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. 2023 Jun 19;58(10):1573–1580. doi: 10.1007/s00127-023-02513-0

The relationship between genetic liability, childhood maltreatment, and IQ: findings from the EU-GEI multicentric case–control study

Lucia Sideli 1,2,3,✉, Monica Aas 2,4,5,6, Diego Quattrone 4, Daniele La Barbera 3, Caterina La Cascia 3, Laura Ferraro 3, Luis Alameda 2,7,8,9, Eva Velthorst 10, Giulia Trotta 2, Giada Tripoli 2,3,11, Adriano Schimmenti 12, Andrea Fontana 1, Charlotte Gayer-Anderson 13,14, Simona Stilo 2,15, Fabio Seminerio 3, Crocettarachele Sartorio 3, Giovanna Marrazzo 3, Antonio Lasalvia 16, Sarah Tosato 16, Ilaria Tarricone 17, Domenico Berardi 18, Giuseppe D’Andrea 18; EU-GEI WP2 Group, Celso Arango 19, Manuel Arrojo 20, Miguel Bernardo 21,22, Julio Bobes 23, Julio Sanjuán 24, Jose Luis Santos 25, Paulo Rossi Menezes 26, Cristina Marta Del-Ben 27, Hannah E Jongsma 28,29, Peter B Jones 30,31, James B Kirkbride 28, Pierre-Michel Llorca 31, Andrea Tortelli 32, Baptiste Pignon 33,34,35, Lieuwe de Haan 36, Jean-Paul Selten 37,38, Jim Van Os 2,38,39, Bart P Rutten 38, Richard Bentall 40, Marta Di Forti 4, Robin M Murray 2, Craig Morgan 13,14,#, Helen L Fisher 4,14,#
PMCID: PMC10460355  PMID: 37335320

Abstract

This study investigated if the association between childhood maltreatment and cognition among psychosis patients and community controls was partially accounted for by genetic liability for psychosis. Patients with first-episode psychosis (N = 755) and unaffected controls (N = 1219) from the EU-GEI study were assessed for childhood maltreatment, intelligence quotient (IQ), family history of psychosis (FH), and polygenic risk score for schizophrenia (SZ-PRS). Controlling for FH and SZ-PRS did not attenuate the association between childhood maltreatment and IQ in cases or controls. Findings suggest that these expressions of genetic liability cannot account for the lower levels of cognition found among adults maltreated in childhood.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00127-023-02513-0.

Keywords: Childhood adversity, Cognition, Family history of psychosis, First episode, Polygenic risk score, Psychosis

Introduction

Literature suggests that the association between childhood maltreatment (i.e., abuse and neglect) and later cognitive functioning might be weaker among people with psychosis compared with unaffected controls [1]. Indeed, in a previous study on the EU-GEI sample of patients with first-episode psychosis (FEP) and community controls, we found that the association between reported exposure to maltreatment in childhood and a lower Intelligence Quotient (IQ) in adulthood was weaker among patients than controls [2]. This difference might be due to the confounding effect of other risk factors associated with both childhood maltreatment and cognition that are more prevalent among people with psychosis than unaffected controls, such as genetic liability to psychotic disorders [3–7]. Moreover, among individuals with psychosis, the impact of environmental risk factors (such as maltreatment) on cognition might be reduced by a floor effect related to genetic liability and neurodevelopmental alterations [8, 9].

Only a few studies have explored the relationship between genetic liability, childhood maltreatment, and cognition among people experiencing psychosis. For instance, the NAPLS-3 study found that among youth at clinically high risk for psychosis, family history of psychosis (FH) was associated with both greater trauma exposure and lower IQ compared with no-FH [10]. Polygenic risk scores for schizophrenia (SZ-PRS) [11, 12] have been associated with lower IQ in the general population [9, 13–15], but the findings have not consistently been replicated among people with schizophrenia [16–18]. Although SZ-PRS has also shown a modest association with childhood maltreatment [19], to our knowledge no study has investigated the role of genetic liability for psychosis in the association between childhood maltreatment and cognition.

Therefore, in this study, we aimed to investigate whether the association between childhood maltreatment (overall maltreatment, and abuse and neglect separately) and IQ could be partially accounted for by genetic liability (defined as either having FH or based on SZ-PRS). We hypothesised that genetic liability to psychosis would contribute to attenuating the association between reported exposure to maltreatment in childhood and lower IQ in adulthood among FEP patients but not among controls.

Methods

Participants and procedure

The EU-GEI study is a multi-centre case–control study carried out between May 2010 and April 2015 in five European countries and Brazil [20, 21]. The study was approved by the Internal Review Boards of the study centres and conducted according to International ethical standards.

People with FEP were individuals aged 18–64, living in the study catchment areas, who approached mental health services for the first time for a primary diagnosis of a psychotic disorder (ICD-10 diagnoses: F20–F33) during the study period. Community controls were individuals who were representative of the same population as the cases, and who had never been referred or treated for psychotic disorders. Information about inclusion and exclusion criteria, sampling methods, and diagnostic procedures, have been detailed elsewhere [21, 22] and are described in the Supplementary Materials.

Measures

Cognitive functioning was estimated from IQ, assessed using an abbreviated, psychometrically robust version of the Wechsler Adult Intelligence Scales (WAIS-III) [23–25].

Genetic liability was defined as: (a) family history of psychosis (FH) and (b) polygenic risk scores for schizophrenia (SZ-PRS). FH was defined as having a first-degree relative affected by a psychotic disorder and assessed using the Family Interview for Genetic Studies (FIGS) [26]. SZ-PRSs were calculated only on the sub-sample of European ancestry participants, using the genotype procedure, population stratification, and SZ-PRS calculation as described previously [27–29] and in the Supplementary Materials.

Self-reported exposure to childhood maltreatment was assessed using the Childhood Trauma Questionnaire (CTQ) [30]. Mean ratings for physical, sexual, and emotional abuse items were used to create a childhood abuse score, mean ratings for physical and emotional neglect items were used to create a childhood neglect score, and the mean of all items was used to create an overall childhood maltreatment score. Consistent with previous studies [2, 8], these variables were dichotomised using the 80th percentile of the control group’s score as the cut-off value. These cut-offs were identical to those used in the original study [2]. In the subset with SZ-PRS data, the empirically derived cut-off used to calculate dichotomic measures of childhood abuse (present/absent) was slightly lower than that used in the original study (1.33 vs. 1.40, respectively).

Analyses

General linear regression models stratified for cases and controls were conducted to explore whether the association between overall childhood maltreatment (and separately childhood abuse and childhood neglect) and IQ (model 1), was attenuated by the inclusion in the model of FH or SZ-PRS (model 2). The analyses were then additionally controlled for sex, age, ethnicity, education, study country, and lifetime cannabis use (model 3); and then also for current use of antipsychotics (model 4) only in the FEP group. Measurement of covariates is described in the Supplementary Materials. Results are reported as regression coefficients (B) and standardized regression coefficients (β). Analyses were run using the Statistical Package for the Social Sciences (SPSS) program version 27.0.

Results

Association between childhood maltreatment, FH, and IQ

Information about FH was available for 91.1% of the FEP cases (n = 755) and 95% of controls (n = 1219) from the original sample (see Supplementary Table 1 for sample demographics). Associations between case status and (i) childhood maltreatment and (ii) lower IQ are reported in Supplementary Table 2 and were similar to those detected in the full sample [2].

In the crude models, IQs were on average substantially lower among community controls exposed to childhood maltreatment (B =  − 5.29 [− 7.86, − 2.72], p < 0.001), childhood abuse (B =  − 6.27 [− 8.89, − 3.65], p < 0.001), and childhood neglect (B =  − 5.16 [− 7.69, − 2.63], p < 0.001), compared with unexposed controls. Among people with FEP, only childhood neglect was associated with lower IQ (B =  − 2.90 [− 5.50, − 0.29], p = 0.029) (see Table 1 & Supplementary Table 3)—and to a more modest extent than among controls.

Table 1.

Association between childhood maltreatment and IQ controlled for family history of psychosis and social and clinical confounders

Unstandardized models Model 1 Model 2 Model 3 Model 4
B 95% CI p Ba 95% CI p Ba+b 95% CI p Ba+b+c 95% CI p
Controls N = 1219 N = 1219 N = 1216
 Overall maltreatment*  − 5.29  − 7.86, − 2.72  < 0.001  − 5.25  − 7.82; − 2.68  < 0.001  − 2.30  − 4.55; − 0.54 0.045
 Abuse  − 6.27  − 8.89, − 3.65  < 0.001  − 6.22  − 8.85; − 3.60  < 0.001  − 3.08  − 5.36; − 0.79 0.008
 Neglect  − 5.16  − 7.69, − 2.63  < 0.001  − 5.11  − 7.65; − 2.57  < 0.001  − 2.67  − 4.91; − 0.44 0.019
FEP patients N = 755 N = 755 N = 754 N = 705
 Overall maltreatment*  − 2.17  − 4.78, − 0.45 0.104  − 2.09  − 4.71; 0.53 0.118  − 0.41  − 2.75; 1.92 0.729  − 0.07  − 2.50; 2.35 0.954
 Abuse  − 0.42  − 2.70; 2.61 0.975 0.01  − 2.65; 2.66 0.996 1.57  − 0.78; 3.92 0.191 2.25  − 0.20; 4.70 0.071
 Neglect  − 2.90  − 5.50, − 0.29 0.029  − 2.80  − 5.42; − 0.19 0.036  − 0.96  − 3.28; 1.38 0.422  − 0.63  − 3.06; 1.80 0.613
Standardized models Model 1 Model 2 Model 3 Model 4
Beta 95% CI p Betaa 95% CI p Betaa+b 95% CI p Betaa+b+c 95% CI p
Controls N = 1219 N = 1219 N = 1216
 Overall maltreatment*  − 0.30  − 0.44; − 0.15  < 0.001  − 0.30  − 0.44; − 0.15  < 0.001  − 0.13  − 0.26; − 0.00 0.045
 Abuse  − 0.35  − 0.50; − 0.21  < 0.001  − 0.35  − 0.50; − 0.20  < 0.001  − 0.17  − 0.30; − 0.04 0.008
 Neglect  − 0.29  − 0.43; − 0.15  < 0.001  − 0.29  − 0.43; − 0.15  < 0.001  − 0.15  − 0.28; − 0.03 0.019
FEP patients N = 755 N = 755 N = 754 N = 705
 Overall maltreatment*  − 0.12  − 0.26; 0.03 0.104  − 0.12  − 0.26; 0.03 0.118  − 0.02  − 0.15; 0.11 0.729  − 0.00  − 0.14; 0.13 0.954
 Abuse  − 0.00  − 0.15; 0.15 0.975  − 0.00  − 0.15; 0.15 0.996 0.09  − 0.04; 0.22 0.191 0.13  − 0.01; 0.26 0.071
 Neglect  − 0.16  − 0.30; − 0.02 0.029  − 0.16  − 0.30; − 0.01 0.036  − 0.05  − 0.18; 08 0.422  − 0.04  − 0.17; 0.10 0.613
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CI confidence intervals, FEP first-episode psychosis, IQ intelligence quotient

aAdjusted for family history of psychosis

bAdjusted for sex, age, ethnicity, education, study country, and lifetime cannabis use

cAdjusted for antipsychotic treatment

*Exposure to overall childhood maltreatment, and separately childhood abuse, and childhood neglect were defined as mean CTQ > 80th percentile of the control group; significant associations (p < 0.05) are shown in bold type

FH was more prevalent among FEP cases than among controls (OR = 3.10 [2.23, 4.31], p < 0.001). FH was associated with childhood abuse in the control group (OR = 1.94 [1.09, 3.47], p = 0.025) and with childhood neglect in both groups (controls: OR = 1.88 [1.06, 3.32], p = 0.030; FEP: OR = 1.54 [1.02, 2.33], p = 0.039). FH was not strongly associated with IQ in either group (controls: B =  − 1.95 [− 6.52, 2.62], p = 0.403; FEP: B =  − 2.10 [− 5.81, 1.62], p = 0.269) (see Supplementary Table 3). Multivariable analyses suggested that including FH in the model did not attenuate the association between childhood maltreatment and IQ in cases or in controls (see Table 1).

Association between childhood maltreatment, SZ-PRS, and IQ

Eight-hundred and fifty community controls and 488 FEP patients (i.e., 66.2% and 58.9% of the original sample, respectively) had complete measures of childhood maltreatment, IQ, and SZ-PRS (see Supplementary Table 4 for sample demographics).

In the control group, a 4–5-point decrease in IQ was associated with childhood maltreatment (B =  − 5.11 [− 8.12, − 2.10], p < 0.001), abuse (B =  − 4.27 [− 7.12, − 1.41], p = 0.003), and neglect (B =  − 5.18 [− 8.09, − 2.28], p < 0.001). In the FEP group, the association between childhood maltreatment (B =  − 1.86 [− 5.10, 1.39], p = 0.261), abuse (B =  − 0.51 [− 3.75, 2.73], p = 0.757), neglect (B =  − 2.13 [− 5.34; 1.09], p = 0.194), and IQ were of a similar size to those detected in the analyses of the full sample, although failed to reach significance.

SZ-PRS were higher in FEP cases than in controls (B = 0.54 [0.43, 0.65], p < 0.001). In the case group, SZ-PRS was modestly associated with childhood maltreatment (OR = 1.32 [1.03, 1.68], p = 0.027) and with childhood neglect (OR = 1.26 [0.99, 1.60], p = 0.060). However, in the control group, no associations were found (SZ-PRS and childhood maltreatment OR = 1.00 [0.78, 1.27], p = 0.970; abuse OR = 1.00 [0.79, 1.26], p = 0.974; neglect OR = 0.98 [0.77, 1.25], p = 0.890).

In the control group, higher SZ-PRS was marginally associated with lower IQ (B =  − 1.42 [− 2.93, 0.92], p = 0.066), as well as in the case group (p = 0.180). Multivariable analyses suggest that including SZ-PRS did not reduce the childhood maltreatment-IQ association in either the case or control group (see Supplementary Table 5).

Discussion

This study found that although FH and SZ-PRS were associated with a greater likelihood of reporting childhood maltreatment (indicating a potential gene-environment correlation), they were not so strongly associated with IQ, and did not attenuate the crude association between childhood maltreatment and IQ in either FEP cases or unaffected controls. These findings are consistent with previous studies suggesting that, although FH is three-to-seven times more common among patients compared to controls [31, 32], its effect on psychosis risk seems relatively independent from the effect of childhood maltreatment, and vice versa [33, 34].

In the subset of European ancestry participants with complete information about childhood maltreatment, IQ, and SZ-PRS, there was evidence of an association between childhood maltreatment and poor cognition, which failed to reach statistical significance among FEP cases. This is different from our previous analysis of this dataset [2] and might be due either to insufficient power, or to the exclusion of non-European ancestry FEP patients (i.e., potentially the relationship between childhood maltreatment and IQ might be more evident among non-European ancestry FEP patients), or to both. Among both cases and controls, SZ-PRS was weakly associated with IQ and did not attenuate the crude association between childhood maltreatment and IQ. This suggests that childhood maltreatment and genetic liability for schizophrenia may be independently associated with poor cognitive functioning.

In conclusion, our findings suggest that two measures of genetic liability for psychosis (FH and SZ-PRS) cannot account for the lower levels of cognition found among adults maltreated in childhood. Future research should use large longitudinal studies to prospectively investigate the impact of genetic liability and childhood maltreatment on different stages of cognitive development. Presently, the reason why the association between childhood adversity and cognition in patients with a psychotic disorder is weaker than in controls remains to be elucidated.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 87 KB) (86.7KB, docx)

Acknowledgements

The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) WP2 Group members includes: Amoretti, Silvia, PhD, Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Departament de Medicina, Institut de Neurociències (UBNeuro), Universitat de Barcelona (UB), Institut d’Investigacions Biomèdiques, August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain; Andreu-Bernabeu, Álvaro, Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain; Baudin, Grégoire, MSc, AP-HP, Groupe Hospitalier “Mondor,” Pôle de Psychiatrie, Créteil, France, Institut National de la Santé et de la Recherche Médicale, U955, Créteil, France; Beards, Stephanie, PhD, Department of Health Service and Population Research, Institute of Psychiatry, King’s College London, London, England; Bonetto, Chiara, PhD, Section of Psychiatry, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy; Bonora, Elena, PhD, Department of Medical and Surgical Science, Genetic Unit, Alma Mater Studiorium Università di Bologna, Bologna, Italy; Cabrera, Bibiana, MSc, PhD, Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, Barcelona, Spain, CIBERSAM, Spain; Carracedo, Angel, MD, PhD, Fundación Pública Galega de Medicina Xenómica, Hospital Clínico Universitario, CIBERER, Santiago de Compostela, Spain; Charpeaud, Thomas, MD, Fondation Fondamental, Créteil, France, CMP B CHU, Clermont Ferrand, France, and Université Clermont Auvergne, Clermont-Ferrand, France; Costas, Javier, PhD, Fundación Pública Galega de Medicina Xenómica, Hospital Clínico Universitario, Santiago de Compostela, Spain; Cristofalo, Doriana, MA, Section of Psychiatry, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy; Cuadrado, Pedro, MD, Villa de Vallecas Mental Health Department, Villa de Vallecas Mental Health Centre, Hospital Universitario Infanta Leonor/Hospital Virgen de la Torre, Madrid, Spain; Durán-Cutilla, Manuel, MD, Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, Institute of Psychiatry and Mental Health, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain; Ferchiou, Aziz, MD, AP-HP, Groupe Hospitalier “Mondor”, Pôle de Psychiatrie, Créteil, France, Institut National de la Santé et de la Recherche Médicale, U955, Créteil, France; Fraguas, David, MD, PhD, Biomedical Research Networking Center for Mental Health Network (CIBERSAM), Barcelona, Spain; Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, Institute of Psychiatry and Mental Health, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain; Franke, Nathalie, MSc, Department of Psychiatry, Early Psychosis Section, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Frijda, Flora, MSc, Etablissement Public de Santé Maison Blanche, Paris, France; Garcia-Portilla, Paz, MD, PhD, Department of Medicine, Psychiatry Area, School of Medicine, Universidad de Oviedo, ISPA, INEUROPA, CIBERSAM, Oviedo, Spain; González Peñas, Javier, Hospital Gregorio Marañón, IiSGM, School of Medicine, Madrid, Spain; Hubbard, Kathryn, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London; Jamain, Stéphane, PhD, Institut National de la Santé et de la Recherche Médicale, U955, Créteil, France, Faculté de Médecine, Université Paris-Est, Créteil, France, and Fondation Fondamental, Créteil, France; Jiménez-López, Estela, MSc, Department of Psychiatry, Servicio de Psiquiatría Hospital “Virgen de la Luz,” Cuenca, Spain; Leboyer, Marion, MD, PhD, AP-HP, Groupe Hospitalier “Mondor,” Pôle de Psychiatrie, Créteil, France, Institut National de la Santé et de la Recherche Médicale, U955, Créteil, France, Faculté de Médecine, Université Paris-Est, Créteil, France, and Fondation Fondamental, Créteil, France; Llorente, Cloe, MD, Department of Psychiatry, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, Investigación Sanitaria del Hospital Gregorio Marañón (CIBERSAM), Madrid, Spain; López Montoya, Gonzalo, PhD, Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM (CIBERSAM), Madrid, Spain; Lorente-Rovira, Esther, PhD, Department of Psychiatry, School of Medicine, Universidad de Valencia, CIBERSAM, Valencia, Spain; M Díaz-Caneja, Covadonga, Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain; Marcelino Loureiro, Camila, MD, Departamento de Neurociências e Ciencias do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brasil, and Núcleo de Pesquina em Saúde Mental Populacional, Universidade de São Paulo, São Paulo, Brasil; Matteis, Mario, MD, Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM (CIBERSAM), Madrid, Spain; Messchaart, Elles, MSc, Rivierduinen Centre for Mental Health, Leiden, the Netherlands; Moltó, Ma Dolores, Department of Genetics, University of Valencia, Campus of Burjassot, Biomedical Research Institute INCLIVA, Valencia, Spain, Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Madrid, Spain; Mezquida, Gisela, PhD, Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Departament de Medicina, Institut de Neurociències (UBNeuro), Universitat de Barcelona (UB), Institut d’Investigacions Biomèdiques, August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain; Moreno, Carmen, MD, Department of Psychiatry, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM (CIBERSAM), Madrid, Spain; Muratori, Roberto, MD, Department of Mental Health and Pathological Addiction, Local Health Authority, Bologna, Italy; Nacher Juan, Neurobiology Unit, Department of Cell Biology, Interdisciplinary Research Structure for Biotechnology and Biomedicine (BIOTECMED), Universitat de València, Valencia, Spain, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM): Spanish National Network for Research in Mental Health, Madrid, Spain, Fundación Investigación Hospital Clínico de Valencia, INCLIVA, Valencia, Spain; Parellada, Mara, MD, PhD, Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM (CIBERSAM), Madrid, Spain; Rapado-Castro, Marta, PhD, Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, Institute of Psychiatry and Mental Health, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain; Ruggeri, Mirella, MD, PhD, Section of Psychiatry, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy; Richard, Jean-Romain, MSc, Institut National de la Santé et de la Recherche Médicale, U955, Créteil, France, and Fondation Fondamental, Créteil, France; Rodríguez Solano, José Juan, MD, Puente de Vallecas Mental Health Department, Hospital Universitario Infanta Leonor/Hospital Virgen de la Torre, Centro de Salud Mental Puente de Vallecas, Madrid, Spain; Sáiz, Pilar A, Department of Psychiatry, School of Medicine, University of Oviedo, CIBERSAM. Instituto de Neurociencias del Principado de Asturias, INEUROPA, Oviedo, Spain; Servicio de Salud del Principado de Asturias (SESPA), Oviedo, Spain; Sánchez-Gutierrez, Teresa, Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, C/Doctor Esquerdo 46, 28007 Madrid, Spain. Faculty of Health Science. Universidad Internacional de La Rioja (UNIR), Madrid, Spain; Sánchez, Emilio, MD, Department of Psychiatry, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM (CIBERSAM), Madrid, Spain; Schürhoff, Franck, MD, PhD, AP-HP, Groupe Hospitalier “Mondor,” Pôle de Psychiatrie, Créteil, France, Institut National de la Santé et de la Recherche Médicale, U955, Créteil, France, Faculté de Médecine, Université Paris-Est, Créteil, France, and Fondation Fondamental, Créteil, France; Seri, Marco, MD, Department of Medical and Surgical Science, Genetic Unit, Alma Mater Studiorium Università di Bologna, Bologna, Italy; Shuhama, Rosana, PhD, Departamento de Neurociências e Ciencias do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brasil, and Núcleo de Pesquina emSaúde Mental Populacional, Universidade de São Paulo, São Paulo, Brasil; Termorshuizen, Fabian, PhD, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht University Medical Centre, Maastricht, the Netherlands, and Rivierduinen Centre for Mental Health, Leiden, the Netherlands; Tronche, Anne-Marie, MD, Fondation Fondamental, Créteil, France, CMP B CHU, Clermont Ferrand, France, and Université Clermont Auvergne, ClermontFerrand, France; van Dam, Daniella, PhD, Department of Psychiatry, Early Psychosis Section, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; van der Ven, Elsje, PhD, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht University Medical Centre, Maastricht, the Netherlands, and Rivierduinen Centre for Mental Health, Leiden, the Netherlands.

Amoretti Silvia, Andreu-Bernabeu Álvaro, Baudin Grégoire, Beards Stephanie, Bonetto Chiara, Bonora Elena, Cabrera Bibiana, Carracedo Angel, Charpeaud Thomas, Costas Javier, Cristofalo Doriana, Cuadrado Pedro, Durán-Cutilla Manuel, Ferchiou Aziz, Fraguas David, Franke Nathalie, Frijda Flora, Llorente Cloe, Garcia-Portilla Paz, González Peñas Javier, Hubbard Kathryn, Jamain Stéphane, Jiménez-López Estela, Leboyer Marion, López Montoya Gonzalo, Lorente-Rovira Esther, M. Díaz-Caneja Covadonga, Marcelino Loureiro Camila, Matteis Mario, Messchaart Elles, Moltó Ma Dolores, Mezquida Gisela, Moreno Carmen, Muratori Roberto, Nacher Juan, Parellada Mara, Rapado-Castro Marta, Ruggeri Mirella, Richard Jean-Romain, Rodríguez Solano José Juan, A. Sáiz Pilar, Sánchez-Gutierrez Teresa, Sánchez Emilio, Schürhoff Franck, Seri Marco, Shuhama Rosana, Termorshuizen Fabian, Tronche Anne-Marie, van Dam Daniella, van der Ven Elsje

Author contributions

DQ, DLB, CLC, LF, EV, GT, CG-A, SS, FS, CS, GM, AL, ST, IT, DB, GDA, CA, MA, MB, JB, JS, JLS, PMR, CMD-B, HEJ, PBJ, JBK, P-ML, AT, BP, LdH, J-PS, JvO, BPR, RB, MDF, RMM, CM, and all the authors in the EU-GEI group collected or supervised the data collection. LS did the data analysis and wrote the first draft of the manuscript. AF contributed to creation of the tables. MA and DQ assisted with the genetic analysis. All authors provided a careful methodological revision of the manuscript, contributed to and approved the final draft. CM and HLF have equally supervised this work and they are joint senior authors.

Funding

We are grateful to the EU-GEI study participants for their essential contribution to this project. The EU-GEI Study is funded by grant agreement HEALTH-F2-2010–241909 (Project EU-GEI) from the European Community’s Seventh Framework Programme, and Grant 2012/0417–0 from the São Paulo Research Foundation. B.P.F. Rutten is funded by a VIDI award (no. 91.718.336) from the Netherlands Scientific Organization. H. L. Fisher, C. Gayer-Anderson, and C. Morgan are supported by the Economic and Social Research Council (ESRC) Centre for Society and Mental Health at King’s College London [ES/S012567/1]. D. Quattrone is supported by the Medical Research Council Clinical Academic Research Partnership [MR/W030608/1]. M. Aas is supported by an MRC fellowship (#MR/WO27720/1). C. Arango has received support from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), co-financed by the European Union, ERDF Funds from the European Commission, “A way of making Europe”, financed by the European Union—NextGenerationEU (PMP21/00051, PI19/01024), CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program, European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project PRISM-2 (Grant agreement No.101034377), Project AIMS-2-TRIALS (Grant agreement No 777394), Horizon Europe, the National Institute of Mental Health of the National Institutes of Health under Award Number 1U01MH124639-01 (Project ProNET) and Award Number 5P50MH115846-03 (Project FEP-CAUSAL), Fundación Familia Alonso, and Fundación Alicia Koplowitz. The views expressed are those of the authors and not necessarily those of the ESRC or King’s College London.

Declarations

Conflict of interest

Prof. Morgan is the Editor-in-Chief of this journal. Dr. Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. Dr. Bernardo has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Angelini, Casen Recordati, Janssen-Cilag, Menarini, Rovi and Takeda. The other authors have declared that there are no conflicts of interest in relation to the subject of this study.

Footnotes

Craig Morgan and Helen L. Fisher have contributed equally to this work and they are joint senior authors.

Contributor Information

Lucia Sideli, Email: l.sideli@lumsa.it.

EU-GEI WP2 Group:

Silvia Amoretti, Álvaro Andreu-Bernabeu, Grégoire Baudin, Stephanie Beards, Chiara Bonetto, Elena Bonora, Bibiana Cabrera, Angel Carracedo, Thomas Charpeaud, Javier Costas, Doriana Cristofalo, Pedro Cuadrado, Manuel Durán-Cutilla, Aziz Ferchiou, David Fraguas, Nathalie Franke, Flora Frijda, Paz Garcia-Portilla, Javier González Peñas, Kathryn Hubbard, Stéphane Jamain, Estela Jiménez-López, Marion Leboyer, Cloe Llorente, Gonzalo López Montoya, Esther Lorente-Rovira, Covadonga M. Díaz-Caneja, Camila Marcelino Loureiro, Mario Matteis, Elles Messchaart, Ma Dolores Moltó , Gisela Mezquida, Carmen Moreno, Roberto Muratori, Juan Nacher, Mara Parellada, Marta Rapado-Castro, Mirella Ruggeri, Jean-Romain Richard, José Juan Rodríguez Solano, Pilar A. Sáiz, Teresa Sánchez-Gutierrez, Emilio Sánchez, Franck Schürhoff, Marco Seri, Rosana Shuhama, Fabian Termorshuizen, Anne-Marie Tronche, Daniella van Dam, and Elsje van der Ven

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