The association between cannabis and psychosis is established, but the role of underlying genetics is unclear. We used data from the EU-GEI case-control study and UK Biobank to examine the independent and combined effect of heavy cannabis use and schizophrenia polygenic risk score (PRS) on risk for psychosis.

Genome-wide association study summary statistics from the Psychiatric Genomics Consortium and the Genomic Psychiatry Cohort were used to calculate schizophrenia and cannabis use disorder (CUD) PRS for 1098 participants from the EU-GEI study and 143600 from the UK Biobank. Both datasets had information on cannabis use.

In both samples, schizophrenia PRS and cannabis use independently increased risk of psychosis. Schizophrenia PRS was not associated with patterns of cannabis use in the EU-GEI cases or controls or UK Biobank cases. It was associated with lifetime and daily cannabis use among UK Biobank participants without psychosis, but the effect was substantially reduced when CUD PRS was included in the model. In the EU-GEI sample, regular users of high-potency cannabis had the highest odds of being a case independently of schizophrenia PRS (OR daily use high-potency cannabis adjusted for PRS = 5.09, 95% CI 3.08–8.43, p = 3.21 × 10−10). We found no evidence of interaction between schizophrenia PRS and patterns of cannabis use.

Regular use of high-potency cannabis remains a strong predictor of psychotic disorder independently of schizophrenia PRS, which does not seem to be associated with heavy cannabis use. These are important findings at a time of increasing use and potency of cannabis worldwide.

Positive, negative and disorganised psychotic symptom dimensions are associated with clinical and developmental variables, but differing definitions complicate interpretation. Additionally, some variables have had little investigation.

To investigate associations of psychotic symptom dimensions with clinical and developmental variables, and familial aggregation of symptom dimensions, in multiple samples employing the same definitions.

We investigated associations between lifetime symptom dimensions and clinical and developmental variables in two twin and two general psychosis samples. Dimension symptom scores and most other variables were from the Operational Criteria Checklist. We used logistic regression in generalised linear mixed models for combined sample analysis (n = 875 probands). We also investigated correlations of dimensions within monozygotic (MZ) twin pairs concordant for psychosis (n = 96 pairs).

Higher symptom scores on all three dimensions were associated with poor premorbid social adjustment, never marrying/cohabiting and earlier age at onset, and with a chronic course, most strongly for the negative dimension. The positive dimension was also associated with Black and minority ethnicity and lifetime cannabis use; the negative dimension with male gender; and the disorganised dimension with gradual onset, lower premorbid IQ and substantial within twin-pair correlation. In secondary analysis, disorganised symptoms in MZ twin probands were associated with lower premorbid IQ in their co-twins.

These results confirm associations that dimensions share in common and strengthen the evidence for distinct associations of co-occurring positive symptoms with ethnic minority status, negative symptoms with male gender and disorganised symptoms with substantial familial influences, which may overlap with influences on premorbid IQ.

Incidence of first-episode psychosis (FEP) varies substantially across geographic regions. Phenotypes of subclinical psychosis (SP), such as psychotic-like experiences (PLEs) and schizotypy, present several similarities with psychosis. We aimed to examine whether SP measures varied across different sites and whether this variation was comparable with FEP incidence within the same areas. We further examined contribution of environmental and genetic factors to SP.

We used data from 1497 controls recruited in 16 different sites across 6 countries. Factor scores for several psychopathological dimensions of schizotypy and PLEs were obtained using multidimensional item response theory models. Variation of these scores was assessed using multi-level regression analysis to estimate individual and between-sites variance adjusting for age, sex, education, migrant, employment and relational status, childhood adversity, and cannabis use. In the final model we added local FEP incidence as a second-level variable. Association with genetic liability was examined separately.

Schizotypy showed a large between-sites variation with up to 15% of variance attributable to site-level characteristics. Adding local FEP incidence to the model considerably reduced the between-sites unexplained schizotypy variance. PLEs did not show as much variation. Overall, SP was associated with younger age, migrant, unmarried, unemployed and less educated individuals, cannabis use, and childhood adversity. Both phenotypes were associated with genetic liability to schizophrenia.

Schizotypy showed substantial between-sites variation, being more represented in areas where FEP incidence is higher. This supports the hypothesis that shared contextual factors shape the between-sites variation of psychosis across the spectrum.

Childhood adversity and cannabis use are considered independent risk factors for psychosis, but whether different patterns of cannabis use may be acting as mediator between adversity and psychotic disorders has not yet been explored. The aim of this study is to examine whether cannabis use mediates the relationship between childhood adversity and psychosis.

Data were utilised on 881 first-episode psychosis patients and 1231 controls from the European network of national schizophrenia networks studying Gene–Environment Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse Questionnaire was used to assess exposure to household discord, sexual, physical or emotional abuse and bullying in two periods: early (0–11 years), and late (12–17 years). A path decomposition method was used to analyse whether the association between childhood adversity and psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency of use.

The association between household discord and psychosis was partially mediated by lifetime use of cannabis (indirect effect coef. 0.078, s.e. 0.022, 17%), its potency (indirect effect coef. 0.059, s.e. 0.018, 14%) and by frequency (indirect effect coef. 0.117, s.e. 0.038, 29%). Similar findings were obtained when analyses were restricted to early exposure to household discord.

Harmful patterns of cannabis use mediated the association between specific childhood adversities, like household discord, with later psychosis. Children exposed to particularly challenging environments in their household could benefit from psychosocial interventions aimed at preventing cannabis misuse.

While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis.

We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case–control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.

We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case–control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case–control status.

Controls (86.1%) and FEPp (75.63%) were most likely to report ‘because of friends’ as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: ‘to feel better’ as their RFUC (χ2 = 50.97; p < 0.001). RFUC ‘to feel better’ was associated with being a FEPp (OR 1.74; 95% CI 1.03–2.95) while RFUC ‘with friends’ was associated with being a control (OR 0.56; 95% CI 0.37–0.83). The path model indicated an association between RFUC ‘to feel better’ with heavy cannabis use and with FEPp-control status.

Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use ‘to feel better’. People who reported their reason for first using cannabis to ‘feel better’ were more likely to progress to heavy use and develop a psychotic disorder than those reporting ‘because of friends’.

The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors.

Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change.

Prospective symptom analyses showed small decreases in depression (PHQ-9: −0.43 points) and anxiety [generalised anxiety disorder scale – 7 items (GAD)-7: −0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status.

We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

Schizophrenia (SZ), bipolar disorder (BD) and depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUropean Network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) first episode case–control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD).

Participants (842 cases, 1284 controls) from 16 European EU-GEI sites were successfully genotyped following standard quality control procedures. The sample was stratified based on genomic ancestry and analyses were done only on the subsample representing the European population (573 cases, 1005 controls). Using PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons.

In case–control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case–case comparisons, both PRS-SZ [odds ratio (OR) = 0.7, 95% confidence interval (CI) 0.54–0.92] and PRS-D (OR = 1.31, 95% CI 1.06–1.61) differentiated AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR = 2.14, 95% CI 1.23–3.74).

Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards the potential usefulness of PRSs in specific populations such as high-risk or early psychosis phases.

A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to the number of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing polygenic vulnerability. Here, we investigated, in the largest sample of first-episode psychosis (FEP) cases to date, whether childhood adversity and high polygenic risk scores for schizophrenia (SZ-PRS) combine synergistically to increase the risk of psychosis, over and above the effect of each alone.

We assigned a schizophrenia-polygenic risk score (SZ-PRS), calculated from the Psychiatric Genomics Consortium (PGC2), to all participants in a sample of 384 FEP patients and 690 controls from the case–control component of the EU-GEI study. Only participants of European ancestry were included in the study. A history of childhood adversity was collected using the Childhood Trauma Questionnaire (CTQ). Synergistic effects were estimated using the interaction contrast ratio (ICR) [odds ratio (OR)exposure and PRS − ORexposure − ORPRS + 1] with adjustment for potential confounders.

There was some evidence that the combined effect of childhood adversities and polygenic risk was greater than the sum of each alone, as indicated by an ICR greater than zero [i.e. ICR 1.28, 95% confidence interval (CI) −1.29 to 3.85]. Examining subtypes of childhood adversities, the strongest synergetic effect was observed for physical abuse (ICR 6.25, 95% CI −6.25 to 20.88).

Our findings suggest possible synergistic effects of genetic liability and childhood adversity experiences in the onset of FEP, but larger samples are needed to increase precision of estimates.

The current treatment goal in Major Depressive Disorder (MDD) is functional recovery (Zimmerman M et al, 2012). However, finding the “right dose for the right patient” may be challenging and the dose-response relationship for antidepressant efficacy remains controversial (Hieronymus F et al, 2016). Efficacy evaluated by MADRS increases with higher vortioxetine doses, based on meta-analysis data (Thase ME et al, 2016).

The aim of this exploratory analysis was to assess the impact of different doses on vortioxetine effectiveness in clinical practice in Greece.

In this non-interventional study, open-label vortioxetine was administered at a flexible dosage (5-20 mg/d). Patients receiving 5/10 mg vortioxetine (group A), at the end of the study, were compared to patients receiving 15/20mg vortioxetine (group B). At baseline, 1 and 3 months, depressive symptoms and functioning were assessed by MADRS and SDS. Multiple regression was used for the statistical analyses.

The study included 336 MDD patients. At the end of the study, 64.3% (n=200) of patients were receiving 15/20 mg vortioxetine. Higher vortioxetine dose at month 3 was significantly correlated with higher MADRS total score at baseline (p<0.001). SDS total score change from baseline to month 3 was significantly associated with vortioxetine dose (p<0.001), with group A and group B showing improvements of -9.2±8.2 and -12.1±6.0, respectively- whereas such association was not observed for MADRS total score.

In conclusion, patients with more severe depressive symptoms were treated with higher antidepressant doses. However, beyond symptom improvement, vortioxetine effectiveness on patient functioning seems to increase with higher doses.

A. Galanopoulos and E. Papalexi are full-time employees in Lundbeck Hellas. A. Ettrup is a full-time employee in H. Lundbeck A/S.

A single nucleotide polymorphism within the CACNA1C gene (rs1006737) has been found to confer increased risk of Bipolar Disorder (BD) and has been linked to altered neuronal gating and emotional behaviour. As current models of BD suggest abnormal integration within frontolimbic networks, our aim was to explore the effect of the CACNA1C genotype on prefrontal and limbic activation.

We genotyped 90 participants from the Vulnerability to Bipolar Disorder Study comprising of 41 euthymic BD patients and 49 healthy controls. Functional magnetic resonance imaging data were obtained while participants performed a fearful versus neutral facial affect processing task.

We found a significant diagnosis by genotype interaction with BD patients homozygous for the risk allele having reduced prefrontal activation compared to the other groups.

The present findings support the hypothesis that the rs1006737 polymorphism in the CACNA1C gene confers increased risk of BD by modulating amygdala and PFC activation during emotional processing.

The polymorphism rs1006737 within the CACNA1C gene is associated with increased risk for bipolar disorder (BD) and variations in brain morphology and function of subcortical regions. Here we sought to investigate the influence of CACNA1C polymorphism on key subcortical brain structures implicated in the pathophysiology of BD.

Structural magnetic resonance imaging scans were acquired from 41 euthymic patients with BD and 40 healthy controls, who were also genotyped for the CACNA1C rs1006737 polymorphism. The effect of diagnosis, genotype and their interaction was examined in predefined volumes of interest in the basal ganglia, hypothalamus and amygdala extracted using SPM5.

Carriers of the CACNA1C rs1006737 risk allele showed increased grey matter density in the right amygdala and right hypothalamus irrespective of diagnosis. An interaction between genotype and diagnosis was observed in the left putamen which was smaller in BD patients carrying the risk allele than in healthy controls.

The CACNA1C rs1006737 polymorphism influences anatomical variation within subcortical regions involved in emotional processing.

A single nucleotide polymorphism, rs17070145, in the KIBRA protein, is thought to influence memory function in humans (Papassotiropoulos et al, 2006). We sought to investigate its effect on memory performance in people with Early Onset Schizophrenia (EOS; onset before age of 18) and their first-degree relatives.

53 EOS probands and 117 non-psychotic first-degree relatives were examined on IQ (Wechsler Adult Intelligence Scale-Revised), learning and memory (California Verbal Learning Test; CVLT). the Structured Clinical Interview for DSM-IV yielded four diagnostic groups: EOS probands; relatives with Mood Disorders; other Axis I diagnoses; and no diagnosis (healthy relatives). Analysis of co-variance was performed, with diagnosis and genotype as fixed factors and age as covariate.

Carriers of the rs17070145 T allele achieved higher performance IQ, and recalled more words in short-delayed and long-delayed recall in the CVLT compared to C allele carriers [p< 0.003 and p< 0.009, respectively]. However TT homozygotes made more perseverative errors than C allele carriers [p=0.04]. after applying the Bonferroni for multiple comparisons, a genotype by diagnosis interaction revealed that relatives who were TT homozygotes and had mood disorders performed better on long-delayed recall [p< 0.04] but made more intrusion errors in the CVLT than the CC/CT genotype group.

KIBRA may be involved in:

1. 1. processes that enhance overall competence in non-verbal tasks;

2. 2. phenotypic expression of cognition in mentally unwell relatives of schizophrenia patients.

Schizophrenia patients are typically found to have low IQ both pre- and post-onset, in comparison to the general population. However, a subgroup of patients displays above average IQ pre-onset. The nature of these patients’ illness and its relationship to typical schizophrenia is not well understood. The current study sought to investigate the symptom profile of high-IQ schizophrenia patients.

We identified 29 schizophrenia patients of exceptionally high pre-morbid intelligence (mean estimated pre-morbid intelligence quotient (IQ) of 120), of whom around half also showed minimal decline (less than 10 IQ points) from their estimated pre-morbid IQ. We compared their symptom scores (SAPS, SANS, OPCRIT, MADRS, GAF, SAI-E) with a comparison group of schizophrenia patients of typical IQ using multinomial logistic regression.

The patients with very high pre-morbid IQ had significantly lower scores on negative and disorganised symptoms than typical patients (RRR = 0.019; 95% CI = 0.001, 0.675, P = 0.030), and showed better global functioning and insight (RRR = 1.082; 95% CI = 1.020, 1.148; P = 0.009). Those with a minimal post-onset IQ decline also showed higher levels of manic symptoms (RRR = 8.213; 95% CI = 1.042, 64.750, P = 0.046).

These findings provide evidence for the existence of a high-IQ variant of schizophrenia that is associated with markedly fewer negative symptoms than typical schizophrenia, and lends support to the idea of a psychosis spectrum or continuum over boundaried diagnostic categories.

Emotional lability (EL) is an associated feature of attention-deficit/hyperactivity disorder (ADHD) in adults, contributing to functional impairment. Yet the effect of pharmacological treatments for ADHD on EL symptoms is unknown. We conducted a systematic review and meta-analysis to examine the effects of stimulants and atomoxetine on symptoms of EL and compare these with the effects on core ADHD symptoms.

A systematic search was conducted on the databases Embase, PsychInfo, and Ovid Medline® and the clinicaltrials.gov website. We included randomised, double-blind, placebo-controlled trials of stimulants and atomoxetine in adults aged 18–60 years, with any mental health diagnosis characterised by emotional or mood instability, with at least one outcome measure of EL. All identified trials were on adults with ADHD. A random-effects meta-analysis with standardised mean difference and 95% confidence intervals was used to investigate the effect size on EL and compare this to the effect on core ADHD symptoms.

Of the 3,864 publications identified, nine trials met the inclusion criteria for the meta-analysis. Stimulants and atomoxetine led to large mean weighted effect-sizes for on ADHD symptoms (n = 9, SMD = −0.8, 95% CI:−1.07 to −0.53). EL outcomes showed more moderate but definite effects (n = 9, SMD = −0.41, 95% CI:−0.57 to −0.25).

In this meta-analysis, stimulants and atomoxetine were moderately effective for EL symptoms, while effect size on core ADHD symptoms was twice as large. Methodological issues may partially explain the difference in effect size. Reduced average effect size could also reflect heterogeneity of EL with ADHD pharmacotherapy responsive and non-responsive sub-types. Our findings indicate that EL may be less responsive than ADHD symptoms overall, perhaps indicating the need for adjunctive psychotherapy in some cases. To clarify these questions, our findings need replication in studies selecting subjects for high EL and targeting EL as the primary outcome.

Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients.

We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses.

In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score (B = 0.35; 95% CI 0.14–0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B = −0.22; 95% CI −0.37 to −0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use.

Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.

The value of the nosological distinction between non-affective and affective psychosis has frequently been challenged. We aimed to investigate the transdiagnostic dimensional structure and associated characteristics of psychopathology at First Episode Psychosis (FEP). Regardless of diagnostic categories, we expected that positive symptoms occurred more frequently in ethnic minority groups and in more densely populated environments, and that negative symptoms were associated with indices of neurodevelopmental impairment.

This study included 2182 FEP individuals recruited across six countries, as part of the EUropean network of national schizophrenia networks studying Gene–Environment Interactions (EU-GEI) study. Symptom ratings were analysed using multidimensional item response modelling in Mplus to estimate five theory-based models of psychosis. We used multiple regression models to examine demographic and context factors associated with symptom dimensions.

A bifactor model, composed of one general factor and five specific dimensions of positive, negative, disorganization, manic and depressive symptoms, best-represented associations among ratings of psychotic symptoms. Positive symptoms were more common in ethnic minority groups. Urbanicity was associated with a higher score on the general factor. Men presented with more negative and less depressive symptoms than women. Early age-at-first-contact with psychiatric services was associated with higher scores on negative, disorganized, and manic symptom dimensions.

Our results suggest that the bifactor model of psychopathology holds across diagnostic categories of non-affective and affective psychosis at FEP, and demographic and context determinants map onto general and specific symptom dimensions. These findings have implications for tailoring symptom-specific treatments and inform research into the mood-psychosis spectrum.

The relationship between childhood adversity (CA) and psychotic disorder is well documented. As the adequacy of the current categorical diagnosis of psychosis is being increasingly questioned, we explored independent associations between different types of CA and specific psychotic symptom dimensions in a well-characterized sample of first-episode psychosis (FEP) patients.

This study involved 236 FEP cases aged 18–65 years who presented for the first time to psychiatric services in South London, UK. Psychopathology was assessed with the Positive and Negative Syndrome Scale and confirmatory factor analysis was used to evaluate the statistical fit of the Wallwork/Fortgang five-factor model of psychosis. CA prior to 17 years of age (physical abuse, sexual abuse, parental separation, parental death, and being taken into care) was retrospectively assessed using the Childhood Experience of Care and Abuse Questionnaire.

Childhood sexual abuse [β = 0.96, 95% confidence interval (CI) 0.40–1.52], childhood physical abuse (β = 0.48, 95% CI 0.03–0.93) and parental separation (β = 0.60, 95% CI 0.10–1.11) showed significant associations with the positive dimension; while being taken into care was associated with the excited dimension (β = 0.36, 95% CI 0.08–0.65), independent of the other types of CA. No significant associations were found between parental death and any of the symptom dimensions.

A degree of specificity was found in the relationships between different types of CA and psychosis symptom dimensions in adulthood, suggesting that distinct pathways may be involved in the CA–psychosis association. These potentially different routes to developing psychosis merit further empirical and theoretical exploration.

Visual and verbal episodic memory deficits are putative endophenotypes for schizophrenia; however, the extent of any genetic overlap of these with schizophrenia is unclear. In this study, we set out to quantify the genetic and environmental contributions to variance in visual and verbal memory performance, and to quantify their genetic relationship with schizophrenia.

We applied bivariate genetic modelling to 280 twins in a classic twin study design, including monozygotic (MZ) and dizygotic (DZ) pairs concordant and discordant for schizophrenia, and healthy control twins. We assessed episodic memory using subtests of the Wechsler Memory Scale – Revised (WMS-R).

Genetic influences (i.e. heritability) contributed significantly to variance in immediate recall of both verbal memory and visual learning, and the delayed recall of verbal and visual memory. Liability to schizophrenia was associated with memory impairment, with evidence of significant phenotypic correlations between all episodic memory measures and schizophrenia. Genetic factors were the main source of the phenotypic correlations for immediate recall of visual learning material; both immediate and delayed recall of verbal memory; and delayed recall of visual memory that, for example, shared genetic variance with schizophrenia, which accounted for 88% of the phenotypic correlation (rph=0.41) between the two.

Verbal memory and visual learning and memory are moderately heritable, share a genetic overlap with schizophrenia and are valid endophenotypes for the condition. The inclusion of these endophenotypes in genetic association studies may improve the power to detect susceptibility genes for schizophrenia.