Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 190
Filtrar
2.
Sci Rep ; 10(1): 15760, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978407

RESUMO

Health differences among the elderly and the role of medical treatments are topical issues in aging societies. We demonstrate the use of modern statistical learning methods to develop a data-driven health measure based on 21 years of pharmacy purchase and mortality data of 12,047 aging individuals. The resulting score was validated with 33,616 individuals from two fully independent datasets and it is strongly associated with all-cause mortality (HR 1.18 per point increase in score; 95% CI 1.14-1.22; p = 2.25e-16). When combined with Charlson comorbidity index, individuals with elevated medication score and comorbidity index had over six times higher risk (HR 6.30; 95% CI 3.84-10.3; AUC = 0.802) compared to individuals with a protective score profile. Alone, the medication score performs similarly to the Charlson comorbidity index and is associated with polygenic risk for coronary heart disease and type 2 diabetes.

3.
Twin Res Hum Genet ; 23(2): 87-89, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32638684

RESUMO

Dr Nick Martin has made enormous contributions to the field of behavior genetics over the past 50 years. Of his many seminal papers that have had a profound impact, we focus on his early work on the power of twin studies. He was among the first to recognize the importance of sample size calculation before conducting a study to ensure sufficient power to detect the effects of interest. The elegant approach he developed, based on the noncentral chi-squared distribution, has been adopted by subsequent researchers for other genetic study designs, and today remains a standard tool for power calculations in structural equation modeling and other areas of statistical analysis. The present brief article discusses the main aspects of his seminal paper, and how it led to subsequent developments, by him and others, as the field of behavior genetics evolved into the present era.

4.
Sci Transl Med ; 12(549)2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581134

RESUMO

Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the SOST genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.

5.
Nature ; 583(7814): 83-89, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32460305

RESUMO

A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline1 to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.


Assuntos
Variação Genética , Genoma Humano/genética , Sequenciamento Completo do Genoma , Alelos , Estudos de Casos e Controles , Grupos de Populações Continentais/genética , Epigênese Genética , Feminino , Dosagem de Genes/genética , Genética Populacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Anotação de Sequência Molecular , Locos de Características Quantitativas , Software
6.
Nat Genet ; 52(6): 634-639, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424355

RESUMO

With very large sample sizes, biobanks provide an exciting opportunity to identify genetic components of complex traits. To analyze rare variants, region-based multiple-variant aggregate tests are commonly used to increase power for association tests. However, because of the substantial computational cost, existing region-based tests cannot analyze hundreds of thousands of samples while accounting for confounders such as population stratification and sample relatedness. Here we propose a scalable generalized mixed-model region-based association test, SAIGE-GENE, that is applicable to exome-wide and genome-wide region-based analysis for hundreds of thousands of samples and can account for unbalanced case-control ratios for binary traits. Through extensive simulation studies and analysis of the HUNT study with 69,716 Norwegian samples and the UK Biobank data with 408,910 White British samples, we show that SAIGE-GENE can efficiently analyze large-sample data (N > 400,000) with type I error rates well controlled.


Assuntos
Bancos de Espécimes Biológicos/estatística & dados numéricos , Estudos de Casos e Controles , Exoma , Modelos Lineares , Marcadores Genéticos , Humanos , Lipoproteínas HDL/genética , Modelos Genéticos , Herança Multifatorial , Noruega , Reino Unido , Relação Cintura-Quadril
7.
Am J Hum Genet ; 107(1): 46-59, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32470373

RESUMO

In complex trait genetics, the ability to predict phenotype from genotype is the ultimate measure of our understanding of genetic architecture underlying the heritability of a trait. A complete understanding of the genetic basis of a trait should allow for predictive methods with accuracies approaching the trait's heritability. The highly polygenic nature of quantitative traits and most common phenotypes has motivated the development of statistical strategies focused on combining myriad individually non-significant genetic effects. Now that predictive accuracies are improving, there is a growing interest in the practical utility of such methods for predicting risk of common diseases responsive to early therapeutic intervention. However, existing methods require individual-level genotypes or depend on accurately specifying the genetic architecture underlying each disease to be predicted. Here, we propose a polygenic risk prediction method that does not require explicitly modeling any underlying genetic architecture. We start with summary statistics in the form of SNP effect sizes from a large GWAS cohort. We then remove the correlation structure across summary statistics arising due to linkage disequilibrium and apply a piecewise linear interpolation on conditional mean effects. In both simulated and real datasets, this new non-parametric shrinkage (NPS) method can reliably allow for linkage disequilibrium in summary statistics of 5 million dense genome-wide markers and consistently improves prediction accuracy. We show that NPS improves the identification of groups at high risk for breast cancer, type 2 diabetes, inflammatory bowel disease, and coronary heart disease, all of which have available early intervention or prevention treatments.


Assuntos
Herança Multifatorial/genética , Idoso , Estudos de Coortes , Diabetes Mellitus Tipo 2/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
8.
Nature ; 581(7809): 444-451, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32461652

RESUMO

Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.


Assuntos
Doença/genética , Variação Genética , Genética Médica/normas , Genética Populacional/normas , Genoma Humano/genética , Grupos de Populações Continentais/genética , Feminino , Testes Genéticos , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único/genética , Padrões de Referência , Seleção Genética , Sequenciamento Completo do Genoma
9.
Nat Med ; 26(4): 549-557, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32273609

RESUMO

Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases1-3. We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease onset and on prediction together with clinical risk scores. Compared to having an average PRS, having a high PRS contributed 21% to 38% higher lifetime risk, and 4 to 9 years earlier disease onset. PRSs improved model discrimination over age and sex in type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer, and over clinical risk in type 2 diabetes, breast cancer and prostate cancer. In all diseases, PRSs improved reclassification over clinical thresholds, with the largest net reclassification improvements for early-onset coronary heart disease, atrial fibrillation and prostate cancer. This study provides evidence for the additional value of PRSs in clinical disease prediction. The practical applications of polygenic risk information for stratified screening or for guiding lifestyle and medical interventions in the clinical setting remain to be defined in further studies.


Assuntos
Doenças Cardiovasculares , Predisposição Genética para Doença , Doenças Metabólicas , Herança Multifatorial , Neoplasias , Adulto , Idade de Início , Biomarcadores/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Finlândia/epidemiologia , Marcadores Genéticos/genética , Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla , Humanos , Masculino , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/genética , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Prognóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Medição de Risco , Fatores de Risco , Adulto Jovem
11.
Nat Genet ; 52(3): 353, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32029922

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

12.
Mol Psychiatry ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066829

RESUMO

An important issue affecting genome-wide association studies with deep phenotyping (multiple correlated phenotypes) is determining the suitable family-wise significance threshold. Straightforward family-wise correction (Bonferroni) of p < 0.05 for 4.3 million genotypes and 335 phenotypes would give a threshold of p < 3.46E-11. This would be too conservative because it assumes all tests are independent. The effective number of tests, both phenotypic and genotypic, must be adjusted for the correlations between them. Spectral decomposition of the phenotype matrix and LD-based correction of the number of tested SNPs are currently used to determine an effective number of tests. In this paper, we compare these calculated estimates with permutation-determined family-wise significance thresholds. Permutations are performed by shuffling individual IDs of the genotype vector for this dataset, to preserve correlation of phenotypes. Our results demonstrate that the permutation threshold is influenced by minor allele frequency (MAF) of the SNPs, and by the number of individuals tested. For the more common SNPs (MAF > 0.1), the permutation family-wise threshold was in close agreement with spectral decomposition methods. However, for less common SNPs (0.05 < MAF ≤ 0.1), the permutation threshold calculated over all SNPs was off by orders of magnitude. This applies to the number of individuals studied (here 777) but not to very much larger numbers. Based on these findings, we propose that the threshold to find a particular level of family-wise significance may need to be established using separate permutations of the actual data for several MAF bins.

13.
Nat Neurosci ; 23(2): 185-193, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31932770

RESUMO

Protein-coding de novo mutations (DNMs) are significant risk factors in many neurodevelopmental disorders, whereas schizophrenia (SCZ) risk associated with DNMs has thus far been shown to be modest. We analyzed DNMs from 1,695 SCZ-affected trios and 1,077 published SCZ-affected trios to better understand the contribution to SCZ risk. Among 2,772 SCZ probands, exome-wide DNM burden remained modest. Gene set analyses revealed that SCZ DNMs were significantly concentrated in genes that were highly expressed in the brain, that were under strong evolutionary constraint and/or overlapped with genes identified in other neurodevelopmental disorders. No single gene surpassed exome-wide significance; however, 16 genes were recurrently hit by protein-truncating DNMs, corresponding to a 3.15-fold higher rate than the mutation model expectation (permuted 95% confidence interval: 1-10 genes; permuted P = 3 × 10-5). Overall, DNMs explain a small fraction of SCZ risk, and larger samples are needed to identify individual risk genes, as coding variation across many genes confers risk for SCZ in the population.


Assuntos
Predisposição Genética para Doença/genética , Esquizofrenia/genética , Adulto , Criança , Família , Feminino , Humanos , Masculino , Mutação , Pais , Sequenciamento Completo do Exoma
14.
Bioinformatics ; 36(3): 930-933, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31393554

RESUMO

SUMMARY: Genome-wide association study (GWAS) analyses, at sufficient sample sizes and power, have successfully revealed biological insights for several complex traits. RICOPILI, an open-sourced Perl-based pipeline was developed to address the challenges of rapidly processing large-scale multi-cohort GWAS studies including quality control (QC), imputation and downstream analyses. The pipeline is computationally efficient with portability to a wide range of high-performance computing environments. RICOPILI was created as the Psychiatric Genomics Consortium pipeline for GWAS and adopted by other users. The pipeline features (i) technical and genomic QC in case-control and trio cohorts, (ii) genome-wide phasing and imputation, (iv) association analysis, (v) meta-analysis, (vi) polygenic risk scoring and (vii) replication analysis. Notably, a major differentiator from other GWAS pipelines, RICOPILI leverages on automated parallelization and cluster job management approaches for rapid production of imputed genome-wide data. A comprehensive meta-analysis of simulated GWAS data has been incorporated demonstrating each step of the pipeline. This includes all the associated visualization plots, to allow ease of data interpretation and manuscript preparation. Simulated GWAS datasets are also packaged with the pipeline for user training tutorials and developer work. AVAILABILITY AND IMPLEMENTATION: RICOPILI has a flexible architecture to allow for ongoing development and incorporation of newer available algorithms and is adaptable to various HPC environments (QSUB, BSUB, SLURM and others). Specific links for genomic resources are either directly provided in this paper or via tutorials and external links. The central location hosting scripts and tutorials is found at this URL: https://sites.google.com/a/broadinstitute.org/RICOPILI/home. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

17.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31824658

RESUMO

Attention deficit hyperactivity disorder (ADHD) is a clinically defined disorder, and inattention and hyperactivity/impulsivity are its main symptom domains. The presentation, lifelong continuation and treatment response of ADHD symptoms, however, is highly heterogeneous. To better define, diagnose, treat and prevent ADHD, it is essential that we understand the biological processes underlying all of these elements. In this review, given the high heritability of ADHD, we discuss how and why genetics can foster such progress. We examine what genetics have taught us so far with regard to ADHD definition, classification, clinical presentation, diagnosis and treatment. Finally, we offer a prospect of what genetic studies on ADHD may bring in the future.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Cognição , Formação de Conceito , Humanos , Comportamento Impulsivo
19.
Nat Genet ; 51(12): 1670-1678, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31740837

RESUMO

Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Estudos de Casos e Controles , Extremo Oriente , Genética Populacional , Estudo de Associação Genômica Ampla , Humanos
20.
Nat Neurosci ; 22(12): 1966-1974, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768050

RESUMO

To discover novel genes underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry-matched controls. We observed a significant excess of rare protein-truncating variants among ALS cases, and these variants were concentrated in constrained genes. Through gene level analyses, we replicated known ALS genes including SOD1, NEK1 and FUS. We also observed multiple distinct protein-truncating variants in a highly constrained gene, DNAJC7. The signal in DNAJC7 exceeded genome-wide significance, and immunoblotting assays showed depletion of DNAJC7 protein in fibroblasts in a patient with ALS carrying the p.Arg156Ter variant. DNAJC7 encodes a member of the heat-shock protein family, HSP40, which, along with HSP70 proteins, facilitates protein homeostasis, including folding of newly synthesized polypeptides and clearance of degraded proteins. When these processes are not regulated, misfolding and accumulation of aberrant proteins can occur and lead to protein aggregation, which is a pathological hallmark of neurodegeneration. Our results highlight DNAJC7 as a novel gene for ALS.


Assuntos
Esclerose Amiotrófica Lateral/genética , Exoma/genética , Predisposição Genética para Doença/genética , Proteínas de Choque Térmico/genética , Chaperonas Moleculares/genética , Estudos de Casos e Controles , Feminino , Variação Genética/genética , Humanos , Masculino
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA