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2.
Chest ; 156(2): 298-307, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31034819

RESUMO

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a destructive metastasizing neoplasm of the lung characterized by proliferation of LAM cells in specialized lung nodules. LAM cells are characterized by expression of the prometastatic and cancer-initiating hyaluronan receptor CD44v6, and loss of heterozygosity (LOH) of TSC1 and TSC2. The circulating neoplastic LAM cells are thought to be involved in metastasis. Because LAM cells display properties of neoplastic, metastatic, and stem cell-like cancer cells, we hypothesized that elevated aldehyde dehydrogenase (ALDH) activity, characteristic of cancer and stem cells, is a property of LAM cells. METHODS: We performed an in silico search of ALDH genes in microdissected LAM lung nodules. To identify circulating LAM cells, we osmotically removed red blood cells from whole blood to obtain peripheral blood mononuclear cells, which were then sorted by fluorescence-activated cell sorting based on their level of ALDH activity. RESULTS: Microdissected LAM lung nodules possess a distinctive ALDH gene profile. The cell subpopulation with high ALDH activity, isolated from circulating cells, possessed TSC2 LOH in 8 of 14 patients with LAM. Approximately 60% of the circulating cells with high ALDH activity expressed CD44v6. Cells with TSC2 LOH from patients with LAM and LAM/TSC exhibited different properties in different body locations, but all cell types showed high ALDH activity. CONCLUSIONS: This new procedure allows for isolation of circulating LAM cells from cultured cells, blood, and chylous effusions and shows that circulating LAM cells are heterogeneous with neoplastic, metastatic, and cancer-stem cell-like properties.

3.
Elife ; 72018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30520728

RESUMO

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

4.
Genet Med ; 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30523342

RESUMO

PURPOSE: The acquisition of pathogenic variants in the TERT promoter (TERTp) region is a mechanism of tumorigenesis. In nonmalignant diseases, TERTp variants have been reported only in patients with idiopathic pulmonary fibrosis (IPF) due to germline variants in telomere biology genes. METHODS: We screened patients with a broad spectrum of telomeropathies (n = 136), their relatives (n = 52), and controls (n = 195) for TERTp variants using a customized massively parallel amplicon-based sequencing assay. RESULTS: Pathogenic -124 and -146 TERTp variants were identified in nine (7%) unrelated patients diagnosed with IPF (28%) or moderate aplastic anemia (4.6%); five of them also presented cirrhosis. Five (10%) relatives were also found with these variants, all harboring a pathogenic germline variant in telomere biology genes. TERTp clone selection did not associate with peripheral blood counts, telomere length, and response to danazol treatment. However, it was specific for patients with telomeropathies, more frequently co-occurring with TERT germline variants and associated with aging. CONCLUSION: We extend the spectrum of nonmalignant diseases associated with pathogenic TERTp variants to marrow failure and liver disease due to inherited telomerase deficiency. Specificity of pathogenic TERTp variants for telomerase dysfunction may help to assess the pathogenicity of unclear constitutional variants in the telomere diseases.

5.
Nat Immunol ; 19(12): 1403-1414, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30397350

RESUMO

Repair of tissue damaged during inflammatory processes is key to the return of local homeostasis and restoration of epithelial integrity. Here we describe CD161+ regulatory T (Treg) cells as a distinct, highly suppressive population of Treg cells that mediate wound healing. These Treg cells were enriched in intestinal lamina propria, particularly in Crohn's disease. CD161+ Treg cells had an all-trans retinoic acid (ATRA)-regulated gene signature, and CD161 expression on Treg cells was induced by ATRA, which directly regulated the CD161 gene. CD161 was co-stimulatory, and ligation with the T cell antigen receptor induced cytokines that accelerated the wound healing of intestinal epithelial cells. We identified a transcription-factor network, including BACH2, RORγt, FOSL2, AP-1 and RUNX1, that controlled expression of the wound-healing program, and found a CD161+ Treg cell signature in Crohn's disease mucosa associated with reduced inflammation. These findings identify CD161+ Treg cells as a population involved in controlling the balance between inflammation and epithelial barrier healing in the gut.

6.
J Cell Sci ; 131(22)2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30333138

RESUMO

Although GCN5L1 (also known as BLOC1S1) facilitates mitochondrial protein acetylation and controls endosomal-lysosomal trafficking, the mechanisms underpinning these disparate effects are unclear. As microtubule acetylation modulates endosome-lysosome trafficking, we reasoned that exploring the role of GCN5L1 in this biology may enhance our understanding of GCN5L1-mediated protein acetylation. We show that α-tubulin acetylation is reduced in GCN5L1-knockout hepatocytes and restored by GCN5L1 reconstitution. Furthermore, GCN5L1 binds to the α-tubulin acetyltransferase αTAT1, and GCN5L1-mediated α-tubulin acetylation is dependent on αTAT1. Given that cytosolic GCN5L1 has been identified as a component of numerous multiprotein complexes, we explored whether novel interacting partners contribute to this regulation. We identify RanBP2 as a novel interacting partner of GCN5L1 and αTAT1. Genetic silencing of RanBP2 phenocopies GCN5L1 depletion by reducing α-tubulin acetylation, and we find that RanBP2 possesses a tubulin-binding domain, which recruits GCN5L1 to α-tubulin. Finally, we find that genetic depletion of GCN5L1 promotes perinuclear lysosome accumulation and histone deacetylase inhibition partially restores lysosomal positioning. We conclude that the interactions of GCN5L1, RanBP2 and αTAT1 function in concert to control α-tubulin acetylation and may contribute towards the regulation of cellular lysosome positioning. This article has an associated First Person interview with the first author of the paper.

7.
Atherosclerosis ; 278: 278-285, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30347343

RESUMO

BACKGROUND AND AIMS: High density lipoprotein cholesterol (HDL-C) is associated with risk of cardiovascular disease (CVD); however, therapeutic manipulations of HDL-C have failed to reduce CVD events. This suggests that HDL-C and the atheroprotective capacity of HDL are not directly linked. The goal of this study was to evaluate the relationships between HDL-bound proteins and measures of atherosclerosis burden and HDL function. METHODS: The HDL proteome was analyzed using mass spectrometry in 126 human subjects, who had undergone coronary computed tomography angiography (CCTA) to quantify calcified (CB) and non-calcified (NCB) atherosclerosis burden. Partial least squares regression analysis was used to evaluate associations between HDL-bound proteins and CB, NCB, or cholesterol efflux capacity (CEC). RESULTS: Significant overlap was found among proteins associated with NCB and CEC. Proteins that were associated with NCB displayed an inverse relationship with CEC, supporting a link between this protective function of HDL and clinical plaque burden. CB was associated with a set of proteins mostly distinct from NCB and CEC. When CVD risk factors were evaluated, BMI had a stronger influence on important HDL proteins than gender, age, or HDL-C. Most HDL proteins associated with function or atherosclerosis burden were not significantly correlated with HDL-C. CONCLUSIONS: These findings indicate that the HDL proteome contains information not captured by HDL- C and, therefore, has potential for future development as a biomarker for CVD risk. Additionally, the proteome effects detected in this study may provide HDL compositional goals for evaluating new and existing HDL-modification therapies.

8.
Nat Commun ; 9(1): 4186, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305631

RESUMO

The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men.

9.
Haematologica ; 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30171026

RESUMO

Great effort is spent on developing therapies to improve the dire outcomes of those diagnosed with acute myeloid leukemia, while the methods for quantifying response to therapeutic intervention have lacked sensitivity. As a result, those patients achieving a complete remission remain at risk of subsequent relapse due to disease persistence not evident by conventional cytomorphological methods. Improved risk stratification is possible based on tests designed to detect this residual leukemic burden (measurable residual disease). However, acute myeloid leukemia is a genetically diverse set of diseases, which has made it difficult to develop a single, highly reproducible, and sensitive detection assay for measurable residual disease. To overcome these limitations, we present the development of a digital targeted RNA-sequencing-based approach which detects all newly approved European Leukemia Network molecular targets for measurable residual disease in acute myeloid leukemia in a single standardized assay. Iterative modifications and novel bioinformatics approaches resulted in a greater than one hundred-fold increase in performance compared with commercially available targeted RNA-sequencing approaches and a limit of detection as low as 1 in 100,000 cells comparable with quantitative PCR, the current gold standard for measurable residual disease detection. This assay, which is customizable and expandable, is the first demonstrated use of high-sensitivity RNA-sequencing for measurable residual disease detection in acute myeloid leukemia and thus could serve as a broadly applicable standardized tool.

10.
J Heart Lung Transplant ; 37(8): 967-975, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29933912

RESUMO

BACKGROUND: Observational studies suggest that cell-free DNA (cfDNA) is a biomarker of tissue injury in a range of conditions including organ transplantation. However, the lack of model systems to study cfDNA and its relevance to tissue injury has limited the advancements in this field. We hypothesized that the predictable course of acute humoral xenograft rejection (AHXR) in organ transplants from genetically engineered donors provides an ideal system for assessing circulating cfDNA as a marker of tissue injury. METHODS: Genetically modified pig donor hearts were heterotopically transplanted into baboons (n = 7). Cell-free DNA was extracted from pre-transplant and post-transplant baboon plasma samples for shotgun sequencing. After alignment of sequence reads to pig and baboon reference sequences, we computed the percentage of xenograft-derived cfDNA (xdcfDNA) relative to recipient by counting uniquely aligned pig and baboon sequence reads. RESULTS: The xdcfDNA percentage was high early post-transplantation and decayed exponentially to low stable levels (baseline); the decay half-life was 3.0 days. Post-transplantation baseline xdcfDNA levels were higher for transplant recipients that subsequently developed graft loss than in the 1 animal that did not reject the graft (3.2% vs 0.5%). Elevations in xdcfDNA percentage coincided with increased troponin and clinical evidence of rejection. Importantly, elevations in xdcfDNA percentage preceded clinical signs of rejection or increases in troponin levels. CONCLUSION: Cross-species xdcfDNA kinetics in relation to acute rejection are similar to the patterns in human allografts. These observations in a xenotransplantation model support the body of evidence suggesting that circulating cfDNA is a marker of tissue injury.

11.
Proc Natl Acad Sci U S A ; 115(18): 4767-4772, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29669919

RESUMO

To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of CPB1 and other genes encoding pancreatic secretory enzymes and known pancreatitis susceptibility genes (PRSS1, CPA1, CTRC, and SPINK1) in a hospital series of pancreatic cancer cases and controls. Variants in CPB1, CPA1 (encoding carboxypeptidase B1 and A1), and CTRC were evaluated in a second set of cases with familial pancreatic cancer and controls. More deleterious CPB1 variants, defined as having impaired protein secretion and induction of endoplasmic reticulum (ER) stress in transfected HEK 293T cells, were found in the hospital series of pancreatic cancer cases (5/986, 0.5%) than in controls (0/1,045, P = 0.027). Among familial pancreatic cancer cases, ER stress-inducing CPB1 variants were found in 4 of 593 (0.67%) vs. 0 of 967 additional controls (P = 0.020), with a combined prevalence in pancreatic cancer cases of 9/1,579 vs. 0/2,012 controls (P < 0.01). More ER stress-inducing CPA1 variants were also found in the combined set of hospital and familial cases with pancreatic cancer than in controls [7/1,546 vs. 1/2,012; P = 0.025; odds ratio, 9.36 (95% CI, 1.15-76.02)]. Overall, 16 (1%) of 1,579 pancreatic cancer cases had an ER stress-inducing CPA1 or CPB1 variant, compared with 1 of 2,068 controls (P < 0.00001). No other candidate genes had statistically significant differences in variant prevalence between cases and controls. Our study indicates ER stress-inducing variants in CPB1 and CPA1 are associated with pancreatic cancer susceptibility and implicate ER stress in pancreatic acinar cells in pancreatic cancer development.


Assuntos
Carboxipeptidase B , Carboxipeptidases A , Estresse do Retículo Endoplasmático/genética , Predisposição Genética para Doença , Mutação , Proteínas de Neoplasias , Neoplasias Pancreáticas , Idoso , Idoso de 80 Anos ou mais , Carboxipeptidase B/genética , Carboxipeptidase B/metabolismo , Carboxipeptidases A/genética , Carboxipeptidases A/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
12.
J Heart Lung Transplant ; 37(7): 925-932, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29500138

RESUMO

BACKGROUND: Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation. METHODS: We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs. RESULTS: Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels. CONCLUSION: Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.

13.
Genome Biol Evol ; 9(12): 3225-3237, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29165562

RESUMO

The human population displays wide variety in demographic history, ancestry, content of DNA derived from hominins or ancient populations, adaptation, traits, copy number variation, drug response, and more. These polymorphisms are of broad interest to population geneticists, forensics investigators, and medical professionals. Historically, much of that knowledge was gained from population survey projects. Although many commercial arrays exist for genome-wide single-nucleotide polymorphism genotyping, their design specifications are limited and they do not allow a full exploration of biodiversity. We thereby aimed to design the Diversity of REcent and Ancient huMan (DREAM)-an all-inclusive microarray that would allow both identification of known associations and exploration of standing questions in genetic anthropology, forensics, and personalized medicine. DREAM includes probes to interrogate ancestry informative markers obtained from over 450 human populations, over 200 ancient genomes, and 10 archaic hominins. DREAM can identify 94% and 61% of all known Y and mitochondrial haplogroups, respectively, and was vetted to avoid interrogation of clinically relevant markers. To demonstrate its capabilities, we compared its FST distributions with those of the 1000 Genomes Project and commercial arrays. Although all arrays yielded similarly shaped (inverse J) FST distributions, DREAM's autosomal and X-chromosomal distributions had the highest mean FST, attesting to its ability to discern subpopulations. DREAM performances are further illustrated in biogeographical, identical by descent, and copy number variation analyses. In summary, with approximately 800,000 markers spanning nearly 2,000 genes, DREAM is a useful tool for genetic anthropology, forensic, and personalized medicine studies.


Assuntos
Antropologia/métodos , Genética Populacional/métodos , Genoma Humano , Medicina de Precisão/métodos , Variações do Número de Cópias de DNA , DNA Antigo , Evolução Molecular , Marcadores Genéticos , Genótipo , Humanos , Análise em Microsséries , Linhagem , Polimorfismo de Nucleotídeo Único
14.
Mol Neuropsychiatry ; 3(1): 1-11, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28879196

RESUMO

Suicidal behavior is a complex and devastating phenotype with a heritable component that has not been fully explained by existing common genetic variant analyses. This study represents the first large-scale DNA sequencing project designed to assess the role of rare functional genetic variation in suicidal behavior risk. To accomplish this, whole-exome sequencing data for ∼19,000 genes were generated for 387 bipolar disorder subjects with a history of suicide attempt and 631 bipolar disorder subjects with no prior suicide attempts. Rare functional variants were assessed in all exome genes as well as pathways hypothesized to contribute to suicidal behavior risk. No result survived conservative Bonferroni correction, though many suggestive findings have arisen that merit additional attention. In addition, nominal support for past associations in genes, such as BDNF, and pathways, such as the hypothalamic-pituitary-adrenal axis, was also observed. Finally, a novel pathway was identified that is driven by aldehyde dehydrogenase genes. Ultimately, this investigation explores variation left largely untouched by existing efforts in suicidal behavior, providing a wealth of novel information to add to future investigations, such as meta-analyses.

15.
Front Genet ; 8: 87, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28680441

RESUMO

Recently, the geographical origins of Ashkenazic Jews (AJs) and their native language Yiddish were investigated by applying the Geographic Population Structure (GPS) to a cohort of exclusively Yiddish-speaking and multilingual AJs. GPS localized most AJs along major ancient trade routes in northeastern Turkey adjacent to primeval villages with names that resemble the word "Ashkenaz." These findings were compatible with the hypothesis of an Irano-Turko-Slavic origin for AJs and a Slavic origin for Yiddish and at odds with the Rhineland hypothesis advocating a Levantine origin for AJs and German origins for Yiddish. We discuss how these findings advance three ongoing debates concerning (1) the historical meaning of the term "Ashkenaz;" (2) the genetic structure of AJs and their geographical origins as inferred from multiple studies employing both modern and ancient DNA and original ancient DNA analyses; and (3) the development of Yiddish. We provide additional validation to the non-Levantine origin of AJs using ancient DNA from the Near East and the Levant. Due to the rising popularity of geo-localization tools to address questions of origin, we briefly discuss the advantages and limitations of popular tools with focus on the GPS approach. Our results reinforce the non-Levantine origins of AJs.

16.
Hum Mutat ; 38(9): 1182-1192, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28634997

RESUMO

Precision medicine aims to predict a patient's disease risk and best therapeutic options by using that individual's genetic sequencing data. The Critical Assessment of Genome Interpretation (CAGI) is a community experiment consisting of genotype-phenotype prediction challenges; participants build models, undergo assessment, and share key findings. For CAGI 4, three challenges involved using exome-sequencing data: Crohn's disease, bipolar disorder, and warfarin dosing. Previous CAGI challenges included prior versions of the Crohn's disease challenge. Here, we discuss the range of techniques used for phenotype prediction as well as the methods used for assessing predictive models. Additionally, we outline some of the difficulties associated with making predictions and evaluating them. The lessons learned from the exome challenges can be applied to both research and clinical efforts to improve phenotype prediction from genotype. In addition, these challenges serve as a vehicle for sharing clinical and research exome data in a secure manner with scientists who have a broad range of expertise, contributing to a collaborative effort to advance our understanding of genotype-phenotype relationships.


Assuntos
Transtorno Bipolar/genética , Doença de Crohn/genética , Medicina de Precisão/métodos , Varfarina/uso terapêutico , Sequenciamento Completo do Exoma/métodos , Biologia Computacional/métodos , Bases de Dados Genéticas , Predisposição Genética para Doença , Humanos , Disseminação de Informação , Variantes Farmacogenômicos , Fenótipo , Varfarina/farmacologia
17.
Epigenetics ; 12(8): 637-652, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28557603

RESUMO

Chronic exposure to glucocorticoids (GCs) can lead to psychiatric complications through epigenetic mechanisms such as DNA methylation (DNAm). We sought to determine whether epigenetic changes in a peripheral tissue can serve as a surrogate for those in a relatively inaccessible tissue such as the brain. DNA extracted from the hippocampus and blood of mice treated with GCs or vehicle solution was assayed using a genome-wide DNAm platform (Methyl-Seq) to identify differentially methylated regions (DMRs) induced by GC treatment. We observed that ∼70% of the DMRs in both tissues lost methylation following GC treatment. Of the 3,095 DMRs that mapped to the same genes in both tissues, 1,853 DMRs underwent DNAm changes in the same direction. Interestingly, only 209 DMRs (<7%) overlapped in genomic coordinates between the 2 tissues, suggesting tissue-specific differences in GC-targeted loci. Pathway analysis showed that the DMR-associated genes were members of pathways involved in metabolism, immune function, and neurodevelopment. Also, changes in cell type composition of blood and brain were examined by fluorescence-activated cell sorting. Separation of the cortex into neuronal and non-neuronal fractions and the leukocytes into T-cells, B-cells, and neutrophils showed that GC-induced methylation changes primarily occurred in neurons and T-cells, with the blood tissue also undergoing a shift in the proportion of constituent cell types while the proportion of neurons and glia in the brain remained stable. From the current pilot study, we found that despite tissue-specific epigenetic changes and cellular heterogeneity, blood can serve as a surrogate for GC-induced changes in the brain.


Assuntos
Metilação de DNA , Glucocorticoides/toxicidade , Hipocampo/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Animais , Epigênese Genética , Glucocorticoides/farmacologia , Hipocampo/citologia , Hipocampo/metabolismo , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Sequenciamento Completo do Genoma
19.
Sci Rep ; 6: 35837, 2016 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-27848937

RESUMO

The Druze are an aggregate of communities in the Levant and Near East living almost exclusively in the mountains of Syria, Lebanon and Israel whose ~1000 year old religion formally opposes mixed marriages and conversions. Despite increasing interest in genetics of the population structure of the Druze, their population history remains unknown. We investigated the genetic relationships between Israeli Druze and both modern and ancient populations. We evaluated our findings in light of three hypotheses purporting to explain Druze history that posit Arabian, Persian or mixed Near Eastern-Levantine roots. The biogeographical analysis localised proto-Druze to the mountainous regions of southeastern Turkey, northern Iraq and southeast Syria and their descendants clustered along a trajectory between these two regions. The mixed Near Eastern-Middle Eastern localisation of the Druze, shown using both modern and ancient DNA data, is distinct from that of neighbouring Syrians, Palestinians and most of the Lebanese, who exhibit a high affinity to the Levant. Druze biogeographic affinity, migration patterns, time of emergence and genetic similarity to Near Eastern populations are highly suggestive of Armenian-Turkish ancestries for the proto-Druze.


Assuntos
Emigração e Imigração/história , Grupos Étnicos/genética , Grupos Étnicos/história , Antropologia Cultural , Feminino , História Antiga , Humanos , Israel , Líbano , Masculino , Filogeografia , Síria
20.
JAMA Psychiatry ; 73(6): 590-7, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27120077

RESUMO

IMPORTANCE: Complex disorders, such as bipolar disorder (BD), likely result from the influence of both common and rare susceptibility alleles. While common variation has been widely studied, rare variant discovery has only recently become feasible with next-generation sequencing. OBJECTIVE: To utilize a combined family-based and case-control approach to exome sequencing in BD using multiplex families as an initial discovery strategy, followed by association testing in a large case-control meta-analysis. DESIGN, SETTING, AND PARTICIPANTS: We performed exome sequencing of 36 affected members with BD from 8 multiplex families and tested rare, segregating variants in 3 independent case-control samples consisting of 3541 BD cases and 4774 controls. MAIN OUTCOMES AND MEASURES: We used penalized logistic regression and 1-sided gene-burden analyses to test for association of rare, segregating damaging variants with BD. Permutation-based analyses were performed to test for overall enrichment with previously identified gene sets. RESULTS: We found 84 rare (frequency <1%), segregating variants that were bioinformatically predicted to be damaging. These variants were found in 82 genes that were enriched for gene sets previously identified in de novo studies of autism (19 observed vs. 10.9 expected, P = .0066) and schizophrenia (11 observed vs. 5.1 expected, P = .0062) and for targets of the fragile X mental retardation protein (FMRP) pathway (10 observed vs. 4.4 expected, P = .0076). The case-control meta-analyses yielded 19 genes that were nominally associated with BD based either on individual variants or a gene-burden approach. Although no gene was individually significant after correction for multiple testing, this group of genes continued to show evidence for significant enrichment of de novo autism genes (6 observed vs 2.6 expected, P = .028). CONCLUSIONS AND RELEVANCE: Our results are consistent with the presence of prominent locus and allelic heterogeneity in BD and suggest that very large samples will be required to definitively identify individual rare variants or genes conferring risk for this disorder. However, we also identify significant associations with gene sets composed of previously discovered de novo variants in autism and schizophrenia, as well as targets of the FRMP pathway, providing preliminary support for the overlap of potential autism and schizophrenia risk genes with rare, segregating variants in families with BD.


Assuntos
Transtorno Bipolar/genética , Exoma/genética , Análise de Sequência de DNA , Alelos , Transtorno Autístico/genética , Transtorno Autístico/psicologia , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Proteína do X Frágil de Retardo Mental/genética , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Esquizofrenia/genética , Psicologia do Esquizofrênico
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