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1.
Mol Psychiatry ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591465

RESUMO

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke's R2 = 0.032; liability R2 = 0.017; P < 10-52), Latino (Nagelkerke's R2 = 0.089; liability R2 = 0.021; P < 10-58), and European individuals (Nagelkerke's R2 = 0.089; liability R2 = 0.037; P < 10-113), further highlighting the advantages of incorporating data from diverse human populations.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31421235

RESUMO

OBJECTIVE: Genomic discoveries should be investigated in generalizable child psychiatric samples to justify and inform studies that will evaluate their use for specific clinical purposes. In youth consecutively referred for neuropsychiatric evaluation, we examined: 1) the convergent and discriminant validity of attention-deficit/hyperactivity disorder (ADHD) polygenic risk scores (PRS) in relation to DSM-based ADHD phenotypes; 2) the association of ADHD PRS with phenotypes beyond ADHD that share its liability and have implications for outcome; and 3) the extent to which youth with high ADHD PRS manifest a distinctive clinical profile. METHOD: Participants were 433 youth, ages 7 to 18, from the Longitudinal Study of Genetic Influences on Cognition. We used logistic/linear regression and mixed effects models to examine associations with ADHD-related polygenic variation from the largest ADHD GWAS to date. We replicated key findings in 5140 adult patients from a local health system biobank. RESULTS: Among referred youth, ADHD PRS associated with ADHD diagnoses, cross-diagnostic ADHD symptoms and academic impairment (OR's ∼1.4; R2's ∼2-3%) as well as cross-diagnostic variation in aggression and working memory. In adults, ADHD PRS associated with ADHD and phenotypes beyond the condition that have public health implications. Finally, youth with a high ADHD polygenic burden showed a more severe clinical profile than those with low burden (beta's∼.2). CONCLUSION: Among child and adolescent outpatients, ADHD polygenic risk associated with ADHD and related phenotypes as well as clinical severity. Results extend the scientific foundation for studies of ADHD polygenic risk in the clinical setting and highlight directions for further research.

3.
J Am Soc Nephrol ; 30(9): 1625-1640, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31308072

RESUMO

BACKGROUND: Over the past two decades, the importance of genetic factors in the development of FSGS has become increasingly clear. However, despite many known monogenic causes of FSGS, single gene defects explain only 30% of cases. METHODS: To investigate mutations underlying FSGS, we sequenced 662 whole exomes from individuals with sporadic or familial FSGS. After quality control, we analyzed the exome data from 363 unrelated family units with sporadic or familial FSGS and compared this to data from 363 ancestry-matched controls. We used rare variant burden tests to evaluate known disease-associated genes and potential new genes. RESULTS: We validated several FSGS-associated genes that show a marked enrichment of deleterious rare variants among the cases. However, for some genes previously reported as FSGS related, we identified rare variants at similar or higher frequencies in controls. After excluding such genes, 122 of 363 cases (33.6%) had rare variants in known disease-associated genes, but 30 of 363 controls (8.3%) also harbored rare variants that would be classified as "causal" if detected in cases; applying American College of Medical Genetics filtering guidelines (to reduce the rate of false-positive claims that a variant is disease related) yielded rates of 24.2% in cases and 5.5% in controls. Highly ranked new genes include SCAF1, SETD2, and LY9. Network analysis showed that top-ranked new genes were located closer than a random set of genes to known FSGS genes. CONCLUSIONS: Although our analysis validated many known FSGS-causing genes, we detected a nontrivial number of purported "disease-causing" variants in controls, implying that filtering is inadequate to allow clinical diagnosis and decision making. Genetic diagnosis in patients with FSGS is complicated by the nontrivial rate of variants in known FSGS genes among people without kidney disease.

4.
Transl Psychiatry ; 9(1): 60, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718465

RESUMO

We searched for genetic causes of major psychiatric disorders (bipolar disorder, schizoaffective disorder, and schizophrenia) in a large, densely affected pedigree from Northern Sweden that originated with three pairs of founders born around 1650. We applied a systematic genomic approach to the pedigree via karyotyping (N = 9), genome-wide SNP arrays (N = 418), whole-exome sequencing (N = 26), and whole-genome sequencing (N = 10). Comprehensive analysis did not identify plausible variants of strong effect. Rather, pedigree cases had significantly higher genetic risk scores compared to pedigree and community controls.


Assuntos
Transtorno Bipolar/genética , Genômica/métodos , Transtornos Psicóticos/genética , Esquizofrenia/genética , Adulto , Idoso , Transtorno Bipolar/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Cariotipagem/métodos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Linhagem , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/epidemiologia , Esquizofrenia/epidemiologia , Suécia/epidemiologia , Sequenciamento Completo do Exoma/métodos , Sequenciamento Completo do Genoma/métodos
6.
Am J Hum Genet ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30503522

RESUMO

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain >5% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.

7.
Schizophr Bull ; 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30462333

RESUMO

Background: Epstein-Barr virus (EBV) is a highly prevalent human herpesvirus capable of infecting the central nervous system and establishing persistent infection. Methods: We employed solid phase immunoassay techniques to measure immunoglobulin G (IgG) class antibodies to EBV virions and defined proteins in 432 individuals with schizophrenia and 311 individuals without a history of a psychiatric disorder. Western blot testing was performed to document reactivity to specific EBV proteins. Polygenic risk for schizophrenia was calculated from genome sequencing arrays. Levels of antibodies between the groups were compared by multivariate analyses incorporating clinical, genetic, and demographic measures. Results: Individuals with schizophrenia had marked elevations in the levels of antibodies to EBV virions as compared to the control population. Further analyses indicated increased levels of reactivity to EBV-viral capsid antibody (VCA) but not to EBV nuclear antigen-1 (EBNA-1) or to other human herpesviruses. Western blot analysis confirmed increased reactivity to VCA proteins in the group of individuals with schizophrenia and documented a lack of increased levels of antibodies to EBNA-1. Genetic analyses indicated an additive effect of increased levels of antibodies to EBV virions and genetic susceptibility to schizophrenia, with individuals with elevated levels of both type of markers having a greater than 8.5-fold odds of a schizophrenia diagnosis. Conclusions: Individuals with schizophrenia have increased levels of antibodies to some but not all EBV proteins indicating an aberrant response to EBV infection. This aberrant response may contribute to the immunopathology of schizophrenia and related disorders.

8.
Nature ; 559(7714): 350-355, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29995854

RESUMO

The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6-9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in cis. At three such loci (MPL, TM2D3-TARSL2, and FRA10B), we identified a likely causal variant that acted with high penetrance (5-50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.

9.
Am J Hum Genet ; 102(5): 760-775, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29706349

RESUMO

Finland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assembled a comprehensive view of recent population history (≤100 generations), the timespan during which most rare-disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to that of 16,060 Swedes, Estonians, Russians, and Hungarians from geographically and linguistically adjacent countries with different population histories. We find much more extensive sharing in Finns, with at least one ≥ 5 cM tract on average between pairs of unrelated individuals. By coupling haplotype sharing with fine-scale birth records from more than 25,000 individuals, we find that although haplotype sharing broadly decays with geographical distance, there are pockets of excess haplotype sharing; individuals from northeast Finland typically share several-fold more of their genome in identity-by-descent segments than individuals from southwest regions. We estimate recent effective population-size changes through time across regions of Finland, and we find that there was more continuous gene flow as Finns migrated from southwest to northeast between the early- and late-settlement regions than was dichotomously described previously. Lastly, we show that haplotype sharing is locally enriched by an order of magnitude among pairs of individuals sharing rare alleles and especially among pairs sharing rare disease-causing variants. Our work provides a general framework for using haplotype sharing to reconstruct an integrative view of recent population history and gain insight into the evolutionary origins of rare variants contributing to disease.

10.
Sci Transl Med ; 10(436)2018 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-29643232

RESUMO

Thrombosis is a major cause of morbidity and mortality in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), clonal disorders of hematopoiesis characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. Neutrophil extracellular trap (NET) formation, a component of innate immunity, has been linked to thrombosis. We demonstrate that neutrophils from patients with MPNs are primed for NET formation, an effect blunted by pharmacological inhibition of JAK signaling. Mice with conditional knock-in of Jak2V617F, the most common molecular driver of MPN, have an increased propensity for NET formation and thrombosis. Inhibition of JAK-STAT signaling with the clinically available JAK2 inhibitor ruxolitinib abrogated NET formation and reduced thrombosis in a deep vein stenosis murine model. We further show that expression of PAD4, a protein required for NET formation, is increased in JAK2V617F-expressing neutrophils and that PAD4 is required for Jak2V617F-driven NET formation and thrombosis in vivo. Finally, in a population study of more than 10,000 individuals without a known myeloid disorder, JAK2V617F-positive clonal hematopoiesis was associated with an increased incidence of thrombosis. In aggregate, our results link JAK2V617F expression to NET formation and thrombosis and suggest that JAK2 inhibition may reduce thrombosis in MPNs through cell-intrinsic effects on neutrophil function.

11.
Nat Genet ; 50(4): 621-629, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29632380

RESUMO

We introduce an approach to identify disease-relevant tissues and cell types by analyzing gene expression data together with genome-wide association study (GWAS) summary statistics. Our approach uses stratified linkage disequilibrium (LD) score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We applied our approach to gene expression data from several sources together with GWAS summary statistics for 48 diseases and traits (average N = 169,331) and found significant tissue-specific enrichments (false discovery rate (FDR) < 5%) for 34 traits. In our analysis of multiple tissues, we detected a broad range of enrichments that recapitulated known biology. In our brain-specific analysis, significant enrichments included an enrichment of inhibitory over excitatory neurons for bipolar disorder, and excitatory over inhibitory neurons for schizophrenia and body mass index. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signals.

12.
Proc Natl Acad Sci U S A ; 115(13): 3446-3451, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29531077

RESUMO

People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk APOL1 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with APOL1 We performed an admixture mapping study to identify genetic modifiers of APOL1-associated kidney disease. Individuals with two APOL1 risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the UBD (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the UBD locus correlates with lower levels of UBD expression. In cell-based experiments, the disease-associated APOL1 alleles (known as G1 and G2) lead to increased abundance of UBD mRNA but to decreased levels of UBD protein. UBD gene expression inversely correlates with G1 and G2 APOL1-mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both UBD and APOL1, which interact in a functionally important manner. UBD appears to mitigate APOL1-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in UBD and UBD expression appear to modify the APOL1-associated kidney phenotype.


Assuntos
Afro-Americanos/estatística & dados numéricos , Apolipoproteína L1/genética , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Polimorfismo de Nucleotídeo Único , Ubiquitinas/metabolismo , Alelos , Predisposição Genética para Doença , Genótipo , Glomerulosclerose Segmentar e Focal/etnologia , Humanos , Fatores de Risco , Ubiquitinas/genética
13.
Nature ; 553(7689): 467-472, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29342134

RESUMO

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.


Assuntos
Instabilidade Cromossômica , Citosol/metabolismo , DNA de Neoplasias/metabolismo , Metástase Neoplásica/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/secundário , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular , Instabilidade Cromossômica/genética , Segregação de Cromossomos , Citosol/enzimologia , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Inflamação/genética , Inflamação/metabolismo , Proteínas de Membrana/metabolismo , Mesoderma/metabolismo , Camundongos , Micronúcleos com Defeito Cromossômico , NF-kappa B/metabolismo , Nucleotidiltransferases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Genome Med ; 9(1): 114, 2017 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-29262854

RESUMO

BACKGROUND: Integrating rare variation from trio family and case-control studies has successfully implicated specific genes contributing to risk of neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASD), intellectual disability (ID), developmental disorders (DDs), and epilepsy (EPI). For schizophrenia (SCZ), however, while sets of genes have been implicated through the study of rare variation, only two risk genes have been identified. METHODS: We used hierarchical Bayesian modeling of rare-variant genetic architecture to estimate mean effect sizes and risk-gene proportions, analyzing the largest available collection of whole exome sequence data for SCZ (1,077 trios, 6,699 cases, and 13,028 controls), and data for four NDDs (ASD, ID, DD, and EPI; total 10,792 trios, and 4,058 cases and controls). RESULTS: For SCZ, we estimate there are 1,551 risk genes. There are more risk genes and they have weaker effects than for NDDs. We provide power analyses to predict the number of risk-gene discoveries as more data become available. We confirm and augment prior risk gene and gene set enrichment results for SCZ and NDDs. In particular, we detected 98 new DD risk genes at FDR < 0.05. Correlations of risk-gene posterior probabilities are high across four NDDs (ρ>0.55), but low between SCZ and the NDDs (ρ<0.3). An in-depth analysis of 288 NDD genes shows there is highly significant protein-protein interaction (PPI) network connectivity, and functionally distinct PPI subnetworks based on pathway enrichment, single-cell RNA-seq cell types, and multi-region developmental brain RNA-seq. CONCLUSIONS: We have extended a pipeline used in ASD studies and applied it to infer rare genetic parameters for SCZ and four NDDs ( https://github.com/hoangtn/extTADA ). We find many new DD risk genes, supported by gene set enrichment and PPI network connectivity analyses. We find greater similarity among NDDs than between NDDs and SCZ. NDD gene subnetworks are implicated in postnatally expressed presynaptic and postsynaptic genes, and for transcriptional and post-transcriptional gene regulation in prenatal neural progenitor and stem cells.


Assuntos
Éxons , Estudo de Associação Genômica Ampla/métodos , Transtornos do Neurodesenvolvimento/genética , Polimorfismo Genético , Esquizofrenia/genética , Teorema de Bayes , Loci Gênicos , Humanos , Modelos Genéticos , Mutação , Mapas de Interação de Proteínas
15.
NPJ Genom Med ; 2: 22, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29263833

RESUMO

Recent understanding of the causal role of blood-detectable somatic protein-truncating DNA variants in leukemia prompts questions about the generalizability of such observations across cancer types. We used the cancer genome atlas exome sequencing (~8000 samples) to compare 22 different cancer phenotypes with more than 6000 controls using a case-control study design and demonstrate that mosaic protein truncating variants in these genes are also associated with solid-tumor cancers. The absence of these cancer-associated mosaic variants from the tumors themselves suggest these are not themselves tumor drivers. Through analysis of different cancer phenotypes we observe gene-specificity for mosaic mutations. We confirm a specific link between PPM1D and ovarian cancer, consistent with previous reports linking PPM1D to breast and ovarian cancer. Additionally, glioblastoma, melanoma and lung cancers show gene specific burdens of mosaic protein truncating mutations. Taken together, these results extend existing observations and broadly link solid-tumor cancers to somatic blood DNA changes.

16.
Nat Neurosci ; 20(8): 1150-1161, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28671696

RESUMO

The postsynaptic density (PSD) contains a collection of scaffold proteins used for assembling synaptic signaling complexes. However, it is not known how the core-scaffold machinery associates in protein-interaction networks or how proteins encoded by genes involved in complex brain disorders are distributed through spatiotemporal protein complexes. Here using immunopurification, proteomics and bioinformatics, we isolated 2,876 proteins across 41 in vivo interactomes and determined their protein domain composition, correlation to gene expression levels and developmental integration to the PSD. We defined clusters for enrichment of schizophrenia, autism spectrum disorders, developmental delay and intellectual disability risk factors at embryonic day 14 and adult PSD in mice. Mutations in highly connected nodes alter protein-protein interactions modulating macromolecular complexes enriched in disease risk candidates. These results were integrated into a software platform, Synaptic Protein/Pathways Resource (SyPPRes), enabling the prioritization of disease risk factors and their placement within synaptic protein interaction networks.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/genética , Densidade Pós-Sináptica/genética , Sinapses/metabolismo , Animais , Encefalopatias/genética , Encefalopatias/metabolismo , Modelos Animais de Doenças , Guanilato Quinases/genética , Proteínas de Membrana/genética , Camundongos Transgênicos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Transdução de Sinais/genética , Sinapses/genética
17.
Nature ; 545(7653): 229-233, 2017 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-28445466

RESUMO

Human pluripotent stem cells (hPS cells) can self-renew indefinitely, making them an attractive source for regenerative therapies. This expansion potential has been linked with the acquisition of large copy number variants that provide mutated cells with a growth advantage in culture. The nature, extent and functional effects of other acquired genome sequence mutations in cultured hPS cells are not known. Here we sequence the protein-coding genes (exomes) of 140 independent human embryonic stem cell (hES cell) lines, including 26 lines prepared for potential clinical use. We then apply computational strategies for identifying mutations present in a subset of cells in each hES cell line. Although such mosaic mutations were generally rare, we identified five unrelated hES cell lines that carried six mutations in the TP53 gene that encodes the tumour suppressor P53. The TP53 mutations we observed are dominant negative and are the mutations most commonly seen in human cancers. We found that the TP53 mutant allelic fraction increased with passage number under standard culture conditions, suggesting that the P53 mutations confer selective advantage. We then mined published RNA sequencing data from 117 hPS cell lines, and observed another nine TP53 mutations, all resulting in coding changes in the DNA-binding domain of P53. In three lines, the allelic fraction exceeded 50%, suggesting additional selective advantage resulting from the loss of heterozygosity at the TP53 locus. As the acquisition and expansion of cancer-associated mutations in hPS cells may go unnoticed during most applications, we suggest that careful genetic characterization of hPS cells and their differentiated derivatives be carried out before clinical use.


Assuntos
Genes Dominantes/genética , Genes p53 , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação/genética , Seleção Genética , Proteína Supressora de Tumor p53/genética , Alelos , Contagem de Células , Diferenciação Celular/genética , Divisão Celular/genética , Linhagem Celular , DNA/metabolismo , Análise Mutacional de DNA , Exoma/genética , Células-Tronco Embrionárias Humanas/citologia , Humanos , Perda de Heterozigosidade/genética , Mosaicismo , Neoplasias/genética , Domínios Proteicos , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/metabolismo
18.
Twin Res Hum Genet ; 20(2): 108-118, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28238293

RESUMO

Sequence-based association studies are at a critical inflexion point with the increasing availability of exome-sequencing data. A popular test of association is the sequence kernel association test (SKAT). Weights are embedded within SKAT to reflect the hypothesized contribution of the variants to the trait variance. Because the true weights are generally unknown, and so are subject to misspecification, we examined the efficiency of a data-driven weighting scheme. We propose the use of a set of theoretically defensible weighting schemes, of which, we assume, the one that gives the largest test statistic is likely to capture best the allele frequency-functional effect relationship. We show that the use of alternative weights obviates the need to impose arbitrary frequency thresholds. As both the score test and the likelihood ratio test (LRT) may be used in this context, and may differ in power, we characterize the behavior of both tests. The two tests have equal power, if the weights in the set included weights resembling the correct ones. However, if the weights are badly specified, the LRT shows superior power (due to its robustness to misspecification). With this data-driven weighting procedure the LRT detected significant signal in genes located in regions already confirmed as associated with schizophrenia - the PRRC2A (p = 1.020e-06) and the VARS2 (p = 2.383e-06) - in the Swedish schizophrenia case-control cohort of 11,040 individuals with exome-sequencing data. The score test is currently preferred for its computational efficiency and power. Indeed, assuming correct specification, in some circumstances, the score test is the most powerful test. However, LRT has the advantageous properties of being generally more robust and more powerful under weight misspecification. This is an important result given that, arguably, misspecified models are likely to be the rule rather than the exception in weighting-based approaches.


Assuntos
Interpretação Estatística de Dados , Estudos de Associação Genética/métodos , Modelos Genéticos , Estudos de Casos e Controles , Simulação por Computador , Pesquisa Empírica , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Variação Genética , Estudo de Associação Genômica Ampla , Antígenos HLA/genética , Humanos , Desequilíbrio de Ligação , Masculino , Proteínas/genética , Esquizofrenia/genética , Software , Suécia , Valina-tRNA Ligase/genética
19.
Nat Neurosci ; 19(12): 1563-1565, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27694993

RESUMO

Disruptive, damaging ultra-rare variants in highly constrained genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE). This effect was stronger among highly brain-expressed genes and explained more YOE variance than pathogenic copy number variation but less than common variants. Disruptive, damaging ultra-rare variants in highly constrained genes influence the determinants of YOE in the general population.


Assuntos
Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Educação , Humanos , Análise e Desempenho de Tarefas
20.
Nat Neurosci ; 19(11): 1433-1441, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27694994

RESUMO

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.


Assuntos
Exoma/genética , Predisposição Genética para Doença , Esquizofrenia/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Mutação/genética , Proteínas do Tecido Nervoso/genética , Risco , Suécia
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