RESUMEN
GOALS: The aim was to measure bile acids in human saliva using a sensitive ultraperformance liquid chromatography tandem mass spectrometry analysis method to distinguish quantitative differences in refractory gastroesophageal reflux disease (GERD) patients as compared with proton pump inhibitor (PPI) controlled GERD patients and healthy volunteers. STUDY: Human saliva samples were analyzed from 2 separate studies. The first a meal-controlled pilot, in which premeal and postmeal saliva samples were analyzed from 20 healthy subjects and 20 patients with GERD symptoms controlled by PPIs. In a subsequent exploratory study, saliva was collected from 34 patients with continuing GERD symptoms despite PPI treatment (refractory GERD), 30 healthy subjects, and 30 PPI-controlled GERD patients at ≥4 hours postmeal. RESULTS: In the meal-controlled pilot study, both healthy subjects and patients with PPI-controlled GERD, had total saliva bile acid increase for the first hour after consumption of a meal and returned to baseline levels 4 hours later. There was no difference in bile acid levels between the 2 groups. In the exploratory study, the saliva from patients with refractory GERD had statistically significant higher levels of total bile acid concentration compared with those of healthy volunteers and patients with PPI-controlled GERD (P=0.0181). CONCLUSIONS: Bile acids can be detected and accurately quantitated in human saliva using a sensitive ultraperformance liquid chromatography tandem mass spectrometry assay. Increases above threshold could indicate an underlying disease.This method could potentially be used to evaluate biliary reflux as an underlying pathophysiology of refractory GERD.
Asunto(s)
Reflujo Gastroesofágico , Saliva , Ácidos y Sales Biliares , Cromatografía Liquida , Reflujo Gastroesofágico/diagnóstico , Humanos , Proyectos Piloto , Inhibidores de la Bomba de Protones , Espectrometría de Masas en Tándem , Resultado del TratamientoRESUMEN
Protein-coding de novo mutations (DNMs) are significant risk factors in many neurodevelopmental disorders, whereas schizophrenia (SCZ) risk associated with DNMs has thus far been shown to be modest. We analyzed DNMs from 1,695 SCZ-affected trios and 1,077 published SCZ-affected trios to better understand the contribution to SCZ risk. Among 2,772 SCZ probands, exome-wide DNM burden remained modest. Gene set analyses revealed that SCZ DNMs were significantly concentrated in genes that were highly expressed in the brain, that were under strong evolutionary constraint and/or overlapped with genes identified in other neurodevelopmental disorders. No single gene surpassed exome-wide significance; however, 16 genes were recurrently hit by protein-truncating DNMs, corresponding to a 3.15-fold higher rate than the mutation model expectation (permuted 95% confidence interval: 1-10 genes; permuted P = 3 × 10-5). Overall, DNMs explain a small fraction of SCZ risk, and larger samples are needed to identify individual risk genes, as coding variation across many genes confers risk for SCZ in the population.
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Predisposición Genética a la Enfermedad/genética , Esquizofrenia/genética , Adulto , Niño , Familia , Femenino , Humanos , Masculino , Mutación , Padres , Secuenciación del ExomaRESUMEN
Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
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Trastorno Bipolar/genética , Sitios Genéticos , Trastorno Bipolar/clasificación , Estudios de Casos y Controles , Trastorno Depresivo Mayor/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Trastornos Psicóticos/genética , Esquizofrenia/genética , Biología de SistemasRESUMEN
Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.
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Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Dinamarca , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Herencia Multifactorial/genética , Fenotipo , Factores de RiesgoRESUMEN
BACKGROUND: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. METHODS: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. RESULTS: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. CONCLUSIONS: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.
Asunto(s)
Trastorno Bipolar/genética , Variaciones en el Número de Copia de ADN/genética , Trastornos Psicóticos/genética , Trastorno Bipolar/psicología , Estudios de Casos y Controles , Estudios de Cohortes , Duplicación de Gen/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Herencia Multifactorial , Trastornos Psicóticos/psicología , Esquizofrenia/genéticaRESUMEN
Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Encéfalo/fisiología , Niño , Preescolar , Estudios de Cohortes , Femenino , Regulación de la Expresión Génica/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , RiesgoRESUMEN
Risk of schizophrenia is conferred by alleles occurring across the full spectrum of frequencies from common SNPs of weak effect through to ultra rare alleles, some of which may be moderately to highly penetrant. Previous studies have suggested that some of the risk of schizophrenia is attributable to uncommon alleles represented on Illumina exome arrays. Here, we present the largest study of exomic variation in schizophrenia to date, using samples from the United Kingdom and Sweden (10,011 schizophrenia cases and 13,791 controls). Single variants, genes, and gene sets were analyzed for association with schizophrenia. No single variant or gene reached genome-wide significance. Among candidate gene sets, we found significant enrichment for rare alleles (minor allele frequency [MAF] < 0.001) in genes intolerant of loss-of-function (LoF) variation and in genes whose messenger RNAs bind to fragile X mental retardation protein (FMRP). We further delineate the genetic architecture of schizophrenia by excluding a role for uncommon exomic variants (0.01 ≤ MAF ≥ 0.001) that confer a relatively large effect (odds ratio [OR] > 4). We also show risk alleles within this frequency range exist, but confer smaller effects and should be identified by larger studies.
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Exoma , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Mutación , Polimorfismo de Nucleótido Simple , Esquizofrenia/genética , Estudios de Casos y Controles , Estudios de Cohortes , Estudios de Seguimiento , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , PronósticoRESUMEN
By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 × 10-10). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.
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Exoma/genética , Predisposición Genética a la Enfermedad , Esquizofrenia/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Mutación/genética , Proteínas del Tejido Nervioso/genética , Riesgo , SueciaRESUMEN
More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.
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Penetrancia , Enfermedades por Prión/genética , Estudios de Casos y Controles , Estudios de Cohortes , Predisposición Genética a la Enfermedad , Humanos , Mutación/genética , Priones/genética , Factores de RiesgoRESUMEN
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
Cognitive impairment is a core feature of schizophrenia but there is limited understanding of the genetic relationship between cognition in the general population and schizophrenia. We examine how common variants associated with schizophreniaen massecontribute to childhood cognitive ability in a population-based sample, and the extent to which common genetic variants associated with childhood cognition explain variation in schizophrenia. Schizophrenia polygenic risk scores were derived from the Psychiatric Genomics Consortium (n= 69 516) and tested for association with IQ, attention, processing speed, working memory, problem solving, and social cognition in over 5000 children aged 8 from the Avon Longitudinal Study of Parents and Children birth cohort. Polygenic scores for these cognitive domains were tested for association with schizophrenia in a large UK schizophrenia sample (n= 11 853). Bivariate genome-wide complex trait analysis (GCTA) estimated the amount of shared genetic factors between schizophrenia and cognitive domains. Schizophrenia polygenic risk score was associated with lower performance IQ (P= .001) and lower full IQ (P= .013). Polygenic score for performance IQ was associated with increased risk for schizophrenia (P= 3.56E-04). Bivariate GCTA revealed moderate genetic correlation between schizophrenia and both performance IQ (rG= -.379,P= 6.62E-05) and full IQ (rG= -.202,P= 5.00E-03), with approximately 14% of the genetic component of schizophrenia shared with that for performance IQ. Our results support the presence of shared common genetic factors between schizophrenia and childhood cognitive ability. We observe a genetic relationship between schizophrenia and performance IQ but not verbal IQ or other cognitive variables, which may have implications for studies utilizing cognitive endophenotypes for psychosis.
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Atención/fisiología , Cognición/fisiología , Inteligencia/fisiología , Herencia Multifactorial , Solución de Problemas/fisiología , Desempeño Psicomotor/fisiología , Esquizofrenia/fisiopatología , Percepción Social , Adulto , Niño , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Reino UnidoRESUMEN
We sought to obtain novel insights into schizophrenia pathogenesis by exploiting the association between the disorder and chromosomal copy number (CNV) burden. We combined data from 5,745 cases and 10,675 controls with other published datasets containing genome-wide CNV data. In this much-enlarged sample of 11,355 cases and 16,416 controls, we show for the first time that case CNVs are enriched for genes involved in GABAergic neurotransmission. Consistent with non-genetic reports of GABAergic deficits in schizophrenia, our findings now show disrupted GABAergic signaling is of direct causal relevance, rather than a secondary effect or due to confounding. Additionally, we independently replicate and greatly extend previous findings of CNV enrichment among genes involved in glutamatergic signaling. Given the strong functional links between the major inhibitory GABAergic and excitatory glutamatergic systems, our findings converge on a broad, coherent set of pathogenic processes, providing firm foundations for studies aimed at dissecting disease mechanisms.
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Variaciones en el Número de Copia de ADN/genética , Potenciales Postsinápticos Excitadores/fisiología , Potenciales Postsinápticos Inhibidores/fisiología , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Transducción de Señal/fisiología , Animales , Estudios de Casos y Controles , Humanos , RatonesRESUMEN
BACKGROUND: Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. METHODS: We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. RESULTS: Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow-biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. CONCLUSIONS: Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.).
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Sangre , Transformación Celular Neoplásica/genética , Neoplasias Hematológicas/genética , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/fisiología , Mutación , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Células Clonales , Análisis Mutacional de ADN , Exoma , Neoplasias Hematológicas/fisiopatología , Humanos , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
Structural variation (SV) is a significant component of the genetic etiology of both neurodevelopmental and psychiatric disorders; however, routine guidelines for clinical genetic screening have been established only in the former category. Genome-wide chromosomal microarray (CMA) can detect genomic imbalances such as copy-number variants (CNVs), but balanced chromosomal abnormalities (BCAs) still require karyotyping for clinical detection. Moreover, submicroscopic BCAs and subarray threshold CNVs are intractable, or cryptic, to both CMA and karyotyping. Here, we performed whole-genome sequencing using large-insert jumping libraries to delineate both cytogenetically visible and cryptic SVs in a single test among 30 clinically referred youth representing a range of severe neuropsychiatric conditions. We detected 96 SVs per person on average that passed filtering criteria above our highest-confidence resolution (6,305 bp) and an additional 111 SVs per genome below this resolution. These SVs rearranged 3.8 Mb of genomic sequence and resulted in 42 putative loss-of-function (LoF) or gain-of-function mutations per person. We estimate that 80% of the LoF variants were cryptic to clinical CMA. We found myriad complex and cryptic rearrangements, including a "paired" duplication (360 kb, 169 kb) that flanks a 5.25 Mb inversion that appears in 7 additional cases from clinical CNV data among 47,562 individuals. Following convergent genomic profiling of these independent clinical CNV data, we interpreted three SVs to be of potential clinical significance. These data indicate that sequence-based delineation of the full SV mutational spectrum warrants exploration in youth referred for neuropsychiatric evaluation and clinical diagnostic SV screening more broadly.
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Edad de Inicio , Aberraciones Cromosómicas , Cromosomas Humanos/genética , Variaciones en el Número de Copia de ADN/genética , Trastornos Mentales/genética , Enfermedades Neurodegenerativas/genética , Hibridación Genómica Comparativa , Genoma Humano , Humanos , Trastornos Mentales/epidemiología , Análisis por Micromatrices , Enfermedades Neurodegenerativas/epidemiología , Fenotipo , Estados Unidos/epidemiologíaRESUMEN
An increased rate of de novo copy number variants (CNVs) has been found in schizophrenia (SZ), autism and developmental delay. An increased rate has also been reported in bipolar affective disorder (BD). Here, in a larger BD sample, we aimed to replicate these findings and compare de novo CNVs between SZ and BD. We used Illumina microarrays to genotype 368 BD probands, 76 SZ probands and all their parents. Copy number variants were called by PennCNV and filtered for frequency (<1%) and size (>10 kb). Putative de novo CNVs were validated with the z-score algorithm, manual inspection of log R ratios (LRR) and qPCR probes. We found 15 de novo CNVs in BD (4.1% rate) and 6 in SZ (7.9% rate). Combining results with previous studies and using a cut-off of >100 kb, the rate of de novo CNVs in BD was intermediate between controls and SZ: 1.5% in controls, 2.2% in BD and 4.3% in SZ. Only the differences between SZ and BD and SZ and controls were significant. The median size of de novo CNVs in BD (448 kb) was also intermediate between SZ (613 kb) and controls (338 kb), but only the comparison between SZ and controls was significant. Only one de novo CNV in BD was in a confirmed SZ locus (16p11.2). Sporadic or early onset cases were not more likely to have de novo CNVs. We conclude that de novo CNVs play a smaller role in BD compared with SZ. Patients with a positive family history can also harbour de novo mutations.
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Trastorno Bipolar/genética , Variaciones en el Número de Copia de ADN , Sitios Genéticos , Esquizofrenia/genética , Adolescente , Adulto , Algoritmos , Trastorno Bipolar/fisiopatología , Estudios de Casos y Controles , Niño , Cromosomas Humanos Par 16 , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Esquizofrenia/fisiopatologíaRESUMEN
Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case-control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders.
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Modelos Neurológicos , Mutación/genética , Red Nerviosa/metabolismo , Vías Nerviosas/metabolismo , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Sinapsis/metabolismo , Trastornos Generalizados del Desarrollo Infantil/genética , Proteínas del Citoesqueleto/metabolismo , Exoma/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Humanos , Discapacidad Intelectual/genética , Tasa de Mutación , Red Nerviosa/fisiopatología , Proteínas del Tejido Nervioso/metabolismo , Vías Nerviosas/fisiopatología , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo , Especificidad por SustratoRESUMEN
Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.
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Herencia Multifactorial/genética , Mutación/genética , Esquizofrenia/genética , Trastorno Autístico/genética , Canales de Calcio/genética , Proteínas del Citoesqueleto/genética , Variaciones en el Número de Copia de ADN/genética , Homólogo 4 de la Proteína Discs Large , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Discapacidad Intelectual/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
BACKGROUND: A number of copy number variants (CNVs) have been suggested as susceptibility factors for schizophrenia. For some of these the data remain equivocal, and the frequency in individuals with schizophrenia is uncertain. AIMS: To determine the contribution of CNVs at 15 schizophrenia-associated loci (a) using a large new data-set of patients with schizophrenia (n = 6882) and controls (n = 6316), and (b) combining our results with those from previous studies. METHOD: We used Illumina microarrays to analyse our data. Analyses were restricted to 520 766 probes common to all arrays used in the different data-sets. RESULTS: We found higher rates in participants with schizophrenia than in controls for 13 of the 15 previously implicated CNVs. Six were nominally significantly associated (P<0.05) in this new data-set: deletions at 1q21.1, NRXN1, 15q11.2 and 22q11.2 and duplications at 16p11.2 and the Angelman/Prader-Willi Syndrome (AS/PWS) region. All eight AS/PWS duplications in patients were of maternal origin. When combined with published data, 11 of the 15 loci showed highly significant evidence for association with schizophrenia (P<4.1×10(-4)). CONCLUSIONS: We strengthen the support for the majority of the previously implicated CNVs in schizophrenia. About 2.5% of patients with schizophrenia and 0.9% of controls carry a large, detectable CNV at one of these loci. Routine CNV screening may be clinically appropriate given the high rate of known deleterious mutations in the disorder and the comorbidity associated with these heritable mutations.
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Deleción Cromosómica , Variaciones en el Número de Copia de ADN/genética , Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Esquizofrenia/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Síndrome de Angelman/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Impresión Genómica , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Prader-Willi/genética , Adulto JovenRESUMEN
Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analyzed 6882 cases and 11 255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in additional 14 568 cases and 15 274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P < 0.05); however, none would survive correction for multiple testing. These loci include recurrent deletions at 16p12.1, a locus previously associated with neurodevelopmental disorders (P = 0.0084 in the discovery sample and P = 0.023 in the replication sample). Other plausible candidates include non-recurrent deletions at the glutamate transporter gene SLC1A1, a CNV locus recently suggested to be involved in schizophrenia through linkage analysis, and duplications at 1p36.33 and CGNL1. A burden analysis of large (>500 kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 16 , Cromosomas Humanos Par 1 , Proteínas del Citoesqueleto/genética , Transportador 3 de Aminoácidos Excitadores/genética , Duplicación de Gen , Esquizofrenia/genética , Variaciones en el Número de Copia de ADN , Femenino , Eliminación de Gen , Dosificación de Gen , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , MasculinoRESUMEN
BACKGROUND: Several recurrent copy number variants (CNVs) have been shown to increase the risk of developing schizophrenia (SCZ), developmental delay (DD), autism spectrum disorders (ASD), and various congenital malformations (CM). Their penetrance for SCZ has been estimated to be modest. However, comparisons between their penetrance for SCZ or DD/ASD/CM, or estimates of the total penetrance for any of these disorders have not yet been made. METHODS: We use data from the largest available studies on SCZ and DD/ASD/CM, including a new sample of 6882 cases and 6316 controls, to estimate the frequencies of 70 implicated CNVs in carriers with these disorders, healthy control subjects, and the general population. On the basis of these frequencies, we estimate their penetrance. We also estimate the strength of the selection pressure against CNVs and correlate this against their overall penetrance. RESULTS: The rates of nearly all CNVs are higher in DD/ASD/CM compared with SCZ. The penetrance of CNVs is at least several times higher for the development of a disorder from the group of DD/ASD/CM. The overall penetrance of SCZ-associated CNVs for developing any disorder is high, ranging between 10.6% and 100%. CONCLUSIONS: CNVs associated with SCZ have high pathogenicity. The majority of the increased risk conferred by CNVs is toward the development of an earlier-onset disorder, such as DD/ASD/CM, rather than SCZ. The penetrance of CNVs correlates strongly with their selection coefficients. The improved estimates of penetrance will provide crucial information for genetic counselling.