Search

Concordance for schizophrenia is high in monozygotic twins but the extent to which concordance varies according to the presence of other schizophrenia risk factors is not well established. We aimed to investigate this in systematically ascertained twin samples. DSM-III-R/DSM-IV diagnoses were made from original data or published case histories from four systematically ascertained monozygotic twin samples. Probandwise concordance for schizophrenia was calculated according to the presence of psychotic disorder in first-degree relatives, birth order, gender, and age-at-onset. Logistic regression analysis was also performed to adjust for potential confounders. Psychotic disorder in parents and earlier age-at-onset were significantly associated with higher probandwise concordance for schizophrenia, including after adjustment for potential confounders. For example, when no parents had a psychotic disorder concordance was 34/88 (38.6%) versus 10/16 (62.5%) when one parent was affected; and for age-at-onset <23 years concordance was 25/46 (54.3%), declining to 13/44 (29.5%) for age-at-onset >30 years. These results are consistent with psychotic disorder in parents and age-at-onset being markers of the level of familial liability to schizophrenia and these factors may be useful in genetic counseling of monozygotic twins and in identifying and managing those at particularly high risk, if these findings are further replicated., (© 2018 Wiley Periodicals, Inc.)

This study aimed to test for overlap in genetic influences between psychotic-like experience traits shown by adolescents in the community, and clinically-recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic-like experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self- and parent-ratings in three European community samples aged 15-19 years (Final N incl. siblings = 6,297-10,098). A mega-genome-wide association study (mega-GWAS) for each psychotic-like experience domain was performed. Single nucleotide polymorphism (SNP)-heritability of each psychotic-like experience domain was estimated using genomic-relatedness-based restricted maximum-likelihood (GREML) and linkage disequilibrium- (LD-) score regression. Genetic overlap between specific psychotic-like experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk score (PRS) and LD-score regression. GREML returned SNP-heritability estimates of 3-9% for psychotic-like experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent-rated Negative Symptoms). Mega-GWAS analysis identified one genome-wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic-like experience trait domains (Paranoia and Hallucinations only in non-zero scorers). The major depression PRS significantly predicted Anhedonia and Parent-rated Negative Symptoms in adolescence. Psychotic-like experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically-recognized psychiatric disorders, specifically schizophrenia and major depression., (© 2018 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.)

The nosological status of schizoaffective disorders remains controversial. Twin studies are potentially valuable for investigating relationships between schizoaffective-mania, schizoaffective-depression, and other psychotic syndromes, but no such study has yet been reported. We ascertained 224 probandwise twin pairs [106 monozygotic (MZ), 118 same-sex dizygotic (DZ)], where probands had psychotic or manic symptoms, from the Maudsley Twin Register in London (1948-1993). We investigated Research Diagnostic Criteria schizoaffective-mania, schizoaffective-depression, schizophrenia, mania and depressive psychosis primarily using a non-hierarchical classification, and additionally using hierarchical and data-derived classifications, and a classification featuring broad schizophrenic and manic syndromes without separate schizoaffective syndromes. We investigated inter-rater reliability and co-occurrence of syndromes within twin probands and twin pairs. The schizoaffective syndromes showed only moderate inter-rater reliability. There was general significant co-occurrence between syndromes within twin probands and MZ pairs, and a trend for schizoaffective-mania and mania to have the greatest co-occurrence. Schizoaffective syndromes in MZ probands were associated with relatively high risk of a psychotic syndrome occurring in their co-twins. The classification of broad schizophrenic and manic syndromes without separate schizoaffective syndromes showed improved inter-rater reliability, but high genetic and environmental correlations between the two broad syndromes. The results are consistent with regarding schizoaffective-mania as due to co-occurring elevated liability to schizophrenia, mania, and depression; and schizoaffective-depression as due to co-occurring elevated liability to schizophrenia and depression, but with less elevation of liability to mania. If in due course schizoaffective syndromes show satisfactory inter-rater reliability and some specific etiological factors they could alternatively be regarded as partly independent disorders., (Copyright © 2011 Wiley Periodicals, Inc.)

Genetic factors are likely to influence clinical variation in schizophrenia, but it is unclear which variables are most suitable as phenotypes and which molecular genetic loci are involved. We evaluated clinical variable phenotypes and applied suitable phenotypes in genome-wide covariate linkage analysis. We ascertained 170 affected relative pairs (168 sibling-pairs and two avuncular pairs) with DSM-IV schizophrenia or schizoaffective disorder from the United Kingdom. We defined psychotic symptom dimensions, age at onset (AAO), and illness course using the OPCRIT checklist. We evaluated phenotypes using within sibling-pair correlations and applied suitable phenotypes in multipoint covariate linkage analysis based on 372 microsatellite markers at ∼10 cM intervals. The statistical significance of linkage results was assessed by simulation. The positive and disorganized symptom dimensions, AAO, and illness course qualified as suitable phenotypes. There were no genome-wide significant linkage results. There was suggestive evidence of linkage for the positive dimension on chromosomes 2q32, 10q26, and 20q12; the disorganized dimension on 8p21 and 17q21; and illness course on 2q33 and 22q11. The linkage peak for disorganization on 17q21 remained suggestive after correction for multiple testing. To our knowledge, this is the first study to integrate phenotype evaluation and genome-wide covariate linkage analysis for symptom dimensions and illness history variables in sibling-pairs with schizophrenia. The significant within-pair correlations strengthen the evidence that some clinical variables within schizophrenia are suitable phenotypes for molecular genetic investigations. At present there are no genome-wide significant linkage results for these phenotypes, but a number of suggestive findings warrant further investigation., (Copyright © 2011 Wiley Periodicals, Inc.)

Factor analysis of psychotic symptoms frequently results in positive, negative, and disorganized dimensions, but heritability estimates have not yet been reported. Symptom dimensions are usually only measured in individuals with psychotic disorders. Here, it is valuable to assess influences acting via liability to psychosis and independent modifying effects. We estimated heritability for psychotic symptom dimensions, taking account of these issues. Two-hundred-and-twenty-four probandwise twin pairs (106 monozygotic, 118 same-sex dizygotic), where probands had psychoses, were ascertained from the Maudsley Twin Register in London (1948-1993). Lifetime history of DSM-III-R psychotic disorder and psychotic symptom dimensions was assessed from clinical records and research interviews and rated using the Operational Criteria Checklist. Estimates of heritability and environmental components of variance in liability were made with structural equation modeling using a causal-contingent common pathway model adapted for ascertainment from a clinical register. Significant heritability was found for DSM-III-R psychotic disorder (h² = 90%, 95%CI 68-94%) and the disorganized symptom dimension (h² = 84%, 95%CI 18-93%). The heritability for the disorganized dimension remained significant when influences acting through liability to psychosis were set to zero, suggesting that some influences on disorganization are modifying factors independent of psychosis liability. However, the relative extent of modifying factors versus influences acting through psychosis liability could not be clearly determined. To our knowledge, this study provides the first formal evidence of substantive heritability for the disorganized symptom dimension, and suggests that genetic loci influencing disorganization in individuals with psychoses are in some cases different from loci that influence risk of psychotic disorders themselves., (Copyright © 2010 Wiley-Liss, Inc.)

We investigated which psychotic symptom dimensions are likely to be most useful as phenotypes for genetic linkage and association studies. Two hundred twenty-four probandwise twin pairs (106 monozygotic,118 same-sex dizygotic), where probands had psychosis, were ascertained from the Maudsley Twin Register in London. Dimensions were defined as ordinal symptom scores using the OPCRIT checklist, based on previous factor analyses of this and other samples. To qualify as a potentially useful phenotype, dimensions had to show (a) a satisfactory polychoric model fit and significant within-pair correlation in MZ pairs concordant for DSM-III-R psychosis and (b) that they could not be better defined in terms of other combinations of relevant symptoms, single symptoms, or dichotomized dimension scores. Relationships between dimension scores in twin probands and risk of psychosis in co-twins were also investigated. None of the positive or negative dimensions satisfied the phenotypic criteria. The disorganized dimensions showed significant and substantial correlations which maximized for a narrow definition. Combined negative/disorganized dimensions also showed significant and substantial correlations, but did not have advantages over disorganized dimensions. None of the dimensions were significant predictors of psychosis risk in co-twins. We conclude that, of the dimensions analyzed, the narrow disorganized dimension shows most promise as a phenotype for molecular genetic research.

Some studies have reported associations between COMT and MAO genotypes and aggression, though results have been inconsistent. We examined the relationship between Overt aggression scale (OAS) scores, and both MAOA and MAOB polymorphisms in a well-powered sample of 346 subjects with schizophrenia. We also examined COMT in a Stage II replication sample of 150 individuals, and combined these results with our previously reported (Stage I) findings for COMT. We found no evidence of any associations between OAS ratings and any of the polymorphisms investigated under different genetic models. There was no evidence of epistatic interaction between MAOA and COMT on OAS scores. These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior., (Copyright 2004 Wiley-Liss, Inc.)