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1.
Nat Commun ; 12(1): 5276, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489429

RESUMO

A promise of genomics in precision medicine is to provide individualized genetic risk predictions. Polygenic risk scores (PRS), computed by aggregating effects from many genomic variants, have been developed as a useful tool in complex disease research. However, the application of PRS as a tool for predicting an individual's disease susceptibility in a clinical setting is challenging because PRS typically provide a relative measure of risk evaluated at the level of a group of people but not at individual level. Here, we introduce a machine-learning technique, Mondrian Cross-Conformal Prediction (MCCP), to estimate the confidence bounds of PRS-to-disease-risk prediction. MCCP can report disease status conditional probability value for each individual and give a prediction at a desired error level. Moreover, with a user-defined prediction error rate, MCCP can estimate the proportion of sample (coverage) with a correct prediction.


Assuntos
Predisposição Genética para Doença/genética , Aprendizado de Máquina , Herança Multifatorial/genética , Fatores Etários , Bancos de Espécimes Biológicos , Neoplasias da Mama/genética , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Masculino , Reprodutibilidade dos Testes , Esquizofrenia/genética , Suécia , Reino Unido
2.
Science ; 373(6555): 655-662, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34353948

RESUMO

We report de novo genome assemblies, transcriptomes, annotations, and methylomes for the 26 inbreds that serve as the founders for the maize nested association mapping population. The number of pan-genes in these diverse genomes exceeds 103,000, with approximately a third found across all genotypes. The results demonstrate that the ancient tetraploid character of maize continues to degrade by fractionation to the present day. Excellent contiguity over repeat arrays and complete annotation of centromeres revealed additional variation in major cytological landmarks. We show that combining structural variation with single-nucleotide polymorphisms can improve the power of quantitative mapping studies. We also document variation at the level of DNA methylation and demonstrate that unmethylated regions are enriched for cis-regulatory elements that contribute to phenotypic variation.


Assuntos
Genoma de Planta , Anotação de Sequência Molecular , Zea mays/genética , Centrômero/genética , Mapeamento Cromossômico , Cromossomos de Plantas , Metilação de DNA , Resistência à Doença/genética , Genes de Plantas , Variação Genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Herança Multifatorial/genética , Fenótipo , Doenças das Plantas , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Análise de Sequência de DNA , Tetraploidia , Transcriptoma , Sequenciamento Completo do Genoma
3.
Nat Commun ; 12(1): 4811, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376648

RESUMO

Circulating microRNAs (miRNAs) could improve colorectal cancer (CRC) risk prediction. Here, we derive a blood-based miRNA panel and evaluate its ability to predict CRC occurrence in a population-based cohort of adults aged 50-75 years. Forty-one miRNAs are preselected from independent studies and measured by quantitative-real-time-polymerase-chain-reaction in serum collected at baseline of 198 participants who develop CRC during 14 years of follow-up and 178 randomly selected controls. A 7-miRNA score is derived by logistic regression. Its predictive ability, quantified by the optimism-corrected area-under-the-receiver-operating-characteristic-curve (AUC) using .632+ bootstrap is 0.794. Predictive ability is compared to that of an environmental risk score (ERS) based on known risk factors and a polygenic risk score (PRS) based on 140 previously identified single-nucleotide-polymorphisms. In participants with all scores available, optimism-corrected-AUC is 0.802 for the 7-miRNA score, while AUC (95% CI) is 0.557 (0.498-0.616) for the ERS and 0.622 (0.564-0.681) for the PRS.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , Feminino , Humanos , Modelos Logísticos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real/métodos , Fatores de Risco
4.
J Genet ; 1002021.
Artigo em Inglês | MEDLINE | ID: mdl-34282738

RESUMO

Grain yield is a complex polygenic trait representing a multiplicative end product of contributing yield attributes governed by simple to complex gene interactions. Deciphering the genetics and inheritance of traits/genes influencing yield is a prerequisite to harness the yield potential in any crop species. The objective of the present investigation was to estimate genetic variance components and type of gene action controlling yield and its component traits using six populations (P1, P2, F1, F2, BC1 and BC2) of the three bread wheat crosses. Cross I (25th HRWSN 2105 × WH 1080), cross II (22ndSAWYT323 × RSP 561) and cross III (22ndSAWYT333 × WH 1080) involving elite stripe rust resistant wheat genetic stocks in combination with commercial check varieties were used for analysis. A combination of morpho-physiological, biochemical and disease influencing traits were evaluated, thus exploring the possibility of multi-trait integration in future. Results revealed that the estimated mean effects (m) were highly significant for all the traits in all crosses, indicating that selected traits were quantitatively inherited. The estimate of dominant gene effect was highly significant for plant height, number of tillers per plant in all the three crosses. Grain yield per plant was highly significant in the cross II while total protein content was highly significant in both crosses II and III. Glycine betaine content showed significant additive genes effect. Duplicate epistasis was the most significant for traits like plant height, total protein content and grain yield per plant. Dominance gene effect was more important than additive gene effects in the inheritance of grain yield and most other traits studied. The magnitude of additive X additive gene effects was high and positively significant whereas dominance × dominance was negatively significant for most of the traits studied in the three crosses. Additive × dominance gene effects was of minor significance, thus indicating that selection for grain yield and its components should be delayed to later generations of breeding.


Assuntos
Grão Comestível/genética , Epistasia Genética , Melhoramento Vegetal , Triticum/genética , Pão/normas , Mapeamento Cromossômico , Cruzamentos Genéticos , Humanos , Hibridização Genética , Herança Multifatorial/genética , Fenótipo , Locos de Características Quantitativas , Triticum/classificação , Triticum/crescimento & desenvolvimento
5.
Nat Genet ; 53(8): 1243-1249, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34326547

RESUMO

The genetic effect-size distribution of a disease describes the number of risk variants, the range of their effect sizes and sample sizes that will be required to discover them. Accurate estimation has been a challenge. Here I propose Fourier Mixture Regression (FMR), validating that it accurately estimates real and simulated effect-size distributions. Applied to summary statistics for ten diseases (average [Formula: see text]), FMR estimates that 100,000-1,000,000 cases will be required for genome-wide significant SNPs to explain 50% of SNP heritability. In such large studies, genome-wide significance becomes increasingly conservative, and less stringent thresholds achieve high true positive rates if confounding is controlled. Across traits, polygenicity varies, but the range of their effect sizes is similar. Compared with effect sizes in the top 10% of heritability, including most discovered thus far, those in the bottom 10-50% are orders of magnitude smaller and more numerous, spanning a large fraction of the genome.


Assuntos
Estudo de Associação Genômica Ampla , Modelos Genéticos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Bancos de Espécimes Biológicos , Análise de Fourier , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Análise de Regressão , Reino Unido
6.
Am J Hum Genet ; 108(8): 1488-1501, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34214457

RESUMO

Across species, offspring of related individuals often exhibit significant reduction in fitness-related traits, known as inbreeding depression (ID), yet the genetic and molecular basis for ID remains elusive. Here, we develop a method to quantify enrichment of ID within specific genomic annotations and apply it to human data. We analyzed the phenomes and genomes of ∼350,000 unrelated participants of the UK Biobank and found, on average of over 11 traits, significant enrichment of ID within genomic regions with high recombination rates (>21-fold; p < 10-5), with conserved function across species (>19-fold; p < 10-4), and within regulatory elements such as DNase I hypersensitive sites (∼5-fold; p = 8.9 × 10-7). We also quantified enrichment of ID within trait-associated regions and found suggestive evidence that genomic regions contributing to additive genetic variance in the population are enriched for ID signal. We find strong correlations between functional enrichment of SNP-based heritability and that of ID (r = 0.8, standard error: 0.1). These findings provide empirical evidence that ID is most likely due to many partially recessive deleterious alleles in low linkage disequilibrium regions of the genome. Our study suggests that functional characterization of ID may further elucidate the genetic architectures and biological mechanisms underlying complex traits and diseases.


Assuntos
Estudo de Associação Genômica Ampla , Genômica/métodos , Depressão por Endogamia/genética , Desequilíbrio de Ligação , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Feminino , Humanos , Masculino
7.
Eur J Endocrinol ; 185(4): 441-451, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34288885

RESUMO

Objective,: To investigate the genetic characteristics of idiopathic central precocious puberty (ICPP) and validate its polygenic risk for early puberty. Design and methods: A bootstrap subsampling and genome-wide association study were performed on Taiwanese Han Chinese girls comprising 321 ICPP patients and 148 controls. Using previous GWAS data on pubertal timing, a replication study was performed. A validation group was also investigated for the weighted polygenic risk score (wPRS) of the risk of early puberty. Results: A total of 105 SNPs for the risk of ICPP were identified, of which 22 yielded an area under the receiver operating characteristic curve of 0.713 for the risk of early puberty in the validation group. A replication study showed that 33 SNPs from previous GWAS data of pubertal timing were associated with the risk of ICPP (training group: P-value < 0.05). In the validation group, a cumulative effect was observed between the wPRS and the risk of early puberty in a dose-dependent manner (validation group: Cochran-Armitage trend test: P-value < 1.00E-04; wPRS quartile 2 (Q2) (odds ratio (OR) = 5.00, 95% CI: 1.55-16.16), and wPRS Q3 (OR = 11.67, 95% CI: 2.44-55.83)). Conclusions: This study reveals the ICPP genetic characteristics with 22 independent and 33 reported SNPs in the Han Chinese population from Taiwan. This study may contribute to understand the genetic features and underlying biological pathways that control pubertal timing and pathogenesis of ICPP and also to the identification of individuals with a potential genetic risk of early puberty.


Assuntos
Herança Multifatorial , Puberdade Precoce/genética , Idade de Início , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Estudos de Casos e Controles , Criança , Feminino , Frequência do Gene , Heterogeneidade Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Puberdade/genética , Puberdade Precoce/epidemiologia , Fatores de Risco , Taiwan/epidemiologia
8.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299232

RESUMO

The genetic architecture of complex traits is multifactorial. Genome-wide association studies (GWASs) have identified risk loci for complex traits and diseases that are disproportionately located at the non-coding regions of the genome. On the other hand, we have just begun to understand the regulatory roles of the non-coding genome, making it challenging to precisely interpret the functions of non-coding variants associated with complex diseases. Additionally, the epigenome plays an active role in mediating cellular responses to fluctuations of sensory or environmental stimuli. However, it remains unclear how exactly non-coding elements associate with epigenetic modifications to regulate gene expression changes and mediate phenotypic outcomes. Therefore, finer interrogations of the human epigenomic landscape in associating with non-coding variants are warranted. Recently, chromatin-profiling techniques have vastly improved our understanding of the numerous functions mediated by the epigenome and DNA structure. Here, we review various chromatin-profiling techniques, such as assays of chromatin accessibility, nucleosome distribution, histone modifications, and chromatin topology, and discuss their applications in unraveling the brain epigenome and etiology of complex traits at tissue homogenate and single-cell resolution. These techniques have elucidated compositional and structural organizing principles of the chromatin environment. Taken together, we believe that high-resolution epigenomic and DNA structure profiling will be one of the best ways to elucidate how non-coding genetic variations impact complex diseases, ultimately allowing us to pinpoint cell-type targets with therapeutic potential.


Assuntos
Cromatina/genética , Cromatina/metabolismo , Cromatina/fisiologia , Sítios de Ligação/genética , Imunoprecipitação da Cromatina/métodos , Epigênese Genética/genética , Epigenoma/genética , Epigenômica/métodos , Regulação da Expressão Gênica/genética , Genoma , Estudo de Associação Genômica Ampla/métodos , Código das Histonas/genética , Humanos , Herança Multifatorial/genética , Nucleossomos/metabolismo , Nucleossomos/fisiologia , Polimorfismo de Nucleotídeo Único/genética , RNA não Traduzido/genética , RNA não Traduzido/metabolismo
9.
Nat Commun ; 12(1): 4506, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301930

RESUMO

Polygenic Risk Scores (PRS) for AD offer unique possibilities for reliable identification of individuals at high and low risk of AD. However, there is little agreement in the field as to what approach should be used for genetic risk score calculations, how to model the effect of APOE, what the optimal p-value threshold (pT) for SNP selection is and how to compare scores between studies and methods. We show that the best prediction accuracy is achieved with a model with two predictors (APOE and PRS excluding APOE region) with pT<0.1 for SNP selection. Prediction accuracy in a sample across different PRS approaches is similar, but individuals' scores and their associated ranking differ. We show that standardising PRS against the population mean, as opposed to the sample mean, makes the individuals' scores comparable between studies. Our work highlights the best strategies for polygenic profiling when assessing individuals for AD risk.


Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Alelos , Doença de Alzheimer/diagnóstico , Estudos de Casos e Controles , Frequência do Gene , Genética Populacional/métodos , Genética Populacional/estatística & dados numéricos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genótipo , Humanos , Reprodutibilidade dos Testes , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Sensibilidade e Especificidade
10.
Front Immunol ; 12: 673692, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305903

RESUMO

In a perspective entitled 'From plant survival under severe stress to anti-viral human defense' we raised and justified the hypothesis that transcript level profiles of justified target genes established from in vitro somatic embryogenesis (SE) induction in plants as a reference compared to virus-induced profiles can identify differential virus signatures that link to harmful reprogramming. A standard profile of selected genes named 'ReprogVirus' was proposed for in vitro-scanning of early virus-induced reprogramming in critical primary infected cells/tissues as target trait. For data collection, the 'ReprogVirus platform' was initiated. This initiative aims to identify in a common effort across scientific boundaries critical virus footprints from diverse virus origins and variants as a basis for anti-viral strategy design. This approach is open for validation and extension. In the present study, we initiated validation by experimental transcriptome data available in public domain combined with advancing plant wet lab research. We compared plant-adapted transcriptomes according to 'RegroVirus' complemented by alternative oxidase (AOX) genes during de novo programming under SE-inducing conditions with in vitro corona virus-induced transcriptome profiles. This approach enabled identifying a major complex trait for early de novo programming during SARS-CoV-2 infection, called 'CoV-MAC-TED'. It consists of unbalanced ROS/RNS levels, which are connected to increased aerobic fermentation that links to alpha-tubulin-based cell restructuration and progression of cell cycle. We conclude that anti-viral/anti-SARS-CoV-2 strategies need to rigorously target 'CoV-MAC-TED' in primary infected nose and mouth cells through prophylactic and very early therapeutic strategies. We also discuss potential strategies in the view of the beneficial role of AOX for resilient behavior in plants. Furthermore, following the general observation that ROS/RNS equilibration/redox homeostasis is of utmost importance at the very beginning of viral infection, we highlight that 'de-stressing' disease and social handling should be seen as essential part of anti-viral/anti-SARS-CoV-2 strategies.


Assuntos
Reprogramação Celular/genética , Herança Multifatorial/genética , SARS-CoV-2/patogenicidade , Acetilserotonina O-Metiltransferasa/genética , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Ciclo Celular/genética , Bases de Dados Genéticas , Daucus carota/genética , Daucus carota/crescimento & desenvolvimento , Fermentação , Perfilação da Expressão Gênica , Humanos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tubulina (Proteína)/genética , Vírus/patogenicidade
11.
Curr Cardiol Rep ; 23(8): 107, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196841

RESUMO

PURPOSE OF THE REVIEW: Coronary artery disease (CAD) is a common disease globally attributable to the interplay of complex genetic and lifestyle factors. Here, we review how genomic sequencing advances have broadened the fundamental understanding of the monogenic and polygenic contributions to CAD and how these insights can be utilized, in part by creating polygenic risk estimates, for improved disease risk stratification at the individual patient level. RECENT FINDINGS: Initial studies linking premature CAD with rare familial cases of elevated blood lipids highlighted high-risk monogenic contributions, predominantly presenting as familial hypercholesterolemia (FH). More commonly CAD genetic risk is a function of multiple, higher frequency variants each imparting lower magnitude of risk, which can be combined to form polygenic risk scores (PRS) conveying significant risk to individuals at the extremes. However, gaps remain in clinical validation of PRSs, most notably in non-European populations. With improved and more broadly utilized genomic sequencing technologies, the genetic underpinnings of coronary artery disease are being unraveled. As a result, polygenic risk estimation is poised to become a widely used and powerful tool in the clinical setting. While the use of PRSs to augment current clinical risk stratification for optimization of cardiovascular disease risk by lifestyle change or therapeutic targeting is promising, we await adequately powered, prospective studies, demonstrating the clinical utility of polygenic risk estimation in practice.


Assuntos
Doença da Artéria Coronariana , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Humanos , Herança Multifatorial/genética , Estudos Prospectivos , Fatores de Risco
12.
Nat Commun ; 12(1): 4418, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285202

RESUMO

Studies of the genetic basis of complex traits have demonstrated a substantial role for common, small-effect variant polygenic burden (PB) as well as large-effect variants (LEV, primarily rare). We identify sufficient conditions in which GWAS-derived PB may be used for well-powered rare pathogenic variant discovery or as a sample prioritization tool for whole-genome or exome sequencing. Through extensive simulations of genetic architectures and generative models of disease liability with parameters informed by empirical data, we quantify the power to detect, among cases, a lower PB in LEV carriers than in non-carriers. Furthermore, we uncover clinically useful conditions wherein the risk derived from the PB is comparable to the LEV-derived risk. The resulting summary-statistics-based methodology (with publicly available software, PB-LEV-SCAN) makes predictions on PB-based LEV screening for 36 complex traits, which we confirm in several disease datasets with available LEV information in the UK Biobank, with important implications on clinical decision-making.


Assuntos
Predisposição Genética para Doença , Testes Genéticos/métodos , Modelos Genéticos , Herança Multifatorial/genética , Tomada de Decisão Clínica/métodos , Conjuntos de Dados como Assunto , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Software , Sequenciamento Completo do Genoma
13.
N Engl J Med ; 385(1): 78-86, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34192436

RESUMO

Companies have recently begun to sell a new service to patients considering in vitro fertilization: embryo selection based on polygenic scores (ESPS). These scores represent individualized predictions of health and other outcomes derived from genomewide association studies in adults to partially predict these outcomes. This article includes a discussion of many factors that lower the predictive power of polygenic scores in the context of embryo selection and quantifies these effects for a variety of clinical and nonclinical traits. Also discussed are potential unintended consequences of ESPS (including selecting for adverse traits, altering population demographics, exacerbating inequalities in society, and devaluing certain traits). Recommendations for the responsible communication about ESPS by practitioners are provided, and a call for a society-wide conversation about this technology is made. (Funded by the National Institute on Aging and others.).


Assuntos
Embrião de Mamíferos , Fertilização In Vitro , Testes Genéticos , Variação Genética , Herança Multifatorial/genética , Fenótipo , Diagnóstico Pré-Implantação , Escolaridade , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Humanos , Valor Preditivo dos Testes
14.
J Affect Disord ; 293: 124-132, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34186230

RESUMO

BACKGROUND: Neuroticism is a heritable trait that contributes to the vulnerability to depression. We used polygenic risk scores (PRS) to examine genetic vulnerability to neuroticism and its associations with reward/punishment processing in a clinical sample with mood, anxiety, and substance use disorders. It was hypothesized that higher PRS for neuroticism is associated with attenuated neural responses to reward/punishment. METHOD: Four hundred sixty-nine participants were genotyped and their PRSs for neuroticism were computed. Associations between PRS for neuroticism and anticipatory processing of monetary incentives were examined using functional magnetic resonance imaging. RESULTS: Individuals with higher PRS for neuroticism showed less anticipatory activation in the left amygdala and caudate region to incentives regardless of incentive valence. Further, these individuals exhibited altered sensitivity to gain/loss processing in the right anterior insula. Higher PRSs for neuroticism were also associated with reduced processing of gains in the precuneus. LIMITATIONS: The study population consisted of a transdiagnostic sample with dysfunctions in positive and negative valence processing. PRS for neuroticism may be correlated with current clinical symptoms due to the vulnerability to psychiatric disorders. CONCLUSIONS: Greater genetic loading for neuroticism was associated with attenuated anticipatory responsiveness in reward/punishment processing with altered sensitivity to valences. Thus, a higher genetic risk for neuroticism may limit the degree to which positive and/or negative outcomes influence the current mood state, which may contribute to the development of positive and negative affective dysfunctions in individuals with mood, anxiety, and addictive disorders.


Assuntos
Tonsila do Cerebelo , Herança Multifatorial , Tonsila do Cerebelo/diagnóstico por imagem , Transtornos de Ansiedade/diagnóstico por imagem , Transtornos de Ansiedade/genética , Humanos , Imageamento por Ressonância Magnética , Herança Multifatorial/genética , Neuroticismo
15.
Nat Genet ; 53(6): 840-860, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34059833

RESUMO

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.


Assuntos
Glicemia/genética , Grupo com Ancestrais do Continente Europeu/genética , Característica Quantitativa Herdável , Alelos , Epigênese Genética , Perfilação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Hemoglobina A Glicada/metabolismo , Humanos , Herança Multifatorial/genética , Mapeamento Físico do Cromossomo , Locos de Características Quantitativas/genética
17.
Hum Mol Genet ; 30(16): 1521-1534, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-33987664

RESUMO

It is important to study the genetics of complex traits in diverse populations. Here, we introduce covariate-adjusted linkage disequilibrium (LD) score regression (cov-LDSC), a method to estimate SNP-heritability (${\boldsymbol{h}}_{\boldsymbol{g}}^{\mathbf{2}})$ and its enrichment in homogenous and admixed populations with summary statistics and in-sample LD estimates. In-sample LD can be estimated from a subset of the genome-wide association studies samples, allowing our method to be applied efficiently to very large cohorts. In simulations, we show that unadjusted LDSC underestimates ${\boldsymbol{h}}_{\boldsymbol{g}}^{\mathbf{2}}$ by 10-60% in admixed populations; in contrast, cov-LDSC is robustly accurate. We apply cov-LDSC to genotyping data from 8124 individuals, mostly of admixed ancestry, from the Slim Initiative in Genomic Medicine for the Americas study, and to approximately 161 000 Latino-ancestry individuals, 47 000 African American-ancestry individuals and 135 000 European-ancestry individuals, as classified by 23andMe. We estimate ${\boldsymbol{h}}_{\boldsymbol{g}}^{\mathbf{2}}$ and detect heritability enrichment in three quantitative and five dichotomous phenotypes, making this, to our knowledge, the most comprehensive heritability-based analysis of admixed individuals to date. Most traits have high concordance of ${\boldsymbol{h}}_{\boldsymbol{g}}^{\mathbf{2}}$ and consistent tissue-specific heritability enrichment among different populations. However, for age at menarche, we observe population-specific heritability estimates of ${\boldsymbol{h}}_{\boldsymbol{g}}^{\mathbf{2}}$. We observe consistent patterns of tissue-specific heritability enrichment across populations; for example, in the limbic system for BMI, the per-standardized-annotation effect size $ \tau $* is 0.16 ± 0.04, 0.28 ± 0.11 and 0.18 ± 0.03 in the Latino-, African American- and European-ancestry populations, respectively. Our approach is a powerful way to analyze genetic data for complex traits from admixed populations.


Assuntos
Genética Populacional , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Desequilíbrio de Ligação/genética , Herança Multifatorial/genética , Técnicas de Genotipagem/estatística & dados numéricos , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável
18.
Nat Genet ; 53(6): 817-829, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34002096

RESUMO

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.


Assuntos
Transtorno Bipolar/genética , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , Cromossomos Humanos/genética , Predisposição Genética para Doença , Genoma Humano , Humanos , Complexo Principal de Histocompatibilidade/genética , Herança Multifatorial/genética , Fenótipo , Locos de Características Quantitativas/genética , Fatores de Risco
19.
Nat Genet ; 53(6): 787-793, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33958783

RESUMO

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10-11), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10-8) and WWOX (HR = 2.12, P = 2.37 × 10-8) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.


Assuntos
Cognição , Progressão da Doença , Loci Gênicos , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia , Sinapses/genética , Apolipoproteína E4/genética , Transtornos Cognitivos/genética , Predisposição Genética para Doença , Glucosilceramidase/genética , Humanos , Estudos Longitudinais , Mutação/genética , Doença de Parkinson/fisiopatologia , Modelos de Riscos Proporcionais , Fatores de Risco , Análise de Sobrevida
20.
Nat Commun ; 12(1): 2851, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990562

RESUMO

Genome-wide association studies (GWAS) have cataloged many significant associations between genetic variants and complex traits. However, most of these findings have unclear biological significance, because they often have small effects and occur in non-coding regions. Integration of GWAS with gene regulatory networks addresses both issues by aggregating weak genetic signals within regulatory programs. Here we develop a Bayesian framework that integrates GWAS summary statistics with regulatory networks to infer genetic enrichments and associations simultaneously. Our method improves upon existing approaches by explicitly modeling network topology to assess enrichments, and by automatically leveraging enrichments to identify associations. Applying this method to 18 human traits and 38 regulatory networks shows that genetic signals of complex traits are often enriched in interconnections specific to trait-relevant cell types or tissues. Prioritizing variants within enriched networks identifies known and previously undescribed trait-associated genes revealing biological and therapeutic insights.


Assuntos
Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Herança Multifatorial/genética , Algoritmos , Teorema de Bayes , Simulação por Computador , Mineração de Dados , Genoma Humano , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética
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