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Goldstein J.I.,Massachusetts General Hospital | Goldstein J.I.,The Broad Institute of MIT and Harvard | Fredrik Jarskog L.,University of North Carolina at Chapel Hill | Hilliard C.,University of North Carolina at Chapel Hill | And 37 more authors.
Nature Communications | Year: 2014

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10-14, odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10-10, OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG. © 2014 Macmillan Publishers Limited. All rights reserved.

Cruger A.-M.T.,Bispebjerg Hospital | Kaur-Knudsen D.,Gentofte Hospital | Zachariae C.,Gentofte Hospital | Rasmussen H.B.,Institute of Biological Psychiatry | Thomsen S.F.,Bispebjerg Hospital
Danish Medical Journal | Year: 2015

Introduction: The aim of this study was to examine risk factors and mortality among patients with erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Methods: This was a retrospective evaluation of the medical records of 250 patients from two Danish tertiary dermatological departments during a ten-year period. Results: In a total of 192 cases (77.4%), the primary diagnosis of EM (66.5%), SJS (62.2%) and TEN (100%) was confirmed, whereas the remaining cases (22.6%) were diagnosed differently. Antibiotics and allopurinol were predominantly associated with TEN, whereas SJS was associated with a broad spectrum of drugs. EM was related mainly to viral infections, predominantly herpes (30.6%); 38.2% of the causes of EM remained unknown. Patients with TEN had the highest mortality; i.e. 60% in the course of the ten-year study period: adjusted hazard ratio (HR) = 11.2 (95% confidence interval (CI): 3.65-34.35); p < 0.001 compared with EM patients. The risk of death was also increased among patients with SJS relative to patients with EM: HR = 2.60 (95% CI: 1.10-6.16); p = 0.030; however, this did not remain statistically significant after adjustment for age, co-morbidity, infection, cancer and polypharmacy, HR = 0.99 (95% CI: 0.38-2.57); p = 0.976. ConclusionS: We validated diagnoses in 250 patients with EM, SJS and TEN diagnosed during a ten-year period. The survival of patients with TEN was expectedly low compared with patients with EM. We extend previous findings by showing that after adjustment for confounders, the survival rates of SJS and EM are comparable. Funding: not relevant. Trial registration: not relevant. © 2015, Danish Medical Association. All rights reserved.

Farrell M.S.,University of North Carolina at Chapel Hill | Werge T.,Institute of Biological Psychiatry | Werge T.,Copenhagen University | Werge T.,Lundbeck | And 11 more authors.
Molecular Psychiatry | Year: 2015

Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia. © 2015 Macmillan Publishers Limited.

Hoeffding L.K.,Institute of Biological Psychiatry | Hoeffding L.K.,Lundbeck | Rosengren A.,Institute of Biological Psychiatry | Rosengren A.,Lundbeck | And 8 more authors.
Nordic Journal of Psychiatry | Year: 2016

Background: Epidemiological studies have documented higher than expected comorbidity (or, in some cases, inverse comorbidity) between schizophrenia and several autoimmune disorders. It remains unknown whether this comorbidity reflects shared genetic susceptibility loci. Aims: The present study aimed to investigate whether verified genome wide significant variants of autoimmune disorders confer risk of schizophrenia, which could suggest a common genetic basis. Methods: Seven hundred and fourteen genome wide significant risk variants of 25 autoimmune disorders were extracted from the NHGRI GWAS catalogue and examined for association to schizophrenia in the Psychiatric Genomics Consortium schizophrenia GWAS samples (36,989 cases and 113,075 controls). Results: Two independent loci at 4q24 and 6p21.32–33 originally identified from GWAS of autoimmune diseases were found genome wide associated with schizophrenia (1.7 × 10−8 ≥ p ≥ 4.0 × 10−21). While these observations confirm the existence of shared genetic susceptibility loci between schizophrenia and autoimmune diseases, the findings did not show a significant enrichment. Conclusion: The findings do not support a genetic overlap in common SNPs between autoimmune diseases and schizophrenia that in part could explain the observed comorbidity from epidemiological studies. © 2016 Informa UK Limited, trading as Taylor & Francis Group

Steinhausen H.-C.,University of Aalborg | Steinhausen H.-C.,University of Basel | Steinhausen H.-C.,University of Zurich | Jakobsen H.,University of Aalborg | And 3 more authors.
International Journal of Eating Disorders | Year: 2015

Objective This nation-wide register-based study investigated how often anorexia nervosa (AN) and co-morbid disorders occur in affected families compared with control families. Furthermore, the study addressed the impact of sex, year of birth, and degree of urbanization in terms of risk factors.Method A total of N=2,370 child and adolescent psychiatric subjects born between 1951 and 1996 and registered in the Danish Psychiatric Central Research Register (DPCRR) had any mental disorder before the age of 18 and developed AN at some point during their life-time. In addition, N=7,035 controls without any psychiatric diagnosis before age 18 and matched for age, sex, and residential region were included. Psychiatric diagnoses were also obtained on the first-degree relatives as a part of the Danish Three Generation Study (3GS). A family load component was obtained by using various mixed regression models.Results AN occurred significantly more often in case than in control families. AN Risk factors included having a sibling with AN, affective disorders in family members, and co-morbid affective, anxiety, obsessive-compulsive, personality, or substance use disorders. Furthermore, female sex, and ascending year of birth were significantly associated with having AN. Urbanization was not related to the family load of AN and case-relatives did not develop AN earlier than control relatives.Discussion These findings based on a very large and representative dataset provide evidence for the family aggregation and further risk factors in AN. © 2014 Wiley Periodicals, Inc.

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