Cancer risk in individuals with autism spectrum disorder.

BACKGROUND: Whether individuals with autism spectrum disorders (ASDs) have a higher-than-expected risk of cancer remains unknown. PATIENTS AND METHODS: We carried out a population-based cohort study including 2.3 million individuals live-born to mothers from Nordic countries during 1987-2013 in Sweden with follow-up through 2016 (up to age 30 years). Individuals with ASD were ascertained through the Swedish National Patient Register. We estimated the relative risk of cancer in relation to ASD by odds ratios (ORs) and associated 95% confidence intervals (CIs) derived from logistic regression, after detailed adjustment for potential confounders. We also carried out a sibling comparison to address familial confounding and a genetic correlation analysis using the genome-wide association study summary statistics to address confounding due to potential polygenetic pleiotropy between ASD and cancer. RESULTS: We observed an overall increased risk of any cancer among individuals with ASD (OR 1.3, 95% CI 1.2-1.5), compared with individuals without ASD. The association for any cancer was primarily noted for narrowly defined autistic disorder (OR 1.7, 95% CI 1.3-2.1) and ASD with comorbid birth defects (OR 2.1, 95% CI 1.5-2.9) or both birth defects and intellectual disability (ID; OR 4.8, 95% CI 3.4-6.6). An association was also suggested for ASD with comorbid ID (OR 1.4; 95% CI 0.9-2.1), but was not statistically significant. ASD alone (i.e. without comorbid ID or birth defects) was not associated with an increased risk of any cancer (OR 1.0, 95% CI 0.8-1.2). Sibling comparison and genetic correlation analysis showed little evidence for familial confounding or confounding due to polygenetic pleiotropy between ASD and cancer. CONCLUSIONS: ASD per se is not associated with an increased risk for cancer in early life. The increased cancer risk among individuals with ASD is likely mainly attributable to co-occurring ID and/or birth defects in ASD.

Prenatal exposure to acetaminophen and children's language development at 30 months.

OBJECTIVE: To examine prenatal APAP exposure in relation to language development in offspring at 30 months of age. METHOD: A population-based pregnancy cohort study including 754 women who enrolled in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study in pregnancy week 8-13. Two exposure measures were used: (1) maternally reported number of APAP tablets taken between conception and enrollment; (2) APAP urinary concentration at enrollment. Language development at 30 months was assessed by nurse's evaluation and parental questionnaire, including the number of words the child used (<25, 25-50 and >50). Main study outcome; parental report of use of fewer than 50 words, termed language delay (LD). RESULTS: 59.2% of women enrolled in weeks 8-13 reported taking APAP between conception and enrollment. APAP was measurable in all urine samples and urinary APAP was correlated with the number of APAP taken during pregnancy (P<0.01). Language delay was more prevalent in boys (12.6%) than girls (4.1%) (8.5% in total). Both the number of APAP tablets and urinary APAP concentration were associated with greater LD in girls but not in boys. The adjusted odds ratio (OR) for LD among girls whose mothers reported >6 vs. 0 APAP tablets was 5.92 (95% confidence interval (CI) 1.10-31.94). The OR for LD in girls whose mothers' urinary APAP was in the highest compared to the lowest quartile was 10.34 (95% CI 1.37-77.86). While it cannot be ruled out, our available data do not support confounding by indication. CONCLUSIONS: Given the prevalence of prenatal APAP use and the importance of language development, these findings, if replicated, would suggest that pregnant women should limit their use of this analgesic during pregnancy.

Cognitive development prior to onset of psychosis.

Schizophrenia patients commonly exhibit substantial and diffuse cognitive impairment. Evidence suggests that subtle cognitive deficits are already apparent in childhood and adolescence, many years prior to onset of psychosis. While there is almost unequivocal evidence of some degree of cognitive impairment in individuals who later develop schizophrenia, the literature remains inconclusive regarding the exact nature of this impairment and warrants careful review and interpretation. Meta-analytic findings suggest that individuals who later develop schizophrenia, but not related disorders, such as bipolar disorder, exhibit a premorbid IQ deficit of around 8 points. Several studies have also found evidence for premorbid deficits across most cognitive domains, such as language, processing speed and executive functions. Longitudinal studies, although rare, suggest that individuals who go on to develop schizophrenia may show a course of increasing cognitive impairment prior to onset of psychosis. While evidence regarding the etiology of premorbid deficits is scarce, common and rare genetic variants, as well as environmental factors such as obstetric complications and cannabis use may play an important role and warrant further examination. In this selected review, we give an overview of population-based studies on premorbid cognitive deficits in schizophrenia, with a special focus on evidence regarding the specificity, profile and course of these deficits.

Advantageous developmental outcomes of advancing paternal age.

Advanced paternal age (APA) at conception has been associated with negative outcomes in offspring, raising concerns about increasing age at fatherhood. Evidence from evolutionary and psychological research, however, suggests possible link between APA and a phenotypic advantage. We defined such advantage as educational success, which is positively associated with future socioeconomic status. We hypothesised that high IQ, strong focus on the subject of interest and little concern about 'fitting in' will be associated with such success. Although these traits are continuously distributed in the population, they cluster together in so-called 'geeks'. We used these measures to compute a 'geek index' (GI), and showed it to be strongly predictive of future academic attainment, beyond the independent contribution of the individual traits. GI was associated with paternal age in male offspring only, and mediated the positive effects of APA on education outcomes, in a similar sexually dimorphic manner. The association between paternal age and GI was partly mediated by genetic factors not correlated with age at fatherhood, suggesting contribution of de novo factors to the 'geeky' phenotype. Our study sheds new light on the multifaceted nature of the APA effects and explores the intricate links between APA, autism and talent.

Autism risk following antidepressant medication during pregnancy.

BACKGROUND: Previous studies have examined if maternal antidepressant medication during pregnancy increase the risk of autism spectrum disorder (ASD) in the offspring, but the results have been conflicting. METHODS: In a population-based cohort of 179 007 children born in 2006 and 2007 and followed through 2014 when aged 7 and 8, we estimated relative risks (RRs) of ASD and 95% confidence intervals (CIs) from Cox regression in children exposed to any antidepressant medication during pregnancy, and nine specific antidepressant drugs. Analyses were adjusted for potential confounders and were conducted in the full population sample, and in a clinically relevant sub-sample of mothers with at least one diagnosis of depression or anxiety during life. RESULTS: The adjusted RR of ASD in children of mothers who used antidepressant medication during pregnancy was estimated at 1.23 (95% CI 0.96-1.57), and at 1.07 (95% CI 0.80-1.43) in women with a history of depression or anxiety. Analyses of specific antidepressants initially revealed increased RRs of offspring ASD confined to citalopram and escitalopram (RR: 1.47; 95% CI 0.92-2.35) and clomipramine (RR: 2.86; 95% CI 1.04-7.82). CONCLUSION: Medication with antidepressants during pregnancy does not appear to be causally associated with an increased risk of ASD in the offspring. Instead, the results suggest that the association is explained by factors related to the underlying susceptibility to psychiatric disorders. Based on these findings, the risk of ASD in the offspring should not be a consideration to withhold treatment with commonly used antidepressant drugs from pregnant women.

Advanced paternal age effects in neurodevelopmental disorders-review of potential underlying mechanisms.

Multiple epidemiological studies suggest a relationship between advanced paternal age (APA) at conception and adverse neurodevelopmental outcomes in offspring, particularly with regard to increased risk for autism and schizophrenia. Conclusive evidence about how age-related changes in paternal gametes, or age-independent behavioral traits affect neural development is still lacking. Recent evidence suggests that the origins of APA effects are likely to be multidimensional, involving both inherited predisposition and de novo events. Here we provide a review of the epidemiological and molecular findings to date. Focusing on the latter, we present the evidence for genetic and epigenetic mechanisms underpinning the association between late fatherhood and disorder in offspring. We also discuss the limitations of the APA literature. We propose that different hypotheses relating to the origins of the APA effects are not mutually exclusive. Instead, multiple mechanisms likely contribute, reflecting the etiological complexity of neurodevelopmental disorders.

Early-life metal exposure and schizophrenia: A proof-of-concept study using novel tooth-matrix biomarkers.

BACKGROUND: Despite evidence for the effects of metals on neurodevelopment, the long-term effects on mental health remain unclear due to methodological limitations. Our objective was to determine the feasibility of studying metal exposure during critical neurodevelopmental periods and to explore the association between early-life metal exposure and adult schizophrenia. METHODS: We analyzed childhood-shed teeth from nine individuals with schizophrenia and five healthy controls. We investigated the association between exposure to lead (Pb(2+)), manganese (Mn(2+)), cadmium (Cd(2+)), copper (Cu(2+)), magnesium (Mg(2+)), and zinc (Zn(2+)), and schizophrenia, psychotic experiences, and intelligence quotient (IQ). We reconstructed the dose and timing of early-life metal exposures using laser ablation inductively coupled plasma mass spectrometry. RESULTS: We found higher early-life Pb(2+) exposure among patients with schizophrenia than controls. The differences in log Mn(2+) and log Cu(2+) changed relatively linearly over time to postnatal negative values. There was a positive correlation between early-life Pb(2+) levels and psychotic experiences in adulthood. Moreover, we found a negative correlation between Pb(2+) levels and adult IQ. CONCLUSIONS: In our proof-of-concept study, using tooth-matrix biomarker that provides direct measurement of exposure in the fetus and newborn, we provide support for the role of metal exposure during critical neurodevelopmental periods in psychosis.

Initial severity and efficacy of risperidone in autism: Results from the RUPP trial.

BACKGROUND: Risperidone is a common psychopharmacological treatment for irritability in autism spectrum disorder (ASD). It is not well-established how effective risperidone is across the initial symptom severity range. This study aims to examine the influence of baseline severity on the efficacy of risperidone in the treatment of ASD. METHODS: Participants were from the NIMH funded RUPP multisite, randomized, double-blind trial that compared risperidone to placebo to treat autistic disorder with severe tantrums, aggression, or self-injury. Participants were aged 5 to 17, and randomly assigned to risperidone (n=49) or placebo (n=52). Baseline and change scores were computed with the Aberrant Behavior Checklist (ABC) parent assessed scales with irritability as the primary outcome, as well as the clinician assessed ABC Irritability subscale, and Clinical Global Impression Scale. RESULTS: The relationship between baseline severity and change scores for the risperdone and placebo groups was examined with eight competing three-level mixed-effects models for repeated measure models. Significant (P<0.01) interactions between treatment and baseline severity were observed for parent ABC ratings of irritability and lethargy only. Greater magnitudes of the differences between risperidone and placebo were observed from moderate to very severe baseline severity on irritability and lethargy. Initial severity values over approximately 30 had a strong effect on symptom change [irritability: effect size (ES)=1.9, number needed to treat (NNT)=2, lethargy ES=0.9, NNT=5]. CONCLUSIONS: Parents may expect benefits of risperidone on irritability and lethargy with moderate to severe symptoms of ASD. TRIAL REGISTRATION: Registry name: ClinicalTrials.gov, trial identifier: NCT00005014, URL: http://www.clinicaltrials.gov/ct2/show/NCT00005014?term=NCT00005014&rank=1, registered on March 31, 2000.

ViPAR: a software platform for the Virtual Pooling and Analysis of Research Data.

BACKGROUND: Research studies exploring the determinants of disease require sufficient statistical power to detect meaningful effects. Sample size is often increased through centralized pooling of disparately located datasets, though ethical, privacy and data ownership issues can often hamper this process. Methods that facilitate the sharing of research data that are sympathetic with these issues and which allow flexible and detailed statistical analyses are therefore in critical need. We have created a software platform for the Virtual Pooling and Analysis of Research data (ViPAR), which employs free and open source methods to provide researchers with a web-based platform to analyse datasets housed in disparate locations. METHODS: Database federation permits controlled access to remotely located datasets from a central location. The Secure Shell protocol allows data to be securely exchanged between devices over an insecure network. ViPAR combines these free technologies into a solution that facilitates 'virtual pooling' where data can be temporarily pooled into computer memory and made available for analysis without the need for permanent central storage. RESULTS: Within the ViPAR infrastructure, remote sites manage their own harmonized research dataset in a database hosted at their site, while a central server hosts the data federation component and a secure analysis portal. When an analysis is initiated, requested data are retrieved from each remote site and virtually pooled at the central site. The data are then analysed by statistical software and, on completion, results of the analysis are returned to the user and the virtually pooled data are removed from memory. CONCLUSIONS: ViPAR is a secure, flexible and powerful analysis platform built on open source technology that is currently in use by large international consortia, and is made publicly available at [http://bioinformatics.childhealthresearch.org.au/software/vipar/].

Autism risk associated with parental age and with increasing difference in age between the parents.

Advancing paternal and maternal age have both been associated with risk for autism spectrum disorders (ASD). However, the shape of the association remains unclear, and results on the joint associations is lacking. This study tests if advancing paternal and maternal ages are independently associated with ASD risk and estimates the functional form of the associations. In a population-based cohort study from five countries (Denmark, Israel, Norway, Sweden and Western Australia) comprising 5 766 794 children born 1985-2004 and followed up to the end of 2004-2009, the relative risk (RR) of ASD was estimated by using logistic regression and splines. Our analyses included 30 902 cases of ASD. Advancing paternal and maternal age were each associated with increased RR of ASD after adjusting for confounding and the other parent's age (mothers 40-49 years vs 20-29 years, RR=1.15 (95% confidence interval (CI): 1.06-1.24), P-value<0.001; fathers⩾50 years vs 20-29 years, RR=1.66 (95% CI: 1.49-1.85), P-value<0.001). Younger maternal age was also associated with increased risk for ASD (mothers <20 years vs 20-29 years, RR=1.18 (95% CI: 1.08-1.29), P-value<0.001). There was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages. We did not find any support for a modifying effect by the sex of the offspring. In conclusion, as shown in multiple geographic regions, increases in ASD was not only limited to advancing paternal or maternal age alone but also to differences parental age including younger or older similarly aged parents as well as disparately aged parents.

Effects of advanced paternal age on trajectories of social behavior in offspring.

Our study is the first investigation of the effects of advanced paternal age (APA) on the developmental trajectory of social behavior in rodent offspring. Given the strong epidemiological association between APA and sexually dimorphic neurodevelopmental disorders that are characterized by abnormalities in social behavior (autism, schizophrenia), we assessed sociability in male and female inbred mice (C57BL/6J) across postnatal development (N = 104) in relation to paternal age. We found differences in early social behavior in both male and female offspring of older breeders, with differences in this social domain persisting into adulthood in males only. We showed that these social deficits were not present in the fathers of these offspring, confirming a de novo origin of an altered social trajectory in the offspring generation. Our results, highly novel in rodent research, support the epidemiological observations in humans and provide evidence for a causal link between APA, age-related changes in the paternal sperm DNA and neurodevelopmental disorders in their offspring.

Modafinil combined with cognitive training is associated with improved learning in healthy volunteers--a randomised controlled trial.

Improving cognition in people with neuropsychiatric disorders remains a major clinical target. By themselves pharmacological and non-pharmacological approaches have shown only modest effects in improving cognition. In the present study we tested a recently-proposed methodology to combine CT with a 'cognitive-enhancing' drug to improve cognitive test scores and expanded on previous approaches by delivering combination drug and CT, over a long intervention of repeated sessions, and used multiple tasks to reveal the cognitive processes being enhanced. We also aimed to determine whether gains from this combination approach generalised to untrained tests. In this proof of principle randomised-controlled trial thirty-three healthy volunteers were randomised to receive either modafinil or placebo combined with daily cognitive training over two weeks. Volunteers were trained on tasks of new-language learning, working memory and verbal learning following 200 mg modafinil or placebo for ten days. Improvements in trained and untrained tasks were measured. Rate of new-language learning was significantly enhanced with modafinil, and effects were greatest over the first five sessions. Modafinil improved within-day learning rather than between-day retention. No enhancement of gains with modafinil was observed in working memory nor rate of verbal learning. Gains in all tasks were retained post drug-administration, but transfer effects to broad cognitive abilities were not seen. This study shows that combining CT with modafinil specifically elevates learning over early training sessions compared to CT with placebo and provides a proof of principle experimental paradigm for pharmacological enhancement of cognitive remediation.

Genetic modulation of the response bias towards facial displays of anger and happiness.

BACKGROUND: Investigating genetic modulation of emotion processing may contribute to the understanding of heritable mechanisms of emotional disorders. The aim of the present study was to test the effects of catechol-O-methyltransferase (COMT) val158met and serotonin-transporter-linked promoter region (5-HTTLPR) polymorphisms on facial emotion processing in healthy individuals. METHODS: Two hundred and seventy five (167 female) participants were asked to complete a computerized facial affect recognition task, which involved four experimental conditions, each containing one type of emotional face (fearful, angry, sad or happy) intermixed with neutral faces. Participants were asked to indicate whether the face displayed an emotion or was neutral. The COMT-val158met and 5-HTTLPR polymorphisms were genotyped. RESULTS: Met homozygotes (COMT) showed a stronger bias to perceive neutral faces as expressions of anger, compared with val homozygotes. However, the S-homozygotes (5-HTTLPR) showed a reduced bias to perceive neutral faces as expressions of happiness, compared to L-homozygotes. No interaction between 5-HTTLPR and COMT was found. CONCLUSIONS: These results add to the knowledge of individual differences in social cognition that are modulated via serotonergic and dopaminergic systems. This potentially could contribute to the understanding of the mechanisms of susceptibility to emotional disorders.

Abnormal cortisol awakening response predicts worse cognitive function in patients with first-episode psychosis.

BACKGROUND: Cognitive impairment, particularly in memory and executive function, is a core feature of psychosis. Moreover, psychosis is characterized by a more prominent history of stress exposure, and by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In turn, stress exposure and abnormal levels of the main HPA axis hormone cortisol are associated with cognitive impairments in a variety of clinical and experimental samples; however, this association has never been examined in first-episode psychosis (FEP). METHOD: In this study, 30 FEP patients and 26 controls completed assessment of the HPA axis (cortisol awakening response and cortisol levels during the day), perceived stress, recent life events, history of childhood trauma, and cognitive function. The neuropsychological battery comprised general cognitive function, verbal and non-verbal memory, executive function, perception, visuospatial abilities, processing speed, and general knowledge. RESULTS: Patients performed significantly worse on all cognitive domains compared to controls. In patients only, a more blunted cortisol awakening response (that is, more abnormal) was associated with a more severe deficit in verbal memory and processing speed. In controls only, higher levels of perceived stress and more recent life events were associated with a worse performance in executive function and perception and visuospatial abilities. CONCLUSIONS: These data support a role for the HPA axis, as measured by cortisol awakening response, in modulating cognitive function in patients with psychosis; however, this association does not seem to be related to the increased exposure to psychosocial stressors described in these patients.

Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies.

Advanced paternal age has been suggested as a risk factor for autism, but empirical evidence is mixed. This study examines whether the association between paternal age and autism in the offspring (1) persists controlling for documented autism risk factors, including family psychiatric history, perinatal conditions, infant characteristics and demographic variables; (2) may be explained by familial traits associated with the autism phenotype, or confounding by parity; and (3) is consistent across epidemiological studies. Multiple study methods were adopted. First, a Swedish 10-year birth cohort (N=1 075 588) was established. Linkage to the National Patient Register ascertained all autism cases (N=883). Second, 660 families identified within the birth cohort had siblings discordant for autism. Finally, meta-analysis included population-based epidemiological studies. In the birth cohort, autism risk increased monotonically with increasing paternal age. Offspring of men aged ≥50 years were 2.2 times (95% confidence interval: 1.26-3.88: P=0.006) more likely to have autism than offspring of men aged ≤29 years, after controlling for maternal age and documented risk factors for autism. Within-family analysis of discordant siblings showed that affected siblings had older paternal age, adjusting for maternal age and parity (P<0.0001). Meta-analysis demonstrated advancing paternal age association with increased risk of autism across studies. These findings provide the strongest evidence to date that advanced paternal age is a risk factor for autism in the offspring. Possible biological mechanisms include de novo aberration and mutations or epigenetic alterations associated with aging.

Deficits in visual sustained attention differentiate genetic liability and disease expression for schizophrenia from Bipolar Disorder.

BACKGROUND: There is mounting evidence for shared genetic liability to psychoses, particularly with respect to Schizophrenia (SZ) and Bipolar Disorder (BD), which may also involve aspects of cognitive dysfunction. Impaired sustained attention is considered a cardinal feature of psychoses but its association with genetic liability and disease expression in BD remains to be clarified. METHODS: Visual sustained attention was assessed using the Degraded Symbol Continuous Performance Test (DS-CPT) in a sample of 397 individuals consisting of 50 remitted SZ patients, 119 of their first degree relatives, 47 euthymic BD patients, 88 of their first degree relatives and 93 healthy controls. Relatives with a personal history of schizophrenia or bipolar spectrum disorders were excluded. Performance on the DS-CPT was evaluated based on the response criterion (the amount of perceptual evidence required to designate a stimulus as a target) and sensitivity (a signal-detection theory measure of signal/noise discrimination). RESULTS: We found no effect of genetic risk or diagnosis for either disorder on response criterion. In contrast, impaired sensitivity was seen in SZ patients and to a lesser degree in their relatives but not in BD patients and their relatives. These findings were not attributable to IQ, medication, age of onset or duration of illness. CONCLUSIONS: Our results argue for the specificity of visual sustained attention impairment in differentiating SZ from BD. They also suggest that compromised visual information processing is a significant contributor to these deficits in SZ.

Combining dimensional and categorical representation of psychosis: the way forward for DSM-V and ICD-11?

BACKGROUND: There is good evidence that psychotic symptoms segregate into symptom dimensions. However, it is still unclear how these dimensions are associated with risk indicators and other clinical variables, and whether they have advantages over categorical diagnosis in clinical practice. We investigated symptom dimensions in a first-onset psychosis sample and examined their associations with risk indicators and clinical variables. We then examined the relationship of categorical diagnoses to the same variables. METHOD: We recruited 536 patients as part of a population-based, incidence study of psychosis. Psychopathology was assessed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). A principal axis factor analysis was performed on symptom scores. The relationship of dimension scores with risk indicators and with clinical variables was then examined employing regression analyses. Finally, regression models were compared to assess the contribution of dimensions versus diagnosis in explaining these variables. RESULTS: Factor analysis gave rise to a five-factor solution of manic, reality distortion, negative, depressive and disorganization symptom dimensions. The scores of identified dimensions were differentially associated with specific variables. The manic dimension had the highest number of significant associations; strong correlations were observed with shorter duration of untreated psychosis, acute mode of onset and compulsory admission. Adding dimensional scores to diagnostic categories significantly increased the amount of variability explained in predicting these variables; the reverse was also true but to a lesser extent. CONCLUSIONS: Categorical and dimensional representations of psychosis are complementary. Using both appears to be a promising strategy in conceptualising psychotic illnesses.

Pathways to functional outcomes in schizophrenia: the role of premorbid functioning, negative symptoms and intelligence.

BACKGROUND: Social and intellectual premorbid functioning are generally estimated retrospectively, and related to clinical or hospitalization outcomes in schizophrenia. Yet the relationship between premorbid functioning assessed prior to psychiatric hospitalization and postmorbid functional outcomes has not been examined. OBJECTIVES: To test competing models of the relationship between (a) functional outcomes with (b) premorbid functioning assessed on nationally administered tests prior to psychiatric hospitalization, postmorbid intellectual functioning and symptomatology using a historical prospective design. METHODS: Ninety one inpatient and outpatient males with schizophrenia or schizoaffective disorder, aged 19 to 35, were examined using the Positive and Negative Syndrome Scale, the WAIS-III and Strauss and Carpenter social and occupational functional outcome scale. Premorbid intelligence and social functioning data were obtained from national standardized tests administered during high school prior to first hospitalization for schizophrenia. RESULTS: Path modeling showed that premorbid intelligence and behavioral functioning directly predicted postmorbid IQ and negative symptoms, and indirectly predicted postmorbid social and occupational functioning via negative symptoms. Item level analysis indicated that better social and occupational outcomes occurred in a group with few negative symptoms. CONCLUSIONS: Premorbid functioning, postmorbid IQ and negative symptoms are related, yet the relationship between premorbid functioning and postmorbid functional outcomes appears to be mediated by postmorbid negative symptoms.

Increased number of offspring in first degree relatives of psychotic individuals: a partial explanation for the persistence of psychotic illnesses.

OBJECTIVE: As patients with psychotic illness have fewer offspring than controls, the persistence of psychotic illness is puzzling. We hypothesized that unaffected first-degree relatives of patients have more offspring than controls. METHOD: Probands were 4904, individuals with non-affective psychotic disorders identified from a hospitalization registry. Unaffected first degree relatives and matched controls were identified from the Israeli Population Registry. The number of offspring of unaffected parents, biological siblings and controls was ascertained. RESULTS: Unaffected parents of psychotic patients had more offspring/person than controls; 4.5 +/- 2.7 vs. 3.4 +/- 2.2, P = 0.000. Unaffected parents from familial psychosis families (more than one affected family member) had 1.83 more offspring than controls; unaffected parents from non-familial psychosis families had 0.97 more offspring than controls (both P < 0.001). CONCLUSION: These findings might imply that genes which increase susceptibility for schizophrenia may be associated with increased number of offspring, perhaps supplying a partial explanation for the persistence of psychosis.