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Genetic and environmental determinants of violence risk in psychotic disorders: a multivariate quantitative genetic study of 1.8 million Swedish twins and siblings.

ABSTRACT: Patients diagnosed with psychotic disorders (for example, schizophrenia and bipolar disorder) have elevated risks of committing violent acts, particularly if they are comorbid with substance misuse. Despite recent insights from quantitative and molecular genetic studies demonstrating considerable pleiotropy in the genetic architecture of these phenotypes, there is currently a lack of large-scale studies that have specifically examined the aetiological links between psychotic disorders and violence. Using a sample of all Swedish individuals born between 1958 and 1989 (n=3 332 101), we identified a total of 923 259 twin-sibling pairs. Patients were identified using the National Patient Register using validated algorithms based on International Classification of Diseases (ICD) 8-10. Univariate quantitative genetic models revealed that all phenotypes (schizophrenia, bipolar disorder, substance misuse, and violent crime) were highly heritable (h(2)=53-71%). Multivariate models further revealed that schizophrenia was a stronger predictor of violence (r=0.32; 95% confidence interval: 0.30-0.33) than bipolar disorder (r=0.23; 0.21-0.25), and large proportions (51-67%) of these phenotypic correlations were explained by genetic factors shared between each disorder, substance misuse, and violence. Importantly, we found that genetic influences that were unrelated to substance misuse explained approximately a fifth (21%; 20-22%) of the correlation with violent criminality in bipolar disorder but none of the same correlation in schizophrenia (Pbipolar disorder<0.001; Pschizophrenia=0.55). These findings highlight the problems of not disentangling common and unique sources of covariance across genetically similar phenotypes as the latter sources may include aetiologically important clues. Clinically, these findings underline the importance of assessing risk of different phenotypes together and integrating interventions for psychiatric disorders, substance misuse, and violence.

SUBMITTER: Sariaslan A

PROVIDER: S-EPMC4842006 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionUsing Swedish nationwide registry data, we investigated the contribution of genetic and environmental risk factors to the etiology of smoking status across stages of pregnancy with increasing degrees of social and psychological pressure to reduce or quit smoking, by twin and sibling modeling.Aims and methodsSmoking status was available before, and during early and late pregnancy from the Medical Birth Register. Twin, full-, and half-sibling pairs, both reared together and apart, born between 1960 and 1990 were obtained from national twin and genealogical registers. Genetic structural equation modeling in OpenMx was applied to the population-based data to estimate shared genetic and/or environmental covariance across stages of pregnancy, accounting for maternal birth cohort and age at pregnancy.ResultsAnalyses of paired data on 258 749 individuals suggested that risk factors for smoking status changed across stages of pregnancy. Results predicted substantial heritability (60-70%) and moderate contributions of shared environmental factors (10-15%) for smoking status. Whilst the same shared environmental factors were amplified from before pregnancy to late pregnancy, new primarily unique environmental factors explained ~10% of the variance during early pregnancy which was carried forward to late pregnancy.ConclusionsUsing registry data on women across pregnancy, we replicated that smoking status is highly heritable. Furthermore, we found support for increased impact of shared environmental factors during pregnancy of factors already present prior to pregnancy, and an independent set of mostly new unique environmental factors that may be triggered by increased social pressure to reduce or quit smoking during pregnancy.ImplicationsAs new factors partially explain smoking status during pregnancy and the effects of familial factors increase across pregnancy, efforts to prevent or reduce smoking during pregnancy should receive continued attention, with a focus on both the individual and the family unit.

Project description:ImportanceGeneral and specific factors of psychopathology are associated with future adverse outcomes, indicating that they might be useful for identifying individuals at greatest risk. However, it remains unknown if these associations are attributable to confounders that may influence both the psychopathology factors and later outcomes.ObjectiveTo analyze associations between psychopathology factors and clinically relevant outcomes within family pairs, adjusting for unmeasured confounds by applying co-twin control and sibling comparison designs.Design, setting, and participantsThis longitudinal cohort study with a follow-up range of 9 to 13 years included all Swedish twins born from 1959 to 1985 who participated in the Study of Twin Adults: Genes and Environment (60% response rate) and the oldest pair of all Swedish siblings born from 1959 to 1985 per the Multi-Generation Register. Twins were evaluated based on responses to a hierarchical factor model derived using multivariate statistics. Sibling pairs were evaluated based on psychiatric diagnoses per the Swedish National Patient Register. Information on outcome events and prescriptions were derived from the National Patient Register, Prescribed Drug Register, and Crime Register. Baseline assessment was in August 2005, and data were analyzed from January 2022 to February 2023.ExposuresHierarchical factor model consisting of 1 general and 4 specific factors fit to 48 psychiatric symptoms on which twin participants self-reported in 2005 and 1 general and 3 specific factors fit to 9 register-based psychiatric diagnoses assigned to sibling participants prior to 2005.Main outcomes and measuresOutcomes consisted of 7 register-based events occurring after 2005, including suicidal behavior, substance overdoses, and criminal suspicion or convictions (data available until the end of 2013), and prescription of antidepressants, antialcohol or antiopioid medication, antipsychotics, and stimulants (data available until the end of 2017).ResultsThe study included 32 328 twins (mean [SD] age, 34 [8] years; 16 076 [49.73%] male) and 1 942 106 siblings (mean [SD] age, 34 [7] years; 991 500 [51.05%] male). General psychopathology was significantly associated with all 7 outcomes within sibling pairs (mean within-pair odds ratio [OR], 2.28; 95% CI, 2.19-2.37) and dizygotic twin pairs (within-pairs OR, 1.65; 95% CI, 1.38-1.98) and with 3 outcomes within monozygotic twin pairs (mean within-pairs OR, 1.77; 95% CI, 1.35-2.36). Within sibling pairs, the specific internalizing factor was associated with antidepressant prescriptions (within-pairs OR, 1.65; 95% CI, 1.59-1.71), the specific substance misuse factor was associated prescription of antialcohol and antiopioid medication (within-pairs OR, 2.36; 95% CI, 2.20-2.54), and the specific psychotic factor was associated with antipsychotic medications (within-pairs OR, 1.61; 95% CI, 1.51-1.72). Similar results emerged within twin pairs.Conclusion and relevanceIn this cohort study, general psychopathology was significantly associated with all 7 outcomes within sibling and dizygotic twin pairs and 3 outcomes within monozygotic twin pairs at 10 years. Within twin and sibling pairs, the specific factors were primarily associated with related outcomes. Several of the associations in this cohort study could not be attributed to unmeasured confounds shared by family members, suggesting that interventions toward broad psychopathology dimensions might help reduce the risk of future clinically relevant events.

Project description:Nonalcoholic fatty liver disease (NAFLD) is becoming the major chronic liver disease in many countries. Its pathogenesis is multifactorial, but twin and familial studies indicate significant heritability, which is not fully explained by currently known genetic susceptibility loci. Notably, mutations in genes encoding nuclear lamina proteins, including lamins, cause lipodystrophy syndromes that include NAFLD. We hypothesized that variants in lamina-associated proteins predispose to NAFLD and used a candidate gene-sequencing approach to test for variants in 10 nuclear lamina-related genes in a cohort of 37 twin and sibling pairs: 21 individuals with and 53 without NAFLD. Twelve heterozygous sequence variants were identified in four lamina-related genes (ZMPSTE24, TMPO, SREBF1, SREBF2). The majority of NAFLD patients (>90%) had at least one variant compared to <40% of controls (P < 0.0001). When only insertions/deletions and changes in conserved residues were considered, the difference between the groups was similarly striking (>80% versus <25%; P < 0.0001). Presence of a lamina variant segregated with NAFLD independently of the PNPLA3 I148M polymorphism. Several variants were found in TMPO, which encodes the lamina-associated polypeptide-2 (LAP2) that has not been associated with liver disease. One of these, a frameshift insertion that generates truncated LAP2, abrogated lamin-LAP2 binding, caused LAP2 mislocalization, altered endogenous lamin distribution, increased lipid droplet accumulation after oleic acid treatment in transfected cells, and led to cytoplasmic association with the ubiquitin-binding protein p62/SQSTM1. CONCLUSION:Several variants in nuclear lamina-related genes were identified in a cohort of twins and siblings with NAFLD; one such variant, which results in a truncated LAP2 protein and a dramatic phenotype in cell culture, represents an association of TMPO/LAP2 variants with NAFLD and underscores the potential importance of the nuclear lamina in NAFLD. (Hepatology 2018;67:1710-1725).

Project description:ImportanceFamily and genetic approaches have traditionally been used to evaluate our diagnostic concepts. Using a novel method, the family genetic risk score (FGRS), can we validate the genetic architecture of major affective and psychotic disorders in a national Swedish sample?ObjectiveTo determine whether FGRSs, calculated for the entire Swedish population, can elucidate the genetic relationship between major affective and psychotic disorders and clarify the association of genetic risk with important clinical features of disease.Design, setting, and participantsThis cohort study included the native Swedish population born from January 1, 1950, through December 31, 1995, and followed up through December 31, 2017. Data were collected from Swedish population-based primary care, specialist, and hospital registers, including age at first registration for a psychiatric diagnosis and number of registrations for major depression, bipolar disorder, and schizophrenia. Data were analyzed from October 15, 2020, to February 2, 2021.ExposuresFGRSs for major depression, bipolar disorder, and schizophrenia calculated from morbidity risks for disorders in first- through fifth-degree relatives, controlling for cohabitation.Main outcomes and measuresDiagnoses of major depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other nonaffective psychoses (ONAPs), age at registration, and number of registrations for major depression, bipolar disorder, and schizophrenia. Diagnostic conversion of major depression to bipolar disorder and ONAPs to schizophrenia was assessed by Cox proportional hazards regression models.ResultsThe cohort included 4 129 002 individuals (51.4% male) with a mean (SD) age at follow-up of 45.5 (13.4) years. Mean FGRSs for major depression, bipolar disorder, and schizophrenia produced distinct patterns for major depression, bipolar disorder, schizophrenia, schizoaffective disorder, and ONAPs with large separations between disorders. In major depression, bipolar disorder, and schizophrenia, high FGRSs were associated with early age at onset and high rates of recurrence: a high mean FGRS for bipolar disorder was associated with early age at onset (younger than 25 years, 0.11; 95% CI, 0.11-0.12) and higher recurrence (8 or more registrations, 0.11; 95% CI, 0.11-0.12) in major depression. The schizophrenia FGRS was separately associated with psychotic and nonpsychotic forms of major depression (0.10; 95% CI, 0.06-0.14 vs 0.03; 95% CI, 0.02-0.03) and bipolar disorder (0.22; 95% CI, 0.16-0.28 vs 0.11; 95% CI, 0.09-0.12). The bipolar disorder and schizophrenia FGRSs were associated with conversion from major depression to bipolar disorder (eg, hazard ratio, 1.70 [95% CI, 1.63-1.78] for high vs low bipolar FGRS) and ONAP to schizophrenia (eg, hazard ratio, 1.38 [95% CI, 1.27-1.51] for high vs low schizophrenia FGRS).Conclusions and relevanceIn this Swedish cohort study, the FGRSs for major depression, bipolar disorder, and schizophrenia for the Swedish population clearly separated major affective and psychotic disorders from each other in a larger and more representative patient sample than previously possible. These findings provide possible validation, from a genetic perspective, for these major diagnostic categories. These results replicated and extended prior observations on more limited samples of the association of FGRS with age at onset, recurrence, psychotic subtypes, and diagnostic conversions.

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Genetic and environmental determinants of violence risk in psychotic disorders: a multivariate quantitative genetic study of 1.8 million Swedish twins and siblings.

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