RESUMO
Breast cancer (BC) risk is suspected to be linked to thyroid disorders, however observational studies exploring the association between BC and thyroid disorders gave conflicting results. We proposed an alternative approach by investigating the shared genetic risk factors between BC and several thyroid traits. We report a positive genetic correlation between BC and thyroxine (FT4) levels (corr = 0.13, p-value = 2.0 × 10-4) and a negative genetic correlation between BC and thyroid-stimulating hormone (TSH) levels (corr = -0.09, p-value = 0.03). These associations are more striking when restricting the analysis to estrogen receptor-positive BC. Moreover, the polygenic risk scores (PRS) for FT4 and hyperthyroidism are positively associated to BC risk (OR = 1.07, 95%CI: 1.00-1.13, p-value = 2.8 × 10-2 and OR = 1.04, 95%CI: 1.00-1.08, p-value = 3.8 × 10-2, respectively), while the PRS for TSH is inversely associated to BC risk (OR = 0.93, 95%CI: 0.89-0.97, p-value = 2.0 × 10-3). Using the PLACO method, we detected 49 loci associated to both BC and thyroid traits (p-value < 5 × 10-8), in the vicinity of 130 genes. An additional colocalization and gene-set enrichment analyses showed a convincing causal role for a known pleiotropic locus at 2q35 and revealed an additional one at 8q22.1 associated to both BC and thyroid cancer. We also found two new pleiotropic loci at 14q32.33 and 17q21.31 that were associated to both TSH levels and BC risk. Enrichment analyses and evidence of regulatory signals also highlighted brain tissues and immune system as candidates for obtaining associations between BC and TSH levels. Overall, our study sheds light on the complex interplay between BC and thyroid traits and provides evidence of shared genetic risk between those conditions.
Assuntos
Neoplasias da Mama , Glândula Tireoide , Humanos , Feminino , Neoplasias da Mama/genética , Tireotropina/genética , Tiroxina/genética , Fatores de Risco , Estratificação de Risco GenéticoRESUMO
JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.
Assuntos
Proteína Jagged-2/genética , Distrofias Musculares/genética , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Linhagem Celular , Criança , Pré-Escolar , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Feminino , Glucosiltransferases/genética , Haplótipos/genética , Humanos , Proteína Jagged-1/genética , Proteína Jagged-2/química , Proteína Jagged-2/deficiência , Proteína Jagged-2/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Pessoa de Meia-Idade , Modelos Moleculares , Músculos/metabolismo , Músculos/patologia , Distrofias Musculares/patologia , Mioblastos/metabolismo , Mioblastos/patologia , Linhagem , Fenótipo , Receptores Notch/metabolismo , Transdução de Sinais , Sequenciamento do Exoma , Adulto JovemRESUMO
BACKGROUND: Neurofibromatosis type 1 (NF1) is characterized by the highly variable and unpredictable development of benign peripheral nerve sheath tumours: cutaneous (cNFs), subcutaneous (scNFs) and plexiform (pNFs) neurofibromas. OBJECTIVES: To identify neurofibroma modifier genes, in order to develop a database of patients with NF1. METHODS: All patients were phenotypically evaluated by a medical practitioner using a standardized questionnaire and the causal NF1 variant identified. We enrolled 1333 patients with NF1 who were genotyped for > 7 million common variants. RESULTS: A genome-wide association case-only study identified a significant association with 9q21.33 in the pNF phenotype in the discovery cohort. Twelve, three and four regions suggestive of association at the P ≤ 1 × 10-6 threshold were identified for pNFs, cNFs and scNFs, respectively. Evidence of replication was observed for 4, 2 and 6 loci, including 168 candidate modifier protein-coding genes. Among the candidate modifier genes, some were implicated in the RAS-mitogen-activated protein kinase pathway, cell-cycle control and myelination. Using an original CRISPR/Cas9-based functional assay, we confirmed GAS1 and SPRED2 as pNF and scNF candidate modifiers, as their inactivation specifically affected NF1-mutant Schwann cell growth. CONCLUSIONS: Our study may shed new light on the pathogenesis of NF1-associated neurofibromas and will, hopefully, contribute to the development of personalized care for patients with this deleterious and life-threatening condition.
Assuntos
Neurofibroma Plexiforme , Neurofibroma , Neurofibromatose 1 , Humanos , Neurofibromatose 1/genética , Neurofibroma Plexiforme/complicações , Neurofibroma Plexiforme/genética , Estudo de Associação Genômica Ampla , Neurofibroma/complicações , Neurofibroma/genética , Genótipo , Proteínas Repressoras/genéticaRESUMO
BACKGROUND: Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. OBJECTIVE: We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. METHODS: We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. RESULTS: We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). CONCLUSIONS: We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Assuntos
Neoplasias Pulmonares , Melanoma , Neoplasias Ovarianas , Doença de Parkinson , Neoplasias da Próstata , Humanos , Masculino , Feminino , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Melanoma/epidemiologia , Melanoma/genética , Fatores de RiscoRESUMO
Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome-wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population-based case-control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray-500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid-stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations.
Assuntos
Estudo de Associação Genômica Ampla/métodos , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Glândula Tireoide/etnologia , População Branca/genética , Adulto , Idoso , Estudos de Casos e Controles , Cromossomos Humanos/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Ilhas do Pacífico/etnologia , Neoplasias da Glândula Tireoide/genéticaRESUMO
BACKGROUND: Interferon γ (IFN-γ) release assays (IGRAs) provide an in vitro measurement of antimycobacterial immunity that is widely used as a test for Mycobacterium tuberculosis infection. IGRA outcomes are highly heritable in various populations, but the nature of the involved genetic factors remains unknown. METHODS: We conducted a genome-wide linkage analysis of IGRA phenotypes in families from a tuberculosis household contact study in France and a replication study in families from South Africa to confirm the loci identified. RESULTS: We identified a major locus on chromosome 8q controlling IFN-γ production in response to stimulation with live bacillus Calmette-Guerin (BCG; LOD score, 3.81; P = 1.40 × 10(-5)). We also detected a second locus, on chromosome 3q, that controlled IFN-γ levels in response to stimulation with 6-kDa early secretory antigen target, when accounting for the IFN-γ production shared with that induced by BCG (LOD score, 3.72; P = 1.8 × 10(-5)). Both loci were replicated in South African families, where tuberculosis is hyperendemic. These loci differ from those previously identified as controlling the response to the tuberculin skin test (TST1 and TST2) and the production of TNF-α (TNF1). CONCLUSIONS: The identification of 2 new linkage signals in populations of various ethnic origins living in different M. tuberculosis exposure settings provides new clues about the genetic control of human antimycobacterial immunity.
Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 8 , Regulação Bacteriana da Expressão Gênica/imunologia , Interferon gama/metabolismo , Mycobacterium bovis/imunologia , Estudos de Coortes , Feminino , França , Ligação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Interferon gama/genética , Masculino , Fenótipo , Estudos Prospectivos , África do Sul , Tuberculose/genética , Tuberculose/imunologiaRESUMO
A substantial proportion of subjects exposed to a contagious tuberculosis case display lack of tuberculin skin test (TST) reactivity. We previously mapped a major locus (TST1) controlling lack of TST reactivity in families from an area in South Africa where tuberculosis is hyperendemic. Here, we conducted a household tuberculosis contact study in a French area where the endemicity of tuberculosis is low. A genome-wide analysis of TST negativity identified a significant linkage signal (P < 3 × 10(-5)) in close vicinity of TST1. Combined analysis of the 2 samples increased evidence of linkage (P = 2.4 × 10(-6)), further implicating genetic factors located on 11p14-15. This region overlaps the TNF1 locus controlling mycobacteria-driven tumor necrosis factor α production.
Assuntos
Hipersensibilidade Tardia/genética , Teste Tuberculínico , Tuberculina/imunologia , Tuberculose/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , África do Sul , Adulto JovemRESUMO
The M-type receptor for phospholipase A2 (PLA2R1) is the major target antigen in idiopathic membranous nephropathy (iMN). Our recent genome-wide association study showed that genetic variants in an HLA-DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation. Here, we sequenced PLA2R1 in a cohort of 95 white patients with biopsy-proven iMN and assessed all 30 exons of PLA2R1, including canonical (GT-AG) splice sites, by Sanger sequencing. Sixty patients had anti-PLA2R1 in serum or detectable PLA2R1 antigen in kidney tissue. We identified 18 sequence variants, comprising 2 not previously described, 7 reported as rare variants (<1%) in the Single Nucleotide Polymorphism Database or the 1000 Genomes project, and 9 known to be common polymorphisms. Although we confirmed significant associations among 6 of the identified common variants and iMN, only 9 patients had the private or rare variants, and only 4 of these patients were among the 60 who were PLA2R positive. In conclusion, rare variants in the coding sequence of PLA2R1, including splice sites, are unlikely to explain the pathogenesis of iMN.
Assuntos
Glomerulonefrite Membranosa/genética , Receptores da Fosfolipase A2/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Variação Estrutural do Genoma , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.
Assuntos
Encefalopatias , Humanos , Acetilação , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encefalopatias/genética , Padrões de Herança , Mutação , Fosfatos/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismoRESUMO
BACKGROUND: Tumor necrosis factor (TNF) is a key immune regulator of tuberculosis resistance, as exemplified by the highly increased risk of tuberculosis disease among individuals receiving TNF-blocker therapy. METHODS: We determined the extent of TNF production after stimulation with BCG or BCG plus interferon gamma (IFN-γ) using a whole blood assay in 392 children belonging to 135 nuclear families from an area hyperendemic for tuberculosis in South Africa. We conducted classical univariate and bivariate genome-wide linkage analysis of TNF production using the data from both stimulation protocols by means of an extension of the maximum-likelihood-binomial method for quantitative trait loci to multivariate analysis. RESULTS: Stimulation of whole blood by either BCG or BCG plus IFN-γ resulted in a range of TNF release across subjects. Extent of TNF production following both stimulation protocols was highly correlated (r = 0.81). We failed to identify genetic linkage of TNF release when considering each stimulus separately. However, using a multivariate approach, we detected a major pleiotropic locus (P < 10(-5)) on chromosome region 11p15, termed TNF locus 1 (TNF1), that controlled TNF production after stimulation by both BCG alone and BCG plus IFN-γ. CONCLUSIONS: The TNF1 locus was mapped in the vicinity of the TST1 locus, previously identified in the same family sample, that controls tuberculin skin test (TST) negativity per se, that is, T-cell-independent resistance to Mycobacterium tuberculosis infection. This suggested that there is a connection between TST negativity per se and TNF production.
Assuntos
Vacina BCG/administração & dosagem , Leucócitos/imunologia , Mycobacterium bovis/imunologia , Tuberculose/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Adulto , Análise de Variância , Distribuição de Qui-Quadrado , Criança , Cromossomos Humanos Par 11 , Doenças Endêmicas , Família , Pleiotropia Genética , Humanos , Interferon gama/administração & dosagem , Testes de Liberação de Interferon-gama , Leucócitos/efeitos dos fármacos , Desequilíbrio de Ligação , Fenótipo , Locos de Características Quantitativas , África do Sul/epidemiologia , Tuberculose/sangue , Tuberculose/epidemiologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Background: The choice of efficient antipsychotic therapy for schizophrenia relies on a time-consuming trial-and-error approach, whereas the social and economic burdens of the disease call for faster alternatives. Material & methods: In a search for predictive biomarkers of antipsychotic response, blood methylomes of 28 patients were analyzed before and 4 weeks into risperidone therapy. Results: Several CpGs exhibiting response-specific temporal dynamics were identified in otherwise temporally stable methylomes and noticeable global response-related differences were observed between good and bad responders. These were associated with genes involved in immunity, neurotransmission and neuronal development. Polymorphisms in many of these genes were previously linked with schizophrenia etiology and antipsychotic response. Conclusion: Antipsychotic response seems to be shaped by both stable and medication-induced methylation differences.
The most common way to treat schizophrenia is antipsychotic medication. However, not all antipsychotics work for all patients. The only way to find a suitable antipsychotic is to prescribe one and wait, sometimes for months, to see if it works. Finding an alternative to this trial-and-error method would help reduce patient suffering and costs for healthcare systems. The idea is to look in the DNA of our blood cells for specific marks that can change in response to our lifestyle or health condition. These marks could help us predict how patients will react to the drug. In other words, they can serve as biomarkers of antipsychotic response. The current work examined the blood of schizophrenia patients before and 4 weeks after starting medication. The patients who did not respond well to the drug had different marks on the genes involved in immune defense and nervous system functioning. Some of these genes also play roles in the development of schizophrenia, whereas others can directly affect what happens to the drug in the patient's body. Although marks that predict how patients will react were not identified with certainty, valuable targets for future research were identified.
Assuntos
Antipsicóticos , Esquizofrenia , Humanos , Risperidona/farmacologia , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Metilação de DNA , BenzodiazepinasRESUMO
Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.
Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Humanos , Mesotelioma Maligno/genética , Mesotelioma Maligno/complicações , Mesotelioma/genética , Mesotelioma/patologia , Multiômica , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Neoplasias Pulmonares/patologia , Biomarcadores Tumorais/genéticaRESUMO
Despite increasing insight into the genetics of infertility, the developmental disease processes remain unclear due to the lack of adequate experimental models. The advent of induced pluripotent stem cell (iPSC) technology has provided a unique tool for in vitro disease modeling enabling major advances in our understanding of developmental disease processes. We report the full characterization of complex genetic abnormalities in two infertile patients with either azoospermia or XX male syndrome and we identify genes of potential interest implicated in their infertility. Using the erythroblasts of both patients, we generated primed iPSCs and converted them into a naive-like pluripotent state. Naive-iPSCs were then differentiated into primordial germ-like cells (PGC-LCs). The expression of early PGC marker genes SOX17, CD-38, NANOS3, c-KIT, TFAP2C, and D2-40, confirmed progression towards the early germline stage. Our results demonstrate that iPSCs from two infertile patients with significant genetic abnormalities are capable of efficient production of PGCs. Such in vitro model of infertility will certainly help identifying causative factors leading to early germ cells development failure and provide a valuable tool to explore novel therapeutic strategies.
Assuntos
Azoospermia , Células-Tronco Pluripotentes Induzidas , Azoospermia/genética , Azoospermia/metabolismo , Diferenciação Celular/genética , Eritroblastos , Células Germinativas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , MasculinoRESUMO
Variants identified in earlier genome-wide association studies (GWAS) on differentiated thyroid carcinoma (DTC) explain about 10% of the overall estimated genetic contribution and could not provide complete insights into biological mechanisms involved in DTC susceptibility. Integrating systems biology information from model organisms, genome-wide expression data from tumor and matched normal tissue and GWAS data could help identifying DTC-associated genes, and pathways or functional networks in which they are involved. We performed data mining of GWAS data of the EPITHYR consortium (1551 cases and 1957 controls) using various pathways and protein-protein interaction (PPI) annotation databases and gene expression data from The Cancer Genome Atlas. We identified eight DTC-associated genes at known loci 2q35 (DIRC3), 8p12 (NRG1), 9q22 (FOXE1, TRMO, HEMGN, ANP32B, NANS) and 14q13 (MBIP). Using the EW_dmGWAS approach we found that gene networks related to glycogenolysis, glycogen metabolism, insulin metabolism and signal transduction pathways associated with muscle contraction were overrepresented with association signals (false discovery rate adjusted p-value < 0.05). Additionally, suggestive association of 21 KEGG and 75 REACTOME pathways with DTC indicate a link between DTC susceptibility and functions related to metabolism of cholesterol, amino sugar and nucleotide sugar metabolism, steroid biosynthesis, and downregulation of ERBB2 signaling pathways. Together, our results provide novel insights into biological mechanisms contributing to DTC risk.
Assuntos
Redes Reguladoras de Genes , Predisposição Genética para Doença , Genótipo , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-IdadeRESUMO
Hereditary spastic paraplegia (HSP) with thin corpus callosum (TCC) and mental impairment is a frequent subtype of complicated HSP, often inherited as an autosomal recessive (AR) trait. It is clear from molecular genetic analyses that there are several underlying causes of this syndrome, with at least six genetic loci identified to date. However, SPG11 and SPG15 are the two major genes for this entity. To map the responsible gene in a large AR-HSP-TCC family of Tunisian origin, we investigated a consanguineous family with a diagnosis of AR-HSP-TCC excluded for linkage to the SPG7, SPG11, SPG15, SPG18, SPG21, and SPG32 loci. A genome-wide scan was undertaken using 6,090 SNP markers covering all chromosomes. The phenotypic presentation in five patients was suggestive of a complex HSP that associated an early-onset spastic paraplegia with mild handicap, mental deterioration, congenital cataract, cerebellar signs, and TCC. The genome-wide search identified a single candidate region on chromosome 9, exceeding the LOD score threshold of +3. Fine mapping using additional markers narrowed the candidate region to a 45.1-Mb interval (15.4 cM). Mutations in three candidate genes were excluded. The mapping of a novel AR-HSP-TCC locus further demonstrates the extensive genetic heterogeneity of this condition. We propose that testing for this locus should be performed, after exclusion of mutations in SPG11 and SPG15 genes, in AR-HSP-TCC families, especially when cerebellar ataxia and cataract are present.
Assuntos
Cromossomos Humanos Par 9 , Corpo Caloso/patologia , Paraplegia Espástica Hereditária/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Saúde da Família , Feminino , Genes Recessivos , Ligação Genética , Humanos , Masculino , Modelos Genéticos , Linhagem , Polimorfismo de Nucleotídeo Único , TunísiaRESUMO
A fundamental shortcoming in the current treatment of schizophrenia is the lack of valid criteria to predict who will respond to antipsychotic treatment. The identification of blood-based biological markers of the therapeutic response would enable clinicians to identify the subgroup of patients in whom conventional antipsychotic treatment is ineffective and offer alternative treatments. As part of the Optimisation of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) programme, we conducted an RNA-Seq analysis on 188 subjects with first episode psychosis, all of whom were subsequently treated with amisulpride for 4 weeks. We compared gene expression on total RNA from patients' blood before and after treatment and identified 32 genes for which the expression changed after treatment in good responders only. These findings were replicated in an independent sample of 24 patients with first episode psychosis. Six genes showed a significant difference in expression level between good and poor responders before starting treatment, allowing to predict treatment outcome with a predictive value of 93.8% when combined with clinical features. Collectively, these findings identified new mechanisms to explain symptom improvement after amisulpride medication and highlight the potential of combining gene expression profiling with clinical data to predict treatment response in first episode psychoses.
Assuntos
Antipsicóticos , Transtornos Psicóticos , Amissulprida , Antipsicóticos/uso terapêutico , Europa (Continente) , Expressão Gênica , Humanos , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/genética , Resultado do TratamentoRESUMO
BACKGROUND: Antipsychotic-induced weight gain is a common and debilitating side effect of antipsychotics. Although genome-wide association studies of antipsychotic-induced weight gain have been performed, few genome-wide loci have been discovered. Moreover, these genome-wide association studies have included a wide variety of antipsychotic compounds. AIMS: We aim to gain more insight in the genomic loci affecting antipsychotic-induced weight gain. Given the variable pharmacological properties of antipsychotics, we hypothesized that targeting a single antipsychotic compound would provide new clues about genomic loci affecting antipsychotic-induced weight gain. METHODS: All subjects included for this genome-wide association study (n=339) were first-episode schizophrenia spectrum disorder patients treated with amisulpride and were minimally medicated (defined as antipsychotic use <2 weeks in the previous year and/or <6 weeks lifetime). Weight gain was defined as the increase in body mass index from before until approximately 1 month after amisulpride treatment. RESULTS: Our genome-wide association analyses for antipsychotic-induced weight gain yielded one genome-wide significant hit (rs78310016; ß=1.05; p=3.66 × 10-08; n=206) in a locus not previously associated with antipsychotic-induced weight gain or body mass index. Minor allele carriers had an odds ratio of 3.98 (p=1.0 × 10-03) for clinically meaningful antipsychotic-induced weight gain (⩾7% of baseline weight). In silico analysis elucidated a chromatin interaction with 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1. In an attempt to replicate single-nucleotide polymorphisms previously associated with antipsychotic-induced weight gain, we found none were associated with amisulpride-induced weight gain. CONCLUSION: Our findings suggest the involvement of rs78310016 and possibly 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1 in antipsychotic-induced weight gain. In line with the unique binding profile of this atypical antipsychotic, our findings furthermore hint that biological mechanisms underlying amisulpride-induced weight gain differ from antipsychotic-induced weight gain by other atypical antipsychotics.
Assuntos
Amissulprida/efeitos adversos , Antipsicóticos/efeitos adversos , Transtornos Psicóticos/tratamento farmacológico , Aumento de Peso/efeitos dos fármacos , Adulto , Alelos , Amissulprida/administração & dosagem , Antipsicóticos/administração & dosagem , Estudos de Coortes , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Hidroximetilglutaril-CoA Sintase/genética , Masculino , Polimorfismo de Nucleotídeo Único , Esquizofrenia/tratamento farmacológico , Aumento de Peso/genética , Adulto JovemRESUMO
Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.
Assuntos
Cromatina/metabolismo , Histonas/metabolismo , Interferon Tipo I/biossíntese , Precursores de RNA/metabolismo , Proteínas de Ligação a RNA/genética , Ribonucleoproteína Nuclear Pequena U7/genética , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Linhagem Celular , DNA/imunologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Células HCT116 , Células HEK293 , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Humanos , Proteínas de Membrana/metabolismo , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia , Nucleotídeos Cíclicos/biossíntese , Nucleotidiltransferases/metabolismoRESUMO
Theobroma cacao is an economically important tree of several tropical countries. Its genetic improvement is essential to provide protection against major diseases and improve chocolate quality. We discovered and mapped new expressed sequence tag-single nucleotide polymorphism (EST-SNP) and simple sequence repeat (SSR) markers and constructed a high-density genetic map. By screening 149 650 ESTs, 5246 SNPs were detected in silico, of which 1536 corresponded to genes with a putative function, while 851 had a clear polymorphic pattern across a collection of genetic resources. In addition, 409 new SSR markers were detected on the Criollo genome. Lastly, 681 new EST-SNPs and 163 new SSRs were added to the pre-existing 418 co-dominant markers to construct a large consensus genetic map. This high-density map and the set of new genetic markers identified in this study are a milestone in cocoa genomics and for marker-assisted breeding. The data are available at http://tropgenedb.cirad.fr.