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This corrects the article DOI: 10.1038/mp.2016.97.
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This corrects the article DOI: 10.1038/mp.2015.165.
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The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10-8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.
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Clozapina/efectos adversos , Neutropenia/inducido químicamente , Neutropenia/genética , Proteínas Portadoras/genética , Estudios de Casos y Controles , Clozapina/uso terapéutico , Exoma , Femenino , Estudio de Asociación del Genoma Completo , Cadenas beta de HLA-DQ/genética , Humanos , Masculino , Neutropenia/metabolismo , Oportunidad Relativa , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/genéticaRESUMEN
This corrects the article DOI: 10.1038/mp.2016.97.
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Schizophrenia is a highly heritable disorder. Genome-wide association studies based largely on common alleles have identified over 100 schizophrenia risk loci, but it is also evident from studies of copy number variants (CNVs) and from exome-sequencing studies that rare alleles are also involved. Full characterization of the contribution of rare alleles to the disorder awaits the deployment of sequencing technology in very large sample sizes, meanwhile, as an interim measure, exome arrays allow rare non-synonymous variants to be sampled at a fraction of the cost. In an analysis of exome array data from 13 688 individuals (5585 cases and 8103 controls) from the UK, we found that rare (minor allele frequency < 0.1%) variant association signal was enriched among genes that map to autosomal loci that are genome-wide significant (GWS) in common variant studies of schizophrenia genome-wide association study (PGWAS = 0.01) as well as gene sets known to be enriched for rare variants in sequencing studies (PRARE = 0.026). We also identified the gene-wise equivalent of GWS support for WDR88 (WD repeat-containing protein 88), a gene of unknown function (P = 6.5 × 10(-7)). Rare alleles represented on exome chip arrays contribute to the genetic architecture of schizophrenia, but as is the case for GWAS, very large studies are required to reveal additional susceptibility alleles for the disorder.
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Alelos , Predisposición Genética a la Enfermedad , Proteínas del Tejido Nervioso/genética , Proteínas/genética , Sitios de Carácter Cuantitativo , Carácter Cuantitativo Heredable , Esquizofrenia/genética , Estudios de Casos y Controles , Variaciones en el Número de Copia de ADN , Exoma , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Tamaño de la Muestra , Esquizofrenia/patologíaRESUMEN
The genetic architecture of schizophrenia is complex, involving risk alleles ranging from common alleles of weak effect to rare alleles of large effect, the best exemplar of the latter being large copy number variants (CNVs). It is currently unknown whether pathophysiology in those with defined rare mutations overlaps with that in other individuals with the disorder who do not share the same rare mutation. Under an extreme heterogeneity model, carriers of specific high-penetrance mutations form distinct subgroups. In contrast, under a polygenic threshold model, high-penetrance rare allele carriers possess many risk factors, of which the rare allele is the only one, albeit an important, factor. Under the latter model, cases with rare mutations can be expected to share some common risk alleles, and therefore pathophysiological mechanisms, with cases without the same mutation. Here we show that, compared with controls, individuals with schizophrenia who have known pathogenic CNVs carry an excess burden of common risk alleles (P=2.25 × 10(-17)) defined from a genome-wide association study largely based on individuals without known CNVs. Our finding is not consistent with an extreme heterogeneity model for CNV carriers, but does offer support for the polygenic threshold model of schizophrenia. That this is so provides support for the notion that studies aiming to model the effects of rare variation may uncover pathophysiological mechanisms of relevance to those with the disorder more widely.
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Variaciones en el Número de Copia de ADN/genética , Esquizofrenia/genética , Alelos , Simulación por Computador , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Modelos Genéticos , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genética , Factores de RiesgoRESUMEN
Large (>100 kb), rare (<1% in the population) copy number variants (CNVs) have been shown to confer risk for schizophrenia (SZ), but the findings for bipolar disorder (BD) are less clear. In a new BD sample from the United Kingdom (n=2591), we have examined the occurrence of CNVs and compared this with previously reported samples of 6882 SZ and 8842 control subjects. When combined with previous data, we find evidence for a contribution to BD for three SZ-associated CNV loci: duplications at 1q21.1 (P=0.022), deletions at 3q29 (P=0.03) and duplications at 16p11.2 (P=2.3 × 10(-4)). The latter survives multiple-testing correction for the number of recurrent large CNV loci in the genome. Genes in 20 regions (total of 55 genes) were enriched for rare exonic CNVs among BD cases, but none of these survives correction for multiple testing. Finally, our data provide strong support for the hypothesis of a lesser contribution of very large (>500 kb) CNVs in BD compared with SZ, most notably for deletions >1 Mb (P=9 × 10(-4)).
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Trastorno Bipolar/genética , Variaciones en el Número de Copia de ADN , Femenino , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana Edad , Esquizofrenia/genética , Población BlancaRESUMEN
Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.
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Trastorno Bipolar/genética , Proteínas Portadoras/genética , Adulto , Antimaníacos/uso terapéutico , Biomarcadores Farmacológicos/sangre , Trastorno Bipolar/metabolismo , Proteínas Portadoras/metabolismo , Femenino , Predisposición Genética a la Enfermedad/genética , Variación Genética , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Litio/metabolismo , Litio/uso terapéutico , Compuestos de Litio/uso terapéutico , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Autoinforme , Suecia , Reino UnidoRESUMEN
A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0 Mb) at 22q11.2--the reciprocal of the well-known, risk-inducing deletion of this locus--are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia.
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Anomalías Múltiples/genética , Duplicación Cromosómica/genética , Variaciones en el Número de Copia de ADN/genética , Síndrome de DiGeorge/genética , Predisposición Genética a la Enfermedad , Esquizofrenia/genética , Anomalías Múltiples/epidemiología , Cromosomas Humanos Par 22/genética , Síndrome de DiGeorge/epidemiología , Femenino , Humanos , Masculino , Esquizofrenia/epidemiologíaRESUMEN
Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case-control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P=4.54 × 10(-8)). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P=0.003, BD: P=0.013), whereas the largest CNVs (>500 kb) were significantly enriched only in SCZ cases (P=0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P=0.0035) and 22q11 deletions (P=0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD.