OR for psychotic disorder risk of 6.037 (95 % CI
resulting corrected effect sizes after PRS-CS were then used to calculate 4.847–7.518) for SCZ-PGS, 2.511 (95 % CI 2.048–3.078) for BD-PGS,
individual risk scores using PLINK v.1.9 (Chang et al., 2015). and 1.302 (95 % CI 1.066–1.590) for MDD-PGS. Males and females
showed the same pattern although this was less obvious in MDD-PGS
sex-stratified analyses (Fig. 1C and Supplementary Table 4).

50
M. Mitjans et al. European Neuropsychopharmacology 86 (2024) 49–54

(caption on next page)

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M. Mitjans et al. European Neuropsychopharmacology 86 (2024) 49–54

Fig. 1. A) Percentage of the variance in psychotic disorder risk explained by SCZ-PGS (left), BD-PGS (middle) and MDD-PGS (right) in all patients with psychotic
disorders and in males and females separately. Statistically significant p-values after Bonferroni correction are indicated by stars. B) PGS predictions in case-control
subsamples after bootstrap resampling (5000 permutations) of 400 psychotic disorders patients and 400 healthy controls (selected from the overall CIBERSAM case-
control sample) were performed in males and females, separately. Mean variance explained by SCZ-PGS (left panel), BD-PGS (middle panel) and MDD-PGS (right
panel) on the liability scale (estimated prevalence of 0.01) in males and females. Variance explained in females and males was statistically compared with two-sided t-
tests and is marked with an asterisk when it is significantly different (p < 0.05). C) ORs of psychotic disorders according to quartile distribution of SCZ (left), BD
(middle) and MDD-PGS (right). Subjects were ranked according to each PGS adjusted for sex, CIBERSAM group and the first 10 principal components (PCs)
(CIBERSAM group and 10 PCs in the sex-stratified analyses) from lower to higher and divided into quartiles. The y-axis corresponds to the observed OR (log scale),
and the 95 % confidence intervals. Each quartile is compared with the 1st quartile (baseline). SCZ: Schizophrenia; BD: Bipolar Disorder; MDD: Major Depressive
Disorder; PGS: Polygenic Score.

4. Discussion Methodology, Formal analysis, Visualization, Writing – original draft,

Writing – review & editing. Mar Fatjó-Vilas: Resources, Writing – re­
In this study we show that PGSs for severe mental disorders (SCZ, BD view & editing. Javier González-Peñas: Methodology, Writing – review
and MDD) are associated with broadly defined psychosis in an inde­ & editing. Miriam Acosta-Díez: Writing – review & editing. Marina
pendent Spanish sample, emphasizing the shared genetic architecture Zafrilla-López: Writing – review & editing. Javier Costas: Writing –
among these psychiatric disorders (Lee et al., 2021). review & editing. Celso Arango: Resources, Writing – review & editing.
Our results replicate the ones reported in a previous study investi­ Elisabet Vilella: Resources, Writing – review & editing. Lourdes
gating the association of SCZ-PGS and BD-PGS with psychotic disorders Martorell: Resources, Writing – review & editing. M Dolores Moltó:
in a smaller dataset (Calafato et al., 2018). Regarding the MDD-PGS Resources, Writing – review & editing. Julio Bobes: Resources, Writing
analyses, as far as we know, this is the first study investigating its as­ – review & editing. Benedicto Crespo-Facorro: Resources, Writing –
sociation with broadly defined psychosis. review & editing. Ana González-Pinto: Resources, Writing – review &
Our sensitivity analyses show a similar SCZ / BD / MDD polygenic editing. Lourdes Fañanás: Resources, Writing – review & editing.
architecture across all broad psychotic diagnoses included in this study. Araceli Rosa: Conceptualization, Supervision, Resources, Writing –
Although psychotic disorders present sex differences in age at onset, review & editing. Bárbara Arias: Conceptualization, Supervision, Re­
symptom profile, course and outcome, specific sex-dependent differ­ sources, Writing – review & editing.
ences at the genetic level have been under-explored. To our knowledge,
this is the first study that using PGS analyses captures sex-dependent Author disclosures
differences in the shared genetic vulnerability between mood and psy­
chotic disorders. Our results are in line with recent findings suggesting CA has been a consultant to or has received honoraria or grants from
that sex differences in the genetic architecture of neuropsychiatric and Abbot, Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen
behavioural traits exist but are small and polygenic (Martin et al., 2021). Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche,
The largest genome-wide genotype-by-sex analysis of mood and psy­ Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma,
chotic disorders to date, reported significant sex-dependent effects Sunovion, Takeda and Teva. JB received consulting fees from Takeda as
across and within SCZ, BD, and MDD (Blokland et al., 2022). Moreover, members of the Advisory Board. JB received research grants and served
sex-specific effects of SCZ-PGS have been reported on cognitive func­ as consultant, advisor, or speaker within the last 3 years for: AB-Biotics,
tioning across the lifespan (Koch et al., 2021). Although the clinical Acadia Pharmaceuticals, Alkermes, Angelini, Ambrosetti-Angelini, Bio­
utility of PGS is very limited in the context of psychiatric disorders, our gen, Casen Recordati, D&A Pharma, Exeltis, Gilead, Indivior, GW
findings highlight the importance of considering women and men Pharmaceuticals, Janssen-Cilag, Jazz Pharmaceuticals, Lundbeck,
separately when transferring polygenic scores to clinical practice in the Otsuka, Pfizer, Roche, Sage Therapeutics, Servier, Shire, Takeda. In
future. This will help to optimally inform sex-specific prevention, addition, JB received research funding from the Spanish Ministry of
diagnosis and treatment strategies. Economy and Competitiveness—Centro de Investigación Biomedica en
Our study was subject to some limitations. First, a slight lack of Red area de Salud Mental (CIBERSAM), and Instituto de Salud Carlos III,
statistical power has to be acknowledged due to a limited sample size Spanish Ministry of Health. AG-P has received grants and served as
(De Prisco and Vieta, 2024), specifically in the sex-stratified analyses. consultant, advisor or CME speaker for the following entities: Janssen-
Second, the small effect sizes detected suggest that environmental var­ Cilag, Lundbeck, Otsuka, Alter, Angelini, Novartis, Rovi, Takeda, the
iables are likely to play a substantial role in these associations. Future Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of
PGS analyses may also incorporate environmental factors as well as Science (Carlos III Institute), the Basque Government, and the European
gene–environment interactions, thereby improving the performance of Framework Program of Research. The rest of the authors declare no
PRSs. Third, ascertainment and participation bias may confound iden­ competing interests.
tification of true sex differences. Fourth, the dataset used in our analyses
consisted exclusively of individuals of European ancestry, and thus the Acknowledgments
extrapolation of our findings to other ancestries should not be done
straightforwardly. We would particularly like to thank the study participants for their
Taken together, our results emphasize the use of transdiagnostic contribution and the clinicians and research staff who contributed to
approaches which recognise the multidimensionality of psychopathol­ patient recruitment and management of data.
ogy and enable the investigation of shared genetic risk factors. More­
over, understanding the genetic basis of sex differences in psychiatric Role of funding source
disorders is crucial for developing sex-stratified diagnostics and thera­
peutics and for paving the way for precision medicine. This research was funded by: i) the Institute of Health Carlos III
through projects (PI17/01122, PI18/00467, PI20/01002, PI22/00431,
CRediT authorship contribution statement PI21/00713, PI12/02111; PI12/01885; PS09/01052) and contract
(CP20/00072 to MFV), co-funded by European Regional Development
Marina Mitjans: Conceptualization, Data curation, Methodology, Fund (ERDF)/European Social Fund “Investing in your future”, ii)
Formal analysis, Visualization, Writing – original draft, Writing – review SAF2007–60086, iii) the Comissionat per a Universitats i Recerca del
& editing. Sergi Papiol: Conceptualization, Data curation, DIUE of the Generalitat de Catalunya (AGAUR: 2021SGR01093;

52
M. Mitjans et al. European Neuropsychopharmacology 86 (2024) 49–54

2021SGR00706; 2021SGR01475; 2017SGR444), iv) LaMarató TV3 Martin, J., Khramtsova, E.A., Goleva, S.B., Blokland, G.A.M., Traglia, M., Walters, R.K.,
Hübel, C., Coleman, J.R.I., Breen, G., Børglum, A.D., Demontis, D., Grove, J.,
(202203-30-31-32). Grants PID2022–139740OA-I00 and
Werge, T., Bralten, J., Bulik, C.M., Lee, P.H., Mathews, C.A., Peterson, R.E.,
PID2021–1277760B-I00 funded by MICIU/AEI/10.13039/ Winham, S.J., Wray, N., Edenberg, H.J., Guo, W., Yao, Y., Neale, B.M., Faraone, S.V.,
501100011033 and by FEDER, EU. MM was supported by Horizon 2020 Petryshen, T.L., Weiss, L.A., Duncan, L.E., Goldstein, J.M., Smoller, J.W., Stranger, B.
Marie Sklodowska-Curie Individual Fellowship from the European E., Davis, L.K., 2021. Examining sex-differentiated genetic effects across
neuropsychiatric and behavioral traits. Biol. Psychiatry 89, 1127–1137. https://doi.
Commission under grant agreement no. 841899 (GRASAD). This article org/10.1016/j.biopsych.2020.12.024.
is part of the grant RYC2021–033573-I funded by MICIU/AEI/ Mullins, N., Forstner, A.J., O’Connell, K.S., Coombes, B., Coleman, J.R.I., Qiao, Z., Als, T.
10.13039/501100011033 and by the European Union “NextGener­ D., Bigdeli, T.B., Børte, S., Bryois, J., Charney, A.W., Drange, O.K., Gandal, M.J.,
Hagenaars, S.P., Ikeda, M., Kamitaki, N., Kim, M., Krebs, K., Panagiotaropoulou, G.,
ationEU”/PRTR”. Founders had no further role in study design; in the Schilder, B.M., Sloofman, L.G., Steinberg, S., Trubetskoy, V., Winsvold, B.S.,
collection, analysis and interpretation of data; in the writing of the Won, H.-H., Abramova, L., Adorjan, K., Agerbo, E., Al Eissa, M., Albani, D., Alliey-
report; and in the decision to submit the paper for publication. Rodriguez, N., Anjorin, A., Antilla, V., Antoniou, A., Awasthi, S., Baek, J.H., Bækvad-
Hansen, M., Bass, N., Bauer, M., Beins, E.C., Bergen, S.E., Birner, A., Bøcker
Pedersen, C., Bøen, E., Boks, M.P., Bosch, R., Brum, M., Brumpton, B.M., Brunkhorst-
Supplementary materials Kanaan, N., Budde, M., Bybjerg-Grauholm, J., Byerley, W., Cairns, M., Casas, M.,
Cervantes, P., Clarke, T.-K., Cruceanu, C., Cuellar-Barboza, A., Cunningham, J.,
Curtis, D., Czerski, P.M., Dale, A.M., Dalkner, N., David, F.S., Degenhardt, F.,
Supplementary material associated with this article can be found, in Djurovic, S., Dobbyn, A.L., Douzenis, A., Elvsåshagen, T., Escott-Price, V., Ferrier, I.
the online version, at doi:10.1016/j.euroneuro.2024.04.017. N., Fiorentino, A., Foroud, T.M., Forty, L., Frank, J., Frei, O., Freimer, N.B.,
Frisén, L., Gade, K., Garnham, J., Gelernter, J., Giørtz Pedersen, M., Gizer, I.R.,
Gordon, S.D., Gordon-Smith, K., Greenwood, T.A., Grove, J., Guzman-Parra, J.,
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