Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.034
Filtrar
1.
Methods Mol Biol ; 2212: 55-67, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733350

RESUMO

Epistasis, or gene-gene interaction, contributes substantially to trait variation in organisms ranging from yeast to humans, and modeling epistasis directly is critical to understanding the genotype-phenotype map. However, inference of genetic interactions is challenging compared to inference of individual allele effects due to low statistical power. Furthermore, genetic interactions can appear inconsistent across different quantitative traits, presenting a challenge for the interpretation of detected interactions. Here we present a method called the Combined Analysis of Pleiotropy and Epistasis (CAPE) that combines information across multiple quantitative traits to infer directed epistatic interactions. By combining information across multiple traits, CAPE not only increases power to detect genetic interactions but also interprets these interactions across traits to identify a single interaction that is consistent across all observed data. This method generates informative, interpretable interaction networks that explain how variants interact with each other to influence groups of related traits. This method could potentially be used to link genetic variants to gene expression, physiological endophenotypes, and higher-level disease traits.


Assuntos
Epistasia Genética , Pleiotropia Genética , Modelos Genéticos , Característica Quantitativa Herdável , Software , Redes Reguladoras de Genes , Estudos de Associação Genética , Genótipo , Humanos , Fenótipo , Locos de Características Quantitativas
2.
Methods Mol Biol ; 2212: 225-243, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733359

RESUMO

Unraveling the complex biological mechanisms underlying human health and disease is a great challenge. With genomic data, many aspects can be investigated in great detail, such as interactions between different genetic variants as well as their effects on one or multiple traits. Modeling epistasis and pleiotropy jointly necessitates appropriate statistical methods. A suitable tool for this is C-JAMP, which is a recently proposed method based on copula functions. In this chapter, we outline C-JAMP and how it can be applied to investigate epistatic effects on multiple traits to advance our understanding of biological processes. We further discuss important aspects of this area of research, such as polygenic risk scores and ancestry-specific modeling, which we propose to include in future extensions of the software.


Assuntos
Epistasia Genética , Pleiotropia Genética , Antígenos HLA/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Software , Bancos de Espécimes Biológicos , Índice de Massa Corporal , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Estudos Prospectivos , Locos de Características Quantitativas , Característica Quantitativa Herdável , Reino Unido , Relação Cintura-Quadril
3.
Nat Commun ; 12(1): 860, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558518

RESUMO

The difficulty in finding causative mutations has hampered their use in genomic prediction. Here, we present a methodology to fine-map potentially causal variants genome-wide by integrating the functional, evolutionary and pleiotropic information of variants using GWAS, variant clustering and Bayesian mixture models. Our analysis of 17 million sequence variants in 44,000+ Australian dairy cattle for 34 traits suggests, on average, one pleiotropic QTL existing in each 50 kb chromosome-segment. We selected a set of 80k variants representing potentially causal variants within each chromosome segment to develop a bovine XT-50K genotyping array. The custom array contains many pleiotropic variants with biological functions, including splicing QTLs and variants at conserved sites across 100 vertebrate species. This biology-informed custom array outperformed the standard array in predicting genetic value of multiple traits across populations in independent datasets of 90,000+ dairy cattle from the USA, Australia and New Zealand.


Assuntos
Bovinos/genética , Mapeamento Cromossômico , Pleiotropia Genética , Internacionalidade , Característica Quantitativa Herdável , Animais , Teorema de Bayes , Cromossomos de Mamíferos/genética , Análise por Conglomerados , Feminino , Marcadores Genéticos , Variação Genética , Genoma , Masculino , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes
4.
Nat Commun ; 12(1): 168, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420026

RESUMO

Increasingly, clinical phenotypes with matched genetic data from bio-bank linked electronic health records (EHRs) have been used for pleiotropy analyses. Thus far, pleiotropy analysis using individual-level EHR data has been limited to data from one site. However, it is desirable to integrate EHR data from multiple sites to improve the detection power and generalizability of the results. Due to privacy concerns, individual-level patients' data are not easily shared across institutions. As a result, we introduce Sum-Share, a method designed to efficiently integrate EHR and genetic data from multiple sites to perform pleiotropy analysis. Sum-Share requires only summary-level data and one round of communication from each site, yet it produces identical test statistics compared with that of pooled individual-level data. Consequently, Sum-Share can achieve lossless integration of multiple datasets. Using real EHR data from eMERGE, Sum-Share is able to identify 1734 potential pleiotropic SNPs for five cardiovascular diseases.


Assuntos
Registros Eletrônicos de Saúde/estatística & dados numéricos , Pleiotropia Genética , Comunicação , Bases de Dados Factuais , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Modelos Biológicos , Fenótipo , Polimorfismo de Nucleotídeo Único , Privacidade
5.
Am J Hum Genet ; 108(2): 240-256, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434493

RESUMO

A transcriptome-wide association study (TWAS) integrates data from genome-wide association studies and gene expression mapping studies for investigating the gene regulatory mechanisms underlying diseases. Existing TWAS methods are primarily univariate in nature, focusing on analyzing one outcome trait at a time. However, many complex traits are correlated with each other and share a common genetic basis. Consequently, analyzing multiple traits jointly through multivariate analysis can potentially improve the power of TWASs. Here, we develop a method, moPMR-Egger (multiple outcome probabilistic Mendelian randomization with Egger assumption), for analyzing multiple outcome traits in TWAS applications. moPMR-Egger examines one gene at a time, relies on its cis-SNPs that are in potential linkage disequilibrium with each other to serve as instrumental variables, and tests its causal effects on multiple traits jointly. A key feature of moPMR-Egger is its ability to test and control for potential horizontal pleiotropic effects from instruments, thus maximizing power while minimizing false associations for TWASs. In simulations, moPMR-Egger provides calibrated type I error control for both causal effects testing and horizontal pleiotropic effects testing and is more powerful than existing univariate TWAS approaches in detecting causal associations. We apply moPMR-Egger to analyze 11 traits from 5 trait categories in the UK Biobank. In the analysis, moPMR-Egger identified 13.15% more gene associations than univariate approaches across trait categories and revealed distinct regulatory mechanisms underlying systolic and diastolic blood pressures.


Assuntos
Estudos de Associação Genética , Herança Multifatorial , Transcriptoma , Pressão Sanguínea/genética , Simulação por Computador , Pleiotropia Genética , Humanos , Desequilíbrio de Ligação , Análise da Randomização Mendeliana , Modelos Genéticos , Análise Multivariada , Fenótipo , Polimorfismo de Nucleotídeo Único
6.
Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492

RESUMO

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
7.
Am J Hum Genet ; 108(2): 219-239, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33440170

RESUMO

We present a full-likelihood method to infer polygenic adaptation from DNA sequence variation and GWAS summary statistics to quantify recent transient directional selection acting on a complex trait. Through simulations of polygenic trait architecture evolution and GWASs, we show the method substantially improves power over current methods. We examine the robustness of the method under stratification, uncertainty and bias in marginal effects, uncertainty in the causal SNPs, allelic heterogeneity, negative selection, and low GWAS sample size. The method can quantify selection acting on correlated traits, controlling for pleiotropy even among traits with strong genetic correlation (|rg|=80%) while retaining high power to attribute selection to the causal trait. When the causal trait is excluded from analysis, selection is attributed to its closest proxy. We discuss limitations of the method, cautioning against strongly causal interpretations of the results, and the possibility of undetectable gene-by-environment (GxE) interactions. We apply the method to 56 human polygenic traits, revealing signals of directional selection on pigmentation, life history, glycated hemoglobin (HbA1c), and other traits. We also conduct joint testing of 137 pairs of genetically correlated traits, revealing widespread correlated response acting on these traits (2.6-fold enrichment, p = 1.5 × 10-7). Signs of selection on some traits previously reported as adaptive (e.g., educational attainment and hair color) are largely attributable to correlated response (p = 2.9 × 10-6 and 1.7 × 10-4, respectively). Lastly, our joint test shows antagonistic selection has increased type 2 diabetes risk and decrease HbA1c (p = 1.5 × 10-5).


Assuntos
Genoma Humano , Herança Multifatorial , Seleção Genética , Simulação por Computador , Diabetes Mellitus Tipo 2/genética , Evolução Molecular , Interação Gene-Ambiente , Heterogeneidade Genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Hemoglobina A Glicada/genética , Humanos , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Tamanho da Amostra
8.
Nat Commun ; 12(1): 350, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441555

RESUMO

Causal inference via Mendelian randomization requires making strong assumptions about horizontal pleiotropy, where genetic instruments are connected to the outcome not only through the exposure. Here, we present causal Graphical Analysis Using Genetics (cGAUGE), a pipeline that overcomes these limitations using instrument filters with provable properties. This is achievable by identifying conditional independencies while examining multiple traits. cGAUGE also uses ExSep (Exposure-based Separation), a novel test for the existence of causal pathways that does not require selecting instruments. In simulated data we illustrate how cGAUGE can reduce the empirical false discovery rate by up to 30%, while retaining the majority of true discoveries. On 96 complex traits from 337,198 subjects from the UK Biobank, our results cover expected causal links and many new ones that were previously suggested by correlation-based observational studies. Notably, we identify multiple risk factors for cardiovascular disease, including red blood cell distribution width.


Assuntos
Bancos de Espécimes Biológicos , Pleiotropia Genética/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Doenças Cardiovasculares/genética , Causalidade , Simulação por Computador , Redes Reguladoras de Genes , Variação Genética , Genótipo , Humanos , Análise da Randomização Mendeliana/métodos , Modelos Teóricos , Fenótipo , Fatores de Risco
9.
Nat Genet ; 53(2): 185-194, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33462484

RESUMO

Clinical laboratory tests are a critical component of the continuum of care. We evaluate the genetic basis of 35 blood and urine laboratory measurements in the UK Biobank (n = 363,228 individuals). We identify 1,857 loci associated with at least one trait, containing 3,374 fine-mapped associations and additional sets of large-effect (>0.1 s.d.) protein-altering, human leukocyte antigen (HLA) and copy number variant (CNV) associations. Through Mendelian randomization (MR) analysis, we discover 51 causal relationships, including previously known agonistic effects of urate on gout and cystatin C on stroke. Finally, we develop polygenic risk scores (PRSs) for each biomarker and build 'multi-PRS' models for diseases using 35 PRSs simultaneously, which improved chronic kidney disease, type 2 diabetes, gout and alcoholic cirrhosis genetic risk stratification in an independent dataset (FinnGen; n = 135,500) relative to single-disease PRSs. Together, our results delineate the genetic basis of biomarkers and their causal influences on diseases and improve genetic risk stratification for common diseases.


Assuntos
Biomarcadores/sangue , Biomarcadores/urina , Antígenos HLA/genética , Proteínas/genética , Bancos de Espécimes Biológicos , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Variações do Número de Cópias de DNA , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Pleiotropia Genética , Humanos , Desequilíbrio de Ligação , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica , Serina Endopeptidases/genética , Reino Unido
10.
Nat Genet ; 53(1): 54-64, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33414548

RESUMO

In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10-10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with ß-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.


Assuntos
Saúde , Metabolismo/genética , Diabetes Mellitus Tipo 2/genética , Oftalmopatias/genética , Frequência do Gene/genética , Loci Gênicos , Pleiotropia Genética , Genoma Humano , Receptor do Peptídeo Semelhante ao Glucagon 2/genética , Glicina/metabolismo , Humanos , Modelos Lineares , Análise da Randomização Mendeliana , Erros Inatos do Metabolismo/genética , Metaboloma/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Telangiectasia Retiniana/genética , Tamanho da Amostra , Serina/metabolismo
11.
Nucleic Acids Res ; 49(2): 1075-1093, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33398350

RESUMO

Defects in the posttranscriptional modifications of mitochondrial tRNAs have been linked to human diseases, but their pathophysiology remains elusive. In this report, we investigated the molecular mechanism underlying a deafness-associated tRNAIle 4295A>G mutation affecting a highly conserved adenosine at position 37, 3' adjacent to the tRNA's anticodon. Primer extension and methylation activity assays revealed that the m.4295A>G mutation introduced a tRNA methyltransferase 5 (TRMT5)-catalyzed m1G37 modification of tRNAIle. Molecular dynamics simulations suggested that the m.4295A>G mutation affected tRNAIle structure and function, supported by increased melting temperature, conformational changes and instability of mutated tRNA. An in vitro processing experiment revealed that the m.4295A>G mutation reduced the 5' end processing efficiency of tRNAIle precursors, catalyzed by RNase P. We demonstrated that cybrid cell lines carrying the m.4295A>G mutation exhibited significant alterations in aminoacylation and steady-state levels of tRNAIle. The aberrant tRNA metabolism resulted in the impairment of mitochondrial translation, respiratory deficiency, decreasing membrane potentials and ATP production, increasing production of reactive oxygen species and promoting autophagy. These demonstrated the pleiotropic effects of m.4295A>G mutation on tRNAIle and mitochondrial functions. Our findings highlighted the essential role of deficient posttranscriptional modifications in the structure and function of tRNA and their pathogenic consequence of deafness.


Assuntos
Perda Auditiva Neurossensorial/genética , Mutação Puntual , RNA de Transferência de Isoleucina/genética , Trifosfato de Adenosina/biossíntese , Adulto , Proteínas Arqueais/metabolismo , Autofagia , Sequência de Bases , Linhagem Celular , DNA Mitocondrial/genética , Grupos Étnicos/genética , Feminino , Pleiotropia Genética , Perda Auditiva Neurossensorial/etnologia , Humanos , Isoleucina/metabolismo , Masculino , Herança Materna , Potencial da Membrana Mitocondrial , Methanocaldococcus/enzimologia , Metilação , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Fosforilação Oxidativa , Linhagem , Biossíntese de Proteínas , Processamento Pós-Transcricional do RNA , Proteínas Recombinantes/metabolismo , Aminoacilação de RNA de Transferência , Adulto Jovem , tRNA Metiltransferases/metabolismo
12.
Am J Hum Genet ; 108(1): 36-48, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33352115

RESUMO

Identifying and interpreting pleiotropic loci is essential to understanding the shared etiology among diseases and complex traits. A common approach to mapping pleiotropic loci is to meta-analyze GWAS summary statistics across multiple traits. However, this strategy does not account for the complex genetic architectures of traits, such as genetic correlations and heritabilities. Furthermore, the interpretation is challenging because phenotypes often have different characteristics and units. We propose PLEIO (Pleiotropic Locus Exploration and Interpretation using Optimal test), a summary-statistic-based framework to map and interpret pleiotropic loci in a joint analysis of multiple diseases and complex traits. Our method maximizes power by systematically accounting for genetic correlations and heritabilities of the traits in the association test. Any set of related phenotypes, binary or quantitative traits with different units, can be combined seamlessly. In addition, our framework offers interpretation and visualization tools to help downstream analyses. Using our method, we combined 18 traits related to cardiovascular disease and identified 13 pleiotropic loci, which showed four different patterns of associations.


Assuntos
Pleiotropia Genética/genética , Estudo de Associação Genômica Ampla/métodos , Doenças Cardiovasculares/genética , Predisposição Genética para Doença/genética , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
13.
PLoS Genet ; 16(12): e1009190, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33370286

RESUMO

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.


Assuntos
Densidade Óssea/genética , Regulação da Expressão Gênica/genética , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporose/genética , Animais , Feminino , Ontologia Genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Genótipo , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Osteoblastos/patologia , Osteoclastos/patologia , Osteoporose/metabolismo , Fenótipo , Regiões Promotoras Genéticas , Mapas de Interação de Proteínas , Caracteres Sexuais , Transcriptoma
14.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375029

RESUMO

The transcription factor Forkhead box E1 (FOXE1) is a key player in thyroid development and function and has been identified by genome-wide association studies as a susceptibility gene for papillary thyroid cancer. Several cancer-associated polymorphisms fall into gene regulatory regions and are likely to affect FOXE1 expression levels. However, the possibility that changes in FOXE1 expression modulate thyroid cancer development has not been investigated. Here, we describe the effects of FOXE1 gene dosage reduction on cancer phenotype in vivo. Mice heterozygous for FOXE1 null allele (FOXE1+/-) were crossed with a BRAFV600E-inducible cancer model to develop thyroid cancer in either a FOXE1+/+ or FOXE1+/- genetic background. In FOXE1+/+ mice, cancer histological features are quite similar to that of human high-grade papillary thyroid carcinomas, while cancers developed with reduced FOXE1 gene dosage maintain morphological features resembling less malignant thyroid cancers, showing reduced proliferation index and increased apoptosis as well. Such cancers, however, appear severely undifferentiated, indicating that FOXE1 levels affect thyroid differentiation during neoplastic transformation. These results show that FOXE1 dosage exerts pleiotropic effects on thyroid cancer phenotype by affecting histology and regulating key markers of tumor differentiation and progression, thus suggesting the possibility that FOXE1 could behave as lineage-specific oncogene in follicular cell-derived thyroid cancer.


Assuntos
Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Câncer Papilífero da Tireoide/genética , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Animais , Apoptose/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Fatores de Transcrição Forkhead/metabolismo , Pleiotropia Genética , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo
15.
BMC Bioinformatics ; 21(1): 491, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33129253

RESUMO

BACKGROUND: Advances in genotyping and phenotyping techniques have enabled the acquisition of a great amount of data. Consequently, there is an interest in multivariate statistical analyses that identify genomic regions likely to contain causal mutations affecting multiple traits (i.e., pleiotropy). As the demand for multivariate analyses increases, it is imperative that optimal tools are available to assess their performance. To facilitate the testing and validation of these multivariate approaches, we developed simplePHENOTYPES, an R/CRAN package that simulates pleiotropy, partial pleiotropy, and spurious pleiotropy in a wide range of genetic architectures, including additive, dominance and epistatic models. RESULTS: We illustrate simplePHENOTYPES' ability to simulate thousands of phenotypes in less than one minute. We then provide two vignettes illustrating how to simulate sets of correlated traits in simplePHENOTYPES. Finally, we demonstrate the use of results from simplePHENOTYPES in a standard GWAS software, as well as the equivalence of simulated phenotypes from simplePHENOTYPES and other packages with similar capabilities. CONCLUSIONS: simplePHENOTYPES is a R/CRAN package that makes it possible to simulate multiple traits controlled by loci with varying degrees of pleiotropy. Its ability to interface with both commonly-used marker data formats and downstream quantitative genetics software and packages should facilitate a rigorous assessment of both existing and emerging statistical GWAS and GS approaches. simplePHENOTYPES is also available at https://github.com/samuelbfernandes/simplePHENOTYPES .


Assuntos
Simulação por Computador , Epistasia Genética , Ligação Genética , Pleiotropia Genética , Software , Frequência do Gene/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Análise Multivariada , Fenótipo , Característica Quantitativa Herdável , Fluxo de Trabalho
16.
Nat Commun ; 11(1): 4930, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004804

RESUMO

Inference of causality between gene expression and complex traits using Mendelian randomization (MR) is confounded by pleiotropy and linkage disequilibrium (LD) of gene-expression quantitative trait loci (eQTL). Here, we propose an MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data, even when only one eQTL variant is present. In simulations, MR-link shows false-positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other tested MR methods and coloc. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals with expression and protein QTL summary statistics from blood and liver identifies 25 genes causally linked to LDL-C. These include the known SORT1 and ApoE genes as well as PVRL2, located in the APOE locus, for which a causal role in liver was not known. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.


Assuntos
LDL-Colesterol/sangue , Regulação da Expressão Gênica , Predisposição Genética para Doença , Modelos Genéticos , Locos de Características Quantitativas , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , LDL-Colesterol/metabolismo , Simulação por Computador , Conjuntos de Dados como Assunto , Pleiotropia Genética , Humanos , Desequilíbrio de Ligação , Metabolismo dos Lipídeos/genética , Análise da Randomização Mendeliana , Redes e Vias Metabólicas/genética , Herança Multifatorial , Nectinas/genética , Nectinas/metabolismo , Países Baixos , Proteômica , RNA-Seq
17.
PLoS Genet ; 16(9): e1009036, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32941431

RESUMO

The polygenic nature and the contribution of common genetic variation to autism spectrum disorder (ASD) allude to a high degree of pleiotropy between ASD and other psychiatric and behavioral traits. In a pleiotropic system, a single genetic variant contributes small effects to several phenotypes or disorders. While analyzed broadly, there is a paucity of research studies investigating the shared genetic information between specific neurodevelopmental domains and ASD. We performed a phenome-wide association study of ASD polygenetic risk score (PRS) against 491 neurodevelopmental subdomains ascertained in 4,309 probands from the Philadelphia Neurodevelopmental Cohort (PNC) who lack an ASD diagnosis. Our main analysis calculated ASD PRS in 4,309 PNC probands using the per-SNP effects reported in a recent genome-wide association study of ASD in a case-control design. In a high-resolution manner, our main analysis regressed ASD PRS against 491 neurodevelopmental phenotypes with age, sex, and ten principal components of ancestry as covariates. Follow-up analyses included in the regression model PRS derived from brain-related traits genetically correlated with ASD. Our main finding demonstrated that 11-17-year old probands with the highest ASD genetic risk were able to identify angry faces (R2 = 1.06%, p = 1.38 × 10-7, pBonferroni-corrected = 1.9 × 10-3). This ability replicated in older probands (>18 years; R2 = 0.55%, p = 0.036) and persisted after covarying with other psychiatric disorders, brain imaging traits, and educational attainment (R2 = 0.2%, p = 0.019). We also detected several suggestive associations between ASD PRS and emotionality and connectedness with others. These data (i) indicate how genetic liability to ASD may influence neurodevelopment in the general population, (ii) reinforce epidemiological findings of heightened ability of ASD cases to predict certain social psychological events based on increased systemizing skills, and (iii) recapitulate theories of imbalance between empathizing and systemizing in ASD etiology.


Assuntos
Transtorno do Espectro Autista/genética , Reconhecimento Facial/fisiologia , Adolescente , Adulto , Ira/fisiologia , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Pleiotropia Genética/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial/genética , Fenótipo , Reconhecimento Psicológico/fisiologia , Fatores de Risco
18.
Nat Commun ; 11(1): 4423, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887889

RESUMO

Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.


Assuntos
Carcinogênese/genética , Neoplasias/genética , Adulto , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco
19.
PLoS Biol ; 18(8): e3000836, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804946

RESUMO

Pleiotropy-when a single mutation affects multiple traits-is a controversial topic with far-reaching implications. Pleiotropy plays a central role in debates about how complex traits evolve and whether biological systems are modular or are organized such that every gene has the potential to affect many traits. Pleiotropy is also critical to initiatives in evolutionary medicine that seek to trap infectious microbes or tumors by selecting for mutations that encourage growth in some conditions at the expense of others. Research in these fields, and others, would benefit from understanding the extent to which pleiotropy reflects inherent relationships among phenotypes that correlate no matter the perturbation (vertical pleiotropy). Alternatively, pleiotropy may result from genetic changes that impose correlations between otherwise independent traits (horizontal pleiotropy). We distinguish these possibilities by using clonal populations of yeast cells to quantify the inherent relationships between single-cell morphological features. Then, we demonstrate how often these relationships underlie vertical pleiotropy and how often these relationships are modified by genetic variants (quantitative trait loci [QTL]) acting via horizontal pleiotropy. Our comprehensive screen measures thousands of pairwise trait correlations across hundreds of thousands of yeast cells and reveals ample evidence of both vertical and horizontal pleiotropy. Additionally, we observe that the correlations between traits can change with the environment, genetic background, and cell-cycle position. These changing dependencies suggest a nuanced view of pleiotropy: biological systems demonstrate limited pleiotropy in any given context, but across contexts (e.g., across diverse environments and genetic backgrounds) each genetic change has the potential to influence a larger number of traits. Our method suggests that exploiting pleiotropy for applications in evolutionary medicine would benefit from focusing on traits with correlations that are less dependent on context.


Assuntos
Pleiotropia Genética , Modelos Genéticos , Herança Multifatorial , Locos de Características Quantitativas , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Evolução Biológica , Ciclo Celular/genética , Células Clonais , Variação Genética , Ensaios de Triagem em Larga Escala , Mutação , Fenótipo , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Análise de Célula Única
20.
Nat Commun ; 11(1): 4140, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811829

RESUMO

Investigating the evolution of complex phenotypes and the underlying molecular bases of their variation is critical to understand how organisms adapt to their environment. Applying classical quantitative genetics on a segregating population derived from a Can-0xCol-0 cross, we identify the MADS-box transcription factor FLOWERING LOCUS M (FLM) as a player of the phenotypic variation in plant growth and color. We show that allelic variation at FLM modulates plant growth strategy along the leaf economics spectrum, a trade-off between resource acquisition and resource conservation, observable across thousands of plant species. Functional differences at FLM rely on a single intronic substitution, disturbing transcript splicing and leading to the accumulation of non-functional FLM transcripts. Associations between this substitution and phenotypic and climatic data across Arabidopsis natural populations, show how noncoding genetic variation at a single gene might be adaptive through pleiotropic effects.


Assuntos
Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas/genética , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismo , Processamento de RNA/genética , Alelos , Arabidopsis/metabolismo , Evolução Molecular , Pleiotropia Genética , Variação Genética , Íntrons , Fenótipo , Folhas de Planta/genética , Folhas de Planta/fisiologia , Locos de Características Quantitativas/genética , Temperatura
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...