RESUMO
BACKGROUND: Previous studies have shown that individuals with schizophrenia have a greater risk for psoriasis than a typical person. This suggests that there might be a shared genetic etiology between the 2 conditions. We aimed to characterize the potential shared genetic susceptibility between schizophrenia and psoriasis using genome-wide marker genotype data. METHODS: We obtained genetic data on individuals with psoriasis, schizophrenia and control individuals. We applied a marker-based coheritability estimation procedure, polygenic score analysis, a gene set enrichment test and a least absolute shrinkage and selection operator regression model to estimate the potential shared genetic etiology between the 2 diseases. We validated the results in independent schizophrenia and psoriasis cohorts from Singapore. RESULTS: We included 1139 individuals with psoriasis, 744 with schizophrenia and 1678 controls in our analysis, and we validated the results in independent cohorts, including 441 individuals with psoriasis (and 2420 controls) and 1630 with schizophrenia (and 1860 controls). We estimated that a large fraction of schizophrenia and psoriasis risk could be attributed to common variants (h2SNP = 29% ± 5.0%, p = 2.00 × 10-8), with a coheritability estimate between the traits of 21%. We identified 5 variants within the human leukocyte antigen (HLA) gene region, which were most likely to be associated with both diseases and collectively conferred a significant risk effect (odds ratio of highest risk quartile = 6.03, p < 2.00 × 10-16). We discovered that variants contributing most to the shared heritable component between psoriasis and schizophrenia were enriched in antigen processing and cell endoplasmic reticulum. LIMITATIONS: Our sample size was relatively small. The findings of 5 HLA gene variants were complicated by the complex structure in the HLA region. CONCLUSION: We found evidence for a shared genetic etiology between schizophrenia and psoriasis. The mechanism for this shared genetic basis likely involves immune and calcium signalling pathways.
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Predisposição Genética para Doença , Variação Genética , Psoríase/genética , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Estudos de Casos e Controles , China/etnologia , Estudos de Coortes , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Antígenos HLA/genética , Humanos , Pessoa de Meia-Idade , Herança Multifatorial , Análise de Regressão , Singapura , Adulto JovemRESUMO
A genetic predisposition to central nervous system (CNS) toxicity induced by antimicrobial drugs (antibiotics, antivirals, antifungals, and antiparasitic drugs) has been suspected. Whole genome sequencing of 66 cases and 833 controls was performed to investigate whether antimicrobial drug-induced CNS toxicity was associated with genetic variation. The primary objective was to test whether antimicrobial-induced CNS toxicity was associated with seventeen efflux transporters at the blood-brain barrier. In this study, variants or structural elements in efflux transporters were not significantly associated with CNS toxicity. Secondary objectives were to test whether antimicrobial-induced CNS toxicity was associated with genes over the whole genome, with HLA, or with structural genetic variation. Uncommon variants in and close to three genes were significantly associated with CNS toxicity according to a sequence kernel association test combined with an optimal unified test (SKAT-O). These genes were LCP1 (q = 0.013), RETSAT (q = 0.013) and SFMBT2 (q = 0.035). Two variants were driving the LCP1 association: rs6561297 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]) and the regulatory variant rs10492451 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]). No common genetic variant, HLA-type or structural variation was associated with CNS toxicity. In conclusion, CNS toxicity due to antimicrobial drugs was associated with uncommon variants in LCP1, RETSAT and SFMBT2.
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Anti-Infecciosos , Estudos de Casos e Controles , Anti-Infecciosos/toxicidade , Sistema Nervoso Central , Antibacterianos , Antifúngicos , Proteínas de Membrana TransportadorasRESUMO
Exome sequencing has been proposed as the first-tier genetic testing in autism spectrum disorder (ASD). Here, we performed exome sequencing in autistic individuals with average to high intellectual abilities (N = 207) to identify molecular diagnoses and genetic modifiers of intervention outcomes of social skills group training (SSGT) or standard care. We prioritized variants of clinical significance (VCS), variants of uncertain significance (VUS) and generated a pilot scheme to calculate genetic scores of rare and common variants in ASD-related gene pathways. Mixed linear models were used to test the association between the carrier status of VCS/VUS or the genetic scores with intervention outcomes measured by the social responsiveness scale. Additionally, we combined behavioral and genetic features using a machine learning (ML) model to predict the individual response. We showed a rate of 4.4% and 11.3% of VCS and VUS in the cohort, respectively. Individuals with VCS or VUS had improved significantly less after standard care than non-carriers at post-intervention (ß = 9.35; p = 0.036), while no such association was observed for SSGT (ß = -2.50; p = 0.65). Higher rare variant genetic scores for synaptic transmission and regulation of transcription from RNA polymerase II were separately associated with less beneficial (ß = 8.30, p = 0.0044) or more beneficial (ß = -6.79, p = 0.014) effects after SSGT compared with standard care at follow-up, respectively. Our ML model showed the importance of rare variants for outcome prediction. Further studies are needed to understand genetic predisposition to intervention outcomes in ASD.
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Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/terapia , Transtorno Autístico/genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Habilidades SociaisRESUMO
Numerous studies have been performed over the last decade to exploit the complexity of genomic and transcriptomic lesions driving the initiation of acute myeloid leukemia (AML). These studies have helped improve risk classification and treatment options. Detailed molecular characterization of longitudinal AML samples is sparse, however; meanwhile, relapse and therapy resistance represent the main challenges in AML care. To this end, we performed transcriptome-wide RNA sequencing of longitudinal diagnosis, relapse, and/or primary resistant samples from 47 adult and 23 pediatric AML patients with known mutational background. Gene expression analysis revealed the association of short event-free survival with overexpression of GLI2 and IL1R1, as well as downregulation of ST18. Moreover, CR1 downregulation and DPEP1 upregulation were associated with AML relapse both in adults and children. Finally, machine learning-based and network-based analysis identified overexpressed CD6 and downregulated INSR as highly copredictive genes depicting important relapse-associated characteristics among adult patients with AML. Our findings highlight the importance of a tumor-promoting inflammatory environment in leukemia progression, as indicated by several of the herein identified differentially expressed genes. Together, this knowledge provides the foundation for novel personalized drug targets and has the potential to maximize the benefit of current treatments to improve cure rates in AML.
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Leucemia Mieloide Aguda , Transcriptoma , Adulto , Criança , Perfilação da Expressão Gênica , Genômica , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , MutaçãoRESUMO
The primary dystonias are a genetically heterogeneous group of disorders that can be subdivided in pure dystonias, dystonia-plus syndromes, and paroxymal dystonia. Four pure autosomal dominant dystonia loci have been mapped to date, DYT1, 6, 7, and 13, with varying penetrance. We report the mapping of a novel locus for a late-onset form of pure torsion dystonia in a family from northern Sweden. The disease is inherited in an autosomal dominant manner with a penetrance that may be as high as 90%. The torsion dystonia locus in this family was mapped to chromosome 2q14.3-q21.3 using an Illumina linkage panel. We also confirmed the linkage, using ten tightly linked microsatellite markers in the region, giving a maximum LOD score of 5.59 for marker D2S1260. The disease-critical region is 3.6-8.9 Mb depending on the disease status of one individual carrying a centromeric recombination. Mutational analysis was performed on 22 genes in the disease-critical region, including all known and hypothetical genes in the smaller, 3.6-Mb region, but no disease-specific mutations were identified. Copy number variation analysis of the region did not reveal any deletions or duplications. In order to increase the chances of finding the disease gene, fine-mapping may be necessary to decrease the region of interest. This report will hopefully result in the identification of additional dystonia families with linkage to the same locus, and thereby, refinement of the disease critical region.
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Cromossomos Humanos Par 2 , Distonia Muscular Deformante/genética , Loci Gênicos , Penetrância , Adolescente , Adulto , Idade de Início , Idoso , Mapeamento Cromossômico , Cromossomos Humanos Par 2/genética , Distonia Muscular Deformante/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Linhagem , Adulto JovemRESUMO
Relapse is the leading cause of death of adult and pediatric patients with acute myeloid leukemia (AML). Numerous studies have helped to elucidate the complex mutational landscape at diagnosis of AML, leading to improved risk stratification and new therapeutic options. However, multi-whole-genome studies of adult and pediatric AML at relapse are necessary for further advances. To this end, we performed whole-genome and whole-exome sequencing analyses of longitudinal diagnosis, relapse, and/or primary resistant specimens from 48 adult and 25 pediatric patients with AML. We identified mutations recurrently gained at relapse in ARID1A and CSF1R, both of which represent potentially actionable therapeutic alternatives. Further, we report specific differences in the mutational spectrum between adult vs pediatric relapsed AML, with MGA and H3F3A p.Lys28Met mutations recurrently found at relapse in adults, whereas internal tandem duplications in UBTF were identified solely in children. Finally, our study revealed recurrent mutations in IKZF1, KANSL1, and NIPBL at relapse. All of the mentioned genes have either never been reported at diagnosis in de novo AML or have been reported at low frequency, suggesting important roles for these alterations predominantly in disease progression and/or resistance to therapy. Our findings shed further light on the complexity of relapsed AML and identified previously unappreciated alterations that may lead to improved outcomes through personalized medicine.
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Leucemia Mieloide Aguda , Proteínas de Ciclo Celular , Criança , Genômica , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Medicina de Precisão , RecidivaRESUMO
BACKGROUND: Familial amyloidosis with polyneuropathy (FAP) is an autosomal dominant disease caused by transthyretin (TTR) mutations, of which V30M (TTR c.148G > A, p.Val50Met, "Val30Met") is the most common. Swedish V30M carriers display later age at onset and lower penetrance compared to other populations. METHODS: In the study, 130 Swedish V30M carriers (32 early, 30 late onset and 68 asymptomatic carriers) and 50 controls, 23 French symptomatic V30M carriers and 29 controls and 18 Japanese symptomatic V30M carriers and 29 controls were included. We aimed to identify additional genetic factors in the TTR gene and its surrounding region that could have an impact on phenotype. RESULTS: We identified three SNPs (rs71383038, rs3794885 and rs62093482) with a significant difference in allele frequency between Swedish V30M carriers and controls. The two Swedish V30M homozygous patients present in the study also displayed homozygosity for the CA10 (rs71383038), A (rs3794885) and T (rs62093482) alleles in these SNPs. Hence, these alleles are present on the Swedish V30M haplotype. Of these, rs62093482 is located in the 3'UTR of TTR gene and thus more interesting since SNPs in the 3'UTR can affect gene expression levels by modifying microRNA (miRNA) targeting activity. miRNA target predictions revealed four potential miRNAs with predicted targets unique for the polymorphic allele. CONCLUSIONS: Our results are the first to show the presence of a 3'UTR polymorphism on the V30M haplotype in Swedish carriers, which can serve as a miRNA binding site potentially leading to down-regulated expression from the mutated TTR allele. This finding may be related to the low penetrance and high age at onset of the disease observed in the Swedish patient population.
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Inativação Gênica , Heterozigoto , MicroRNAs/genética , Mutação de Sentido Incorreto , Pré-Albumina/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/genética , Frequência do Gene , Humanos , Pessoa de Meia-Idade , Penetrância , Fenótipo , Polimorfismo de Nucleotídeo Único , Suécia/epidemiologia , Adulto JovemRESUMO
Social skills group training (SSGT) is a frequently used behavioral intervention in autism spectrum disorder (ASD), but the effects are moderate and heterogeneous. Here, we analyzed the effect of polygenic risk score (PRS) and common variants in gene sets on the intervention outcome. Participants from the largest randomized clinical trial of SSGT in ASD to date were selected (N = 188, 99 from SSGT, 89 from standard care) to calculate association between the outcomes in the SSGT trial and PRSs for ASD, attention-deficit hyperactivity disorder (ADHD), and educational attainment. In addition, specific gene sets were selected to evaluate their role on intervention outcomes. Among all participants in the trial, higher PRS for ADHD was associated with significant improvement in the outcome measure, the parental-rated Social Responsiveness Scale. The significant association was due to better outcomes in the standard care group for individuals with higher PRS for ADHD (post-intervention: ß = -4.747, P = 0.0129; follow-up: ß = -5.309, P = 0.0083). However, when contrasting the SSGT and standard care group, an inferior outcome in the SSGT group was associated with higher ADHD PRS at follow-up (ß = 6.67, P = 0.016). Five gene sets within the synaptic category showed a nominal association with reduced response to interventions. We provide preliminary evidence that genetic liability calculated from common variants could influence the intervention outcomes. In the future, larger cohorts should be used to investigate how genetic contribution affects individual response to ASD interventions.
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BACKGROUND: The lifelong accumulation of somatic mutations underlies age-related phenotypes and cancer. Mutagenic forces are thought to shape the genome of aging cells in a tissue-specific way. Whole genome analyses of somatic mutation patterns, based on both types and genomic distribution of variants, can shed light on specific processes active in different human tissues and their effect on the transition to cancer. RESULTS: To analyze somatic mutation patterns, we compile a comprehensive genetic atlas of somatic mutations in healthy human cells. High-confidence variants are obtained from newly generated and publicly available whole genome DNA sequencing data from single non-cancer cells, clonally expanded in vitro. To enable a well-controlled comparison of different cell types, we obtain single genome data (92% mean coverage) from multi-organ biopsies from the same donors. These data show multiple cell types that are protected from mutagens and display a stereotyped mutation profile, despite their origin from different tissues. Conversely, the same tissue harbors cells with distinct mutation profiles associated to different differentiation states. Analyses of mutation rate in the coding and non-coding portions of the genome identify a cell type bearing a unique mutation pattern characterized by mutation enrichment in active chromatin, regulatory, and transcribed regions. CONCLUSIONS: Our analysis of normal cells from healthy donors identifies a somatic mutation landscape that enhances the risk of tumor transformation in a specific cell population from the kidney proximal tubule. This unique pattern is characterized by high rate of mutation accumulation during adult life and specific targeting of expressed genes and regulatory regions.
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Mutagênese , Neoplasias/etiologia , Sequenciamento Completo do Genoma , Idoso , Feminino , HumanosRESUMO
INTRODUCTION: Hereditary transthyretin amyloidosis (ATTR) is a genetic disease caused by a point mutation in the TTR gene that causes the liver to produce an unstable TTR protein. The most effective treatment has been liver transplantation in order to replace the variant TTR producing liver with one that produces only wild-type TTR. ATTR amyloidosis patients' livers are reused for liver sick patients, i.e. the Domino procedure. However, recent findings have demonstrated that ATTR amyloidosis can develop in the recipients within 7-8 years. The aim of this study was to elucidate how the genetic profile of the liver is affected by the disease, and how amyloid deposits affect target tissue. METHODS: Gene expression analysis was used to unravel the genetic profiles of Swedish ATTR V30M patients and controls. Biopsies from adipose tissue and liver were examined. RESULTS AND CONCLUSIONS: ATTR amyloid patients' gene expression profile of the main source organ, the liver, differed markedly from that of the controls, whereas the target organs' gene expression profiles were not markedly altered in the ATTR amyloid patients compared to those of the controls. An impaired ER/protein folding pathway might suggest ER overload due to mutated TTR protein.
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Neuropatias Amiloides Familiares/metabolismo , Transcriptoma/fisiologia , Gordura Abdominal/metabolismo , Adulto , Idoso , Neuropatias Amiloides Familiares/genética , Feminino , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Pré-Albumina/genética , Pré-Albumina/metabolismo , Transcriptoma/genéticaRESUMO
BACKGROUND: Hereditary transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease characterized by extracellular deposits of amyloid fibrils composed of misfolded TTR. The differences in penetrance and age at onset are vast, both between and within populations, with a generally late onset for Swedish carriers. In a recent study the entire TTR gene including the 3' UTR in Swedish, French and Japanese ATTR patients was sequenced. The study disclosed a SNP in the V30M TTR 3' UTR of the Swedish ATTR population that was not present in either the French or the Japanese populations (rs62093482-C>T). This SNP could create a new binding site for miRNA, which would increase degradation of the mutated TTR's mRNA thus decrease variant TTR formation and thereby delay the onset of the disease. The aim of the present study was to disclose differences in allele specific TTR expression among Swedish V30M patients, and to see if selected miRNA had any effect upon the expression. METHODOLOGY/PRINCIPAL FINDINGS: Allele-specific expression was measured on nine liver biopsies from Swedish ATTR patients using SNaPshot Multiplex assay. Luciferase activity was measured on cell lines transfected with constructs containing the TTR 3' UTR. Allele-specific expression measured on liver biopsies from Swedish ATTR patients showed no difference in expression between the two alleles. Neither was there any difference in expression between cell lines co-transfected with two constructs with or without the TTR 3' UTR SNP regardless of added miRNA. CONCLUSIONS/SIGNIFICANCE: The SNP found in the 3' UTR of the TTR gene has no effect on degrading the variant allele's expression and thus has no impact on the diminished penetrance of the trait in the Swedish population. However, the 3' UTR SNP is unique for patients descending from the Swedish founder, and this SNP could be utilized to identify ATTR patients of Swedish descent.