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Schizophrenia (SCZ) is highly heterogenous and no subtypes characterizing treatment response or longitudinal course well. Cognitive impairment is a core clinical feature of SCZ and a determinant of poorer outcome. Genetic overlap between SCZ and cognitive traits is complex, with limited studies of comprehensive epidemiological and genomic evidence. To examine the relation between SCZ and three cognitive traits, educational attainment (EDU), premorbid cognitive ability, and intellectual disability (ID), we used two Swedish samples: a national cohort (14,230 SCZ cases and 3,816,264 controls) and a subsample with comprehensive genetic data (4992 cases and 6009 controls). Population-based analyses confirmed worse cognition as a risk factor for SCZ, and the pedigree and SNP-based genetic correlations were comparable. In the genotyped cases, those with high EDU and premorbid cognitive ability tended to have higher polygenetic risk scores (PRS) of EDU and intelligence and fewer rare exonic variants. Finally, by applying an empirical clustering method, we dissected SCZ cases into four replicable subgroups characterized by EDU and ID. In particular, the subgroup with higher EDU in the national cohort had fewer adverse outcomes including long hospitalization and death. In the genotyped subsample, this subgroup had higher PRS of EDU and no excess of rare genetic burdens than controls. In conclusion, we found extensive evidence of a robust relation between cognitive traits and SCZ, underscoring the importance of cognition in dissecting the heterogeneity of SCZ.

Treatment response and resistance in major depressive disorder (MDD) are suggested to be heritable. Due to significant challenges in defining treatment-related phenotypes, our understanding of their genetic bases is limited. This study aimed to derive a stringent definition of treatment resistance and to investigate genetic overlap between treatment response and resistance in MDD. Using electronic medical records on the use of antidepressants and electroconvulsive therapy (ECT) from Swedish registers, we derived the phenotype of treatment-resistant depression (TRD) within ~ 4 500 individuals with MDD in three Swedish cohorts. Considering antidepressants and lithium are first-line treatment and augmentation used for MDD, respectively, we generated polygenic risk scores of antidepressant and lithium response for individuals with MDD, and evaluated their associations with treatment resistance by comparing TRD with non-TRD. Among 1 778 ECT-treated MDD cases, nearly all (94%) used antidepressants before first ECT, and the vast majority had at least one (84%) or two (61%) antidepressants of adequate duration, suggesting these MDD cases receiving ECT were resistant to antidepressants. We found that TRD cases tend to have lower genetic load of antidepressant response than non-TRD, although the difference was not significant; furthermore, TRD cases had significantly higher genetic load of lithium response (OR = 1.10–1.12 under different definitions). The results support evidence of heritable components in treatment-related phenotypes and highlight the overall genetic profile of lithium-sensitivity in TRD. This finding further provides a genetic explanation for lithium efficacy in treating TRD.

OBJECTIVE In this study, we aimed to determine the lifetime prevalence of substance use disorder (SUD) in a Canadian rheumatoid arthritis (RA) cohort and factors associated with SUD in RA. METHODS Participants with RA (N = 154) were recruited via rheumatology clinics as part of a larger cohort study of psychiatric comorbidity in immune-mediated inflammatory diseases. SUD is defined as the uncontrolled use of a substance despite the harmful consequences of its use. To identify lifetime SUD, the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition was administered to participants. Participants' sociodemographic and RA clinical characteristics were also assessed. We examined factors associated with lifetime SUD using unadjusted and adjusted logistic regression modeling. RESULTS Twenty-three (14.9%) of 154 participants with RA met the criteria for a lifetime diagnosis of SUD. The majority of the participants were women, were White, had postsecondary education, and were on a disease-modifying antirheumatic drug. Factors associated with increased odds of SUD were male sex (adjusted odds ratio [aOR]: 3.63, 95% confidence interval [CI]: 1.03-12.73), younger age (aOR: 0.94, 95% CI: 0.90-0.98), and ever smoking (aOR: 6.44, 95% CI: 1.53-27.07). CONCLUSION We found that approximately 1 in 7 individuals with RA had a lifetime diagnosis of SUD, highlighting the importance of identifying and treating SUD in those with RA. In particular, the following factors were associated with higher odds of SUD: male sex, younger age, and smoking behaviors.

Background and ObjectivesObservational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS.MethodsWe generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 × 10−8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modifiedpvalue threshold for inclusion in the PGS (5 × 10−5) and applying Mendelian randomization (MR) rather than using PGS.ResultsInitial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS: 3.08%, 95% CI: 1.77%, 4.42%;p= 4.33e-06; R2= 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87–1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87–1.28), change in T25FW (per 1SD: 0.07%; 95% CI: −0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: −0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using otherpvalue thresholds or those applying MR.DiscussionGenetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS.

Individuals with schizophrenia (SCZ) have a 2–3-fold higher risk of mortality than the general population. Heritability of mortality in psychiatric disorders has been proposed; however, few have investigated SCZ family history and genetic variation, with all-cause and specific causes of death. We aimed to identify correlates of SCZ mortality using genetic epidemiological and genetic modelling in two samples: a Swedish national population sample and a genotyped subsample. In the Swedish national population sample followed from the first SCZ treatment contact until emigration, death or end of the follow-up, we investigated a standardised measure of SCZ family history. In a subgroup with comprehensive genetic data, we investigated the impact of common and rare genetic variation. Cox proportional hazards regression was used to estimate the association between various factors and mortality (all and specific causes). A total of 13727 SCZ cases fulfilled criteria for the population-based analyses (1268 deaths, 9.2%). The genomic subset contained 4991 cases (1353 deaths, 27.1%). Somatic mutations associated with clonal hematopoiesis with unknown drivers were associated with all-cause mortality (HR 1.77, 95% CI: 1.26–2.49). No other heritable measures were associated with all-cause mortality nor with any specific causes of death. Future studies in larger, comparable cohorts are warranted to further understand the association between hereditary measures and mortality in SCZ.

To develop group-based trajectories of depressive symptoms in immune-mediated inflammatory disease (IMID) to understand their evolution and identify any associated factors, with the overall goal of identifying those at highest risk of higher depressive symptom burden.922 participants had an IMID or anxiety/depression. The PHQ-9 was administered at four visits, and polygenic risk scores (PRS) for major depressive disorder, depressive symptoms, and body mass index (BMI) were generated. Group-based trajectory modelling of PHQ-9 scores estimated distinct trajectories. Regression tested whether specific factors were associated with the trajectories. Mediation analyses assessed whether IMID mediated the association between BMI PRS and trajectories.Three trajectories were identified. Regression demonstrated those in Group 3 ('high symptoms') had significantly higher PRS for the three traits, compared to Group 1 ('minimal symptoms') (OR: 1.34-1.66, P 0.01). Stratified analyses in the IMID subgroup revealed an increased effect for BMI PRS in Group 3 (OR: 2.31, P 0.001), in contrast, BMI PRS was no longer associated in the non-IMID sample. No significant indirect effect of BMI PRS on depressive symptoms trajectories was identified via IMID.A significant association between polygenicity and PHQ-9 trajectories supports a role for genetic inheritance in the variability in depressive symptoms in IMID.

Background: Major depressive disorder (MDD) is a common psychiatric disorder associated with a high disease burden. This study gives a comprehensive overview of the prevalence, outcomes, treatment, and genetic epidemiology of MDD within and across the Scandinavian countries. Methods: This study has aimed to assess and compare across Norway, Denmark, and Sweden 1) the prevalence and trajectories of MDD and comorbidity, 2) outcomes and treatment, and 3) heritability (Denmark and Sweden only). The analyses leveraged data on 272,944 MDD cases (and 6.2 million non-cases) from Norway, Sweden, and Denmark in specialist care in national longitudinal health registers covering 1975–2013. Relying on harmonized public data global comparisons of socioeconomic and health metrics were performed to assess to what extent findings are generalizable. Findings: MDD ranked among the most prevalent psychiatric disorders. For many cases, the disorder trajectory was severe, with varying proportions experiencing recurrence, developing comorbid disorders, requiring inpatient treatment, or dying of suicide. Important country differences in specialist care prevalence and treatment were observed. Heritability estimates were moderate (35–48%). In terms of socioeconomic and health indices, the Scandinavian nations were comparable to one another and grouped with other Western nations. Interpretation: The Scandinavian countries were similar with regards to MDD epidemiological measures, but we show that differences in health care organization need to be taken into consideration when comparing countries. This study demonstrates the utility of using comprehensive population-wide registry data, outlining possibilities for other applications. The findings will be of use to policy makers for developing better prevention and intervention strategies. Funding: Swedish Research Council (Vetenskapsrådet, award D0886501 to PFS), US National Institutes of Mental Health R01 MH123724 (to PFS), European Union's Horizon 2020 Research and Innovation Program ( 847776 and 964874, to OA) and European Research Council grant (grant agreement ID 101042183, to YL).

BackgroundConflicting evidence exists on the impact of the COVID-19 pandemic restrictions on preterm birth (PTB) and stillbirth rates. We aimed to evaluate changes in PTB and stillbirth rates before and during the pandemic period and assess the potential effect modification of socioeconomic status (SES).MethodsUsing the linked administrative health databases from Manitoba, Canada, we conducted a cross-sectional study among all pregnant women, comparing 3.5 years pre-pandemic (1 October 2016 to 29 February 2020) to the first year of the pandemic (1 March 2020 to 31 March 2021). We used generalised linear models to assess the quarterly rates of PTB (ResultsWe examined 70 931 pregnancies in Manitoba during the study period. The risk of PTB increased by 7.7% (95%CI 1.01 to 1.13) and stillbirths by 33% (95% CI 1.08 to 1.64) during the pandemic period. Following COVID-19 restrictions implemented in March 2020, there were increases in the quarterly rates of both PTB (immediate increase (β2)=1.37; p=0.0247) and stillbirths (immediate increase (β2)=0.12; p=0.4434). Among the lower income groups, the pandemic restrictions resulted in an immediate relative increase in PTB and stillbirth rates by 20.12% (immediate increase (β2)=3.17; p=0.0057) and 27.19% (immediate increase (β2)=0.48; p=0.0852). However, over the pandemic, the overall PTB rate significantly decreased as a rebound effect by 0.85% per quarter (p=0.0004), whereas the overall stillbirth rate did not decrease significantly (slope decrease (β3) =−0.01; p=0.8296) compared with the pre-pandemic period. The quarterly rates during the pandemic among the higher income group decreased by 0.39% (p=0.1296) for PTB and increased by 0.07% (p=0.1565) for stillbirth. We observed an effect modification by SES for PTB rates (p=0.047).ConclusionWhile the onset of COVID-19 pandemic restrictions was not associated with significant effects on stillbirth rates, we observed an immediate and rebound effect on PTB rates. The impact of COVID-19 on preterm birth was dependent on SES, with higher influence on families with lower SES. Further studies are needed to detect future trend changes during pandemic waves after 2021 and assess potential underlying mechanisms.

Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

Polygenic scores (PGSs) have emerged as promising tools for complex trait risk prediction. The application of these scores to pharmacogenomics provides new opportunities to improve the prediction of treatment outcomes. To gain insight into this area of research, we conducted a systematic review and accompanying analysis. This review uncovered 51 papers examining the use of PGSs for drug-related outcomes, with the majority of these papers focusing on the treatment of psychiatric disorders (n = 30). Due to difficulties in collecting large cohorts of uniformly treated patients, the majority of pharmacogenomic PGSs were derived from large-scale genome-wide association studies of disease phenotypes that were related to the pharmacogenomic phenotypes under investigation (e.g., schizophrenia-derived PGSs for antipsychotic response prediction). Examination of the research participants included in these studies revealed that the majority of cohort participants were of European descent (78.4%). These biases were also reflected in research affiliations, which were heavily weighted towards institutions located in Europe and North America, with no first or last authors originating from institutions in Africa or South Asia. There was also substantial variability in the methods used to develop PGSs, with between 3 and 6.6 million variants included in the PGSs. Finally, we observed significant inconsistencies in the reporting of PGS analyses and results, particularly in terms of risk model development and application, coupled with a lack of data transparency and availability, with only three pharmacogenomics PGSs deposited on the Polygenic Score Catalog. These findings highlight current gaps and key areas for future pharmacogenomic PGS research.

Schizophrenia (SCZ) is associated with high mortality. DNA methylation levels vary over the life course, and pre-selected combinations of methylation array probes can be used to estimate “methylation age” (mAge). mAge correlates highly with chronological age but when it differs, termed mAge acceleration, it has been previously associated with all-cause mortality. We tested the association between mAge acceleration and mortality in SCZ and controls. We selected 190 SCZ cases and 190 controls from the Sweden Schizophrenia Study. Cases were identified from the Swedish Hospital Discharge Register with ≥5 specialist treatment contacts and ≥5 antipsychotic prescriptions. Controls had no psychotic disorder or antipsychotics. Subjects were selected if they had died or survived during follow-up (2:1 oversampling). Extracted DNA was assayed on the Illumina MethylationEPIC array. mAge was regressed on age at sampling to obtain mAge acceleration. Using Cox proportional hazards regression, the association between mAge acceleration and mortality was tested. After quality control, the following were available: n = 126 SCZ died, 63 SCZ alive, 127 controls died, 62 controls alive. In the primary analyses, we did not find a significant association between mAge acceleration and SCZ mortality (adjusted p > 0.005). Sensitivity analyses excluding SCZ cases with pre-existing cancer demonstrated a significant association between the Hannum mAge acceleration and mortality (hazard ratio = 1.13, 95% confidence interval = 1.04–1.22, p = 0.005). Per our pre-specified criteria, we did not confirm our primary hypothesis that mAge acceleration would predict subsequent mortality in people with SCZ, but we cannot rule out smaller effects or effects in patient subsets.

Major depression (MD) is a heterogeneous disorder; however, the extent to which genetic factors distinguish MD patient subgroups (genetic heterogeneity) remains uncertain. This study sought evidence for genetic heterogeneity in MD. Using UK Biobank cohort, the authors defined 16 MD subtypes within eight comparison groups (vegetative symptoms, symptom severity, comorbid anxiety disorder, age at onset, recurrence, suicidality, impairment and postpartum depression; N~3 000-47 000). To compare genetic component of these subtypes, subtype-specific genome-wide association studies were performed to estimate SNP-heritability, and genetic correlations within subtype comparison and with other related disorders or traits. The findings indicated that MD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (vegetative symptoms, age at onset, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtypes comparisons ranged from 0.55 to 0.86, suggesting genetic profiles are only partially shared among MD subtypes. Furthermore, subtypes that are more clinically challenging, e.g., early-onset, recurrent, suicidal, more severely impaired, had stronger genetic correlations with other psychiatric disorders. MD with atypical-like features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (−0.09) was found in those without atypical-like features. Novel genomic loci with subtype-specific effects were identified. These results provide the most comprehensive evidence to date for genetic heterogeneity within MD, and suggest that the phenotypic complexity of MD can be effectively reduced by studying the subtypes which share partially distinct etiologies.

Major depression (MD) is a heterogeneous disorder; however, the extent to which genetic factors distinguish MD patient subgroups (genetic heterogeneity) remains uncertain. This study sought evidence for genetic heterogeneity in MD. Using UK Biobank cohort, the authors defined 16 MD subtypes within eight comparison groups (vegetative symptoms, symptom severity, comorbid anxiety disorder, age at onset, recurrence, suicidality, impairment and postpartum depression; N∼3 000-47 000). To compare genetic component of these subtypes, subtype-specific genome-wide association studies were performed to estimate SNP-heritability, and genetic correlations within subtype comparison and with other related disorders or traits. The findings indicated that MD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (vegetative symptoms, age at onset, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtype comparisons ranged from 0.55 to 0.86, suggesting genetic profiles are only partially shared among MD subtypes. Furthermore, subtypes that are more clinically challenging, e.g., early-onset, recurrent, suicidal, more severely impaired, had stronger genetic correlations with other psychiatric disorders. MD with atypical-like features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (−0.09) was found in those without atypical-like features. Novel genomic loci with subtype-specific effects were identified. These results provide the most comprehensive evidence to date for genetic heterogeneity within MD, and suggest that the phenotypic complexity of MD can be effectively reduced by studying the subtypes which share partially distinct etiologies.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

Background: Major depressive disorder (MDD) is common in multiple sclerosis (MS) and its incidence rises before MS diagnosis. However, the causality and direction of this association remain unclear. Objective: The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR). Methods: We selected genetic instruments associated with risk of MDD ( n = 660,937 cases; 1,453,489 controls) and MS ( n = 47,429 cases; 68,374 controls). Using two-sample MR, we examined putative causal effects in either direction, with sensitivity analyses to assess pleiotropy. Also, we adjusted for body mass index (BMI) in multivariable MR. Results: We found no effect of genetic liability to MDD on the odds of MS (OR = 1.07/doubling in odds, 95% CI = 0.90–1.28). Similarly, our findings did not support a causal effect of genetic liability to MS on MDD (OR = 1.00/doubling in odds, 95% CI = 0.99–1.01). Despite heterogeneity, sensitivity analyses indicated that bias from pleiotropy was unlikely. Conversely, genetic predisposition toward higher BMI increased the odds of MS (OR = 1.34/SD increase, 95% CI = 1.09–1.65) and MDD (OR = 1.08, 95% CI = 1.01–1.15). Conclusion: This study does not support a causal association between MDD genetic liability and MS susceptibility, and vice versa. Genetic evidence suggesting commonality of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis.

Objective:To evaluate the association between comorbidity and relapse rate in individuals with multiple sclerosis (MS).Methods:We recruited individuals with prevalent relapsing-onset MS from 4 Canadian MS Clinics to participate in a 2-year prospective multicenter cohort study involving cross-sectional assessment of comorbidities and relapses. Comorbidities were recorded using questionnaires, and relapses were captured from medical records at each visit. The association between comorbidities at baseline and relapse rate over the subsequent 2-year follow-up period was examined using Poisson regression, adjusting for age, sex, disability, disease duration, and treatment status.Results:Of 885 participants, 678 (76.6%) were women, averaging age 48.2 years at baseline. Anxiety (40.2%), depression (21.1%), hypertension (17.7%), migraine (18.1%), and hyperlipidemia (11.9%) were the most prevalent comorbidities. The frequency of participants experiencing relapses remained constant at 14.9% and 13.2% in years 1 and 2 post-baseline. After adjustment, participants reporting ≥3 baseline comorbidities (relative to none) had a higher relapse rate over the subsequent 2 years (adjusted rate ratio 1.45, 95% confidence interval [CI] 1.00–2.08). Migraine and hyperlipidemia were associated with increased relapse rate (adjusted rate ratio 1.38; 95% CI 1.01–1.89 and 1.67; 95% CI 1.07–2.61, respectively).Conclusions:Individuals with migraine, hyperlipidemia, or a high comorbidity burden (3 or more conditions) had an increased relapse rate over 2 years. These findings have potential implications for understanding the pathophysiology of MS relapses, and suggest that closer monitoring of individuals with specific or multiple comorbidities may be needed. Future research is needed to understand if the presence of comorbidity warrants a tailored approach to MS management.

Background Substance use disorders (SUDs) impose a substantial individual and societal burden; however, the prevalence and associated factors in persons with inflammatory bowel disease (IBD) are largely unknown. We evaluated the prevalence and risk factors of SUD in an IBD cohort. Methods Inflammatory bowel disease participants (n = 247) were recruited via hospital- and community-based gastroenterology clinics, a population-based IBD research registry, and primary care providers as part of a larger cohort study of psychiatric comorbidity in immune-mediated inflammatory diseases. The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV was administered to participants to identify lifetime SUD, anxiety disorder, and major depressive disorder. Additional questionnaires regarding participants’ sociodemographic and clinical characteristics were also completed. We examined demographic and clinical factors associated with lifetime SUD using unadjusted and adjusted logistic regression modeling. Results Forty-one (16.6%) IBD participants met the criteria for a lifetime diagnosis of an SUD. Factors associated with elevated odds of SUD were ever smoking (adjusted odds ratio [aOR], 2.96; 95% confidence interval [CI], 1.17–7.50), male sex (aOR, 2.44; 95% CI, 1.11–5.36), lifetime anxiety disorder (aOR, 2.41; 95% CI, 1.08–5.37), and higher pain impact (aOR, 1.08; 95% CI, 1.01–1.16). Conclusions One in six persons with IBD experienced an SUD, suggesting that clinicians should maintain high index of suspicion regarding possible SUD, and inquiries about substance use should be a part of care for IBD patients, particularly for men, smokers, and patients with anxiety disorders and pain., Authors evaluated the prevalence and risk factors of SUD in an IBD cohort (n = 247). Forty-one (16.6%) participants experienced a lifetime SUD. Factors associated with elevated odds of SUD were ever smoking, male sex, lifetime anxiety disorder, and higher pain impact.

A high proportion of those with schizophrenia experience treatment non-response, placing them at higher risk for mortality and suicide attempts, compared to treatment responders. The clinical, social, and economic burden of treatment-resistant schizophrenia (TRS) are substantial. Previous genomic and epidemiological studies of TRS were often limited by sample size or lack of comprehensive genomic data. We aimed to systematically understand the clinical, demographic, and genomic correlates of TRS using epidemiological and genetic epidemiological modelling in a Swedish national population sample (n = 24,706) and then in a subgroup with common variant genetic risk scores, rare copy-number variant burden, and rare exonic burden (n = 4936). Population-based analyses identified increasing schizophrenia family history to be significantly associated with TRS (highest quartile of familial burden vs. lowest: adjusted odds ratio (aOR): 1.31, P = 4.8 × 10(−8)). In males, a decrease of premorbid IQ of one standard deviation was significantly associated with greater risk of TRS (minimal aOR: 0.94, P = 0.002). In a subset of cases with extensive genomic data, we found no significant association between the genetic risk scores of four psychiatric disorders and two cognitive traits with TRS (schizophrenia genetic risk score: aOR = 1.07, P = 0.067). The association between copy number variant and rare variant burden measures and TRS did not reach the pre-defined statistical significance threshold (all P ≥ 0.005). In conclusion, direct measures of genomic risk were not associated with TRS; however, premorbid IQ in males and schizophrenia family history were significantly correlated with TRS and points to new insights into the architecture of TRS.

Introduction Adverse drug reactions (ADRs) are a global public health issue. The potential for pharmacogenomic biomarkers has been demonstrated in several therapeutical areas, including HIV infection and oncology. Dimethyl fumarate (DMF) is a licensed disease-modifying therapy for the treatment of multiple sclerosis (MS). The use of DMF in MS has been associated with a severe reduction in lymphocyte counts and reports of progressive multifocal leukoencephalopathy. Here, we outline the protocol for a case–control study designed to discover genomic variants associated with DMF-induced lymphopenia. The ultimate goal is to replicate these findings and create an efficient and adaptable approach towards the identification of genomic markers that could assist in mitigating adverse drug reactions in MS. Methods and analysis The population sample will comprise DMF-exposed patients with MS, with cases representing those who developed lymphopenia and controls who did not. DNA genotyping will take place using a high-throughput genome-wide array. Fine mapping and imputation will be performed to focus in on the potentially causal variants associated with lymphopenia. Multivariable logistic regression will be used to compare genotype and allele frequencies between the cases and the controls, with consideration of potential confounders. The association threshold will be set at p

Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2.3 × 10–8, odds ratio = 8.3, 95% confidence interval = 3.6–19.2). Analysis of an independent cohort of IFN-β-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 × 10–5) and alkaline phosphatase (P = 4.9 × 10-4). We show that these findings may be applicable to predicting IFN-β-induced liver injury, offering insight into its safer use. A genome-wide study identifies common variation near IRF6 associated with liver injury induced by IFN-β in individuals treated for multiple sclerosis. The risk locus is associated with differential expression of IRF6 and may help guide safer use of this biologic.