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1.
Mol Biol (Mosk) ; 53(4): 574-599, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31397433

RESUMO

Pharmacogenetics (PG) investigates the inherited variants of the human genome that underlie individual differences in drug metabolic transformation, delivery, and mechanism of action. Not only the contributions of individual genes, but also their cumulative effect should be considered in the case of polygenic diseases, which include the majority of human diseases. Multiple sclerosis (MS) is a severe autoimmune neurodegenerative disorder of the central nervous system (CNS) and is polygenic in nature. Understanding the role that the immune system plays in the pathogenesis of MS helped to design drugs for its pathogenetic therapy. These drugs are known as the disease-modifying treatments (DMTs). Among these are interferon ß (IFN-ß) and glatiramer acetate (GA), whose treatment efficacy and long-term safety have been proven in many clinical trials. However their efficacy on MS course varies from highly effective to lack of response. Prognostic genetic biomarkers of treatment efficacy can help to identify the MS patient groups where a particular drug is preferential or even strictly indicated to use. The review summarizes the findings from pharmacogenetic studies evaluating the efficacy of IFN-ß and GA in MS patients, including the author's original data.


Assuntos
Herança Multifatorial/genética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Farmacogenética , Medicina de Precisão , Marcadores Genéticos , Acetato de Glatiramer/uso terapêutico , Humanos , Interferon beta/uso terapêutico
2.
Nat Commun ; 10(1): 3009, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285442

RESUMO

Quantitative genetics theory predicts that X-chromosome dosage compensation (DC) will have a detectable effect on the amount of genetic and therefore phenotypic trait variances at associated loci in males and females. Here, we systematically examine the role of DC in humans in 20 complex traits in a sample of more than 450,000 individuals from the UK Biobank and 1600 gene expression traits from a sample of 2000 individuals as well as across-tissue gene expression from the GTEx resource. We find approximately twice as much X-linked genetic variation across the UK Biobank traits in males (mean h2SNP = 0.63%) compared to females (mean h2SNP = 0.30%), confirming the predicted DC effect. Our DC estimates for complex traits and gene expression are consistent with a small proportion of genes escaping X-inactivation in a trait- and tissue-dependent manner. Finally, we highlight examples of biologically relevant X-linked heterogeneity between the sexes that bias DC estimates if unaccounted for.


Assuntos
Genes Ligados ao Cromossomo X/genética , Loci Gênicos/genética , Variação Genética/genética , Herança Multifatorial/genética , Inativação do Cromossomo X/genética , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Modelos Genéticos , Fenótipo , Fatores Sexuais
3.
BMC Bioinformatics ; 20(Suppl 12): 313, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31216978

RESUMO

BACKGROUND: Schizophrenia and autism are examples of polygenic diseases caused by a multitude of genetic variants, many of which are still poorly understood. Recently, both diseases have been associated with disrupted neuron motility and migration patterns, suggesting that aberrant cell motility is a phenotype for these neurological diseases. RESULTS: We formulate the POLYGENIC DISEASE PHENOTYPE Problem which seeks to identify candidate disease genes that may be associated with a phenotype such as cell motility. We present a machine learning approach to solve this problem for schizophrenia and autism genes within a brain-specific functional interaction network. Our method outperforms peer semi-supervised learning approaches, achieving better cross-validation accuracy across different sets of gold-standard positives. We identify top candidates for both schizophrenia and autism, and select six genes labeled as schizophrenia positives that are predicted to be associated with cell motility for follow-up experiments. CONCLUSIONS: Candidate genes predicted by our method suggest testable hypotheses about these genes’ role in cell motility regulation, offering a framework for generating predictions for experimental validation.


Assuntos
Movimento Celular/genética , Doença/genética , Redes Reguladoras de Genes , Herança Multifatorial/genética , Algoritmos , Transtorno Autístico/genética , Estudos de Associação Genética , Humanos , Aprendizado de Máquina , Fenótipo , Curva ROC , Reprodutibilidade dos Testes , Esquizofrenia/genética
4.
J Headache Pain ; 20(1): 72, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31226929

RESUMO

BACKGROUND: Migraine is a complex neurovascular disorder with a strong genetic component. There are rare monogenic forms of migraine, as well as more common polygenic forms; research into the genes involved in both types has provided insights into the many contributing genetic factors. This review summarises advances that have been made in the knowledge and understanding of the genes and genetic variations implicated in migraine etiology. FINDINGS: Migraine is characterised into two main types, migraine without aura (MO) and migraine with aura (MA). Hemiplegic migraine is a rare monogenic MA subtype caused by mutations in three main genes - CACNA1A, ATP1A2 and SCN1A - which encode ion channel and transport proteins. Functional studies in cellular and animal models show that, in general, mutations result in impaired glutamatergic neurotransmission and cortical hyperexcitability, which make the brain more susceptible to cortical spreading depression, a phenomenon thought to coincide with aura symptoms. Variants in other genes encoding ion channels and solute carriers, or with roles in regulating neurotransmitters at neuronal synapses, or in vascular function, can also cause monogenic migraine, hemiplegic migraine and related disorders with overlapping symptoms. Next-generation sequencing will accelerate the finding of new potentially causal variants and genes, with high-throughput bioinformatics analysis methods and functional analysis pipelines important in prioritising, confirming and understanding the mechanisms of disease-causing variants. With respect to common migraine forms, large genome-wide association studies (GWAS) have greatly expanded our knowledge of the genes involved, emphasizing the role of both neuronal and vascular pathways. Dissecting the genetic architecture of migraine leads to greater understanding of what underpins relationships between subtypes and comorbid disorders, and may have utility in diagnosis or tailoring treatments. Further work is required to identify causal polymorphisms and the mechanism of their effect, and studies of gene expression and epigenetic factors will help bridge the genetics with migraine pathophysiology. CONCLUSIONS: The complexity of migraine disorders is mirrored by their genetic complexity. A comprehensive knowledge of the genetic factors underpinning migraine will lead to improved understanding of molecular mechanisms and pathogenesis, to enable better diagnosis and treatments for migraine sufferers.


Assuntos
Transtornos de Enxaqueca/genética , Animais , Depressão Alastrante da Atividade Elétrica Cortical/genética , Estudo de Associação Genômica Ampla , Humanos , Enxaqueca com Aura/fisiopatologia , Herança Multifatorial/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1/genética
5.
J Dairy Sci ; 102(8): 7237-7247, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31155255

RESUMO

Relatedness between reference and test animals has an important effect on the reliability of genomic prediction for test animals. Because genomic prediction has been widely applied in practical cattle breeding and bulls have been selected according to genomic breeding value without progeny testing, the sires or grandsires of candidates might not have phenotypic information and might not be in the reference population when the candidates are selected. The objective of this study was to investigate the decreasing trend of the reliability of genomic prediction given distant reference populations, using genomic best linear unbiased prediction (GBLUP) and Bayesian variable selection models with or without including the quantitative trait locus (QTL) markers detected from sequencing data. The data used in this study consisted of 22,242 bulls genotyped using the 54K SNP array from EuroGenomics. Among them, 1,444 Danish bulls born from 2006 to 2010 were selected as test animals. Different reference populations with varying relationships to test animals were created according to pedigree-based relationships. The reference individuals having a relationship with one or more test animals higher than 0.4 (scenario ρ < 0.4), 0.2 (ρ < 0.2), or 0.1 (ρ < 0.1, where ρ = relationship coefficient) were removed from reference sets; these represented the distance between reference and test animals being 2 generations, 3 generations, and 4 generations, respectively. Imputed whole-genome sequencing data of bulls from Denmark were used to conduct a genome-wide association study (GWAS). A small number of significant variants (QTL markers) from the GWAS were added to the array data. To compare the effects of different models, the basic GBLUP model, a Bayesian selection variable model, a GBLUP model with 2 components of genetic effects, and a Bayesian model with pooled array data and QTL markers were used for estimating genomic estimated breeding values (GEBV) of test animals. The reliability of genomic prediction decreased when the test animals were more generations away from the reference population. The reliability of genomic prediction was 0.461 for 1 generation away and 0.396 for 3 generations away, with the same number of individuals in the reference set, using a GBLUP model with chip markers only. The results showed that using the Bayesian method and QTL markers improved the reliability of genomic prediction in all scenarios of relationship between test and reference animals, in a range of 1.3% and 65.1% (4 generations away with only 841 individuals in the reference set). However, most gains were for predictions of milk yield and fat yield. There was little improvement for predictions of protein yield and mastitis, and no improvement for prediction of fertility, except for scenario ρ < 0.1, in which there was a large improvement for predictions of all traits. On the other hand, models including more than 10% polygenic effect decreased prediction reliability when the relationship between test and reference animals was distant.


Assuntos
Teorema de Bayes , Bovinos/genética , Estudo de Associação Genômica Ampla/veterinária , Mastite Bovina/genética , Leite/metabolismo , Locos de Características Quantitativas/genética , Animais , Cruzamento , Dinamarca , Feminino , Fertilidade/genética , Marcadores Genéticos/genética , Genômica , Genótipo , Masculino , Herança Multifatorial/genética , Linhagem , Fenótipo , Reprodutibilidade dos Testes
6.
Nat Commun ; 10(1): 1776, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992449

RESUMO

Polygenic risk scores (PRS) have shown promise in predicting human complex traits and diseases. Here, we present PRS-CS, a polygenic prediction method that infers posterior effect sizes of single nucleotide polymorphisms (SNPs) using genome-wide association summary statistics and an external linkage disequilibrium (LD) reference panel. PRS-CS utilizes a high-dimensional Bayesian regression framework, and is distinct from previous work by placing a continuous shrinkage (CS) prior on SNP effect sizes, which is robust to varying genetic architectures, provides substantial computational advantages, and enables multivariate modeling of local LD patterns. Simulation studies using data from the UK Biobank show that PRS-CS outperforms existing methods across a wide range of genetic architectures, especially when the training sample size is large. We apply PRS-CS to predict six common complex diseases and six quantitative traits in the Partners HealthCare Biobank, and further demonstrate the improvement of PRS-CS in prediction accuracy over alternative methods.


Assuntos
Predisposição Genética para Doença , Modelos Genéticos , Herança Multifatorial/genética , Característica Quantitativa Herdável , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Teorema de Bayes , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Simulação por Computador , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , Bases de Dados Genéticas/estatística & dados numéricos , Depressão/diagnóstico , Depressão/genética , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
7.
BMC Genomics ; 20(1): 174, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30836959

RESUMO

BACKGROUND: The sample ascertainment bias due to complex population structures remains a major challenge in genome-wide investigations of complex traits. In this study we derived the high-resolution population structure and levels of autozygosity of 377 Lipizzan horses originating from five different European stud farms utilizing the SNP genotype information of the high density 700 k Affymetrix Axiom™ Equine genotyping array. Scanning the genome for overlapping runs of homozygosity (ROH) shared by more than 50% of horses, we identified homozygous regions (ROH islands) in order to investigate the gene content of those candidate regions by gene ontology and enrichment analyses. RESULTS: The high-resolution population network approach revealed well-defined substructures according to the origin of the horses (Austria, Slovakia, Croatia and Hungary). The highest mean genome coverage of ROH (SROH) was identified in the Austrian (SROH = 342.9), followed by Croatian (SROH = 214.7), Slovakian (SROH = 205.1) and Hungarian (SROH = 171.5) subpopulations. ROH island analysis revealed five common islands on ECA11 and ECA14, hereby confirming a closer genetic relationship between the Hungarian and Croatian as well as between the Austrian and Slovakian samples. Private islands were detected for the Hungarian and the Austrian Lipizzan subpopulations. All subpopulations shared a homozygous region on ECA11, nearly identical in position and length containing among other genes the homeobox-B cluster, which was also significantly (p < 0.001) highlighted by enrichment analysis. Gene ontology terms were mostly related to biological processes involved in embryonic morphogenesis and anterior/posterior specification. Around the STX17 gene (causative for greying), we identified a ROH island harbouring the genes NR4A3, STX17, ERP44 and INVS. Within further islands on ECA14, ECA16 and ECA20 we detected the genes SPRY4, NDFIP1, IMPDH2, HSP90AB1, whereas SPRY4 and HSP90AB1 are involved in melanoma metastasis and survival rate of melanoma patients in humans. CONCLUSIONS: We demonstrated that the assessment of high-resolution population structures within one single breed supports the downstream genetic analyses (e.g. the identification of ROH islands). By means of ROH island analyses, we identified the genes SPRY4, NDFIP1, IMPDH2, HSP90AB1, which might play an important role for further studies on equine melanoma. Furthermore, our results highlighted the impact of the homeobox-A and B cluster involved in morphogenesis of Lipizzan horses.


Assuntos
Genética Populacional , Genoma/genética , Cavalos/genética , Herança Multifatorial/genética , Animais , Feminino , Genótipo , Homozigoto , Endogamia , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
8.
PLoS Genet ; 15(3): e1008035, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30893299

RESUMO

Evolutionary theory has produced two conflicting paradigms for the adaptation of a polygenic trait. While population genetics views adaptation as a sequence of selective sweeps at single loci underlying the trait, quantitative genetics posits a collective response, where phenotypic adaptation results from subtle allele frequency shifts at many loci. Yet, a synthesis of these views is largely missing and the population genetic factors that favor each scenario are not well understood. Here, we study the architecture of adaptation of a binary polygenic trait (such as resistance) with negative epistasis among the loci of its basis. The genetic structure of this trait allows for a full range of potential architectures of adaptation, ranging from sweeps to small frequency shifts. By combining computer simulations and a newly devised analytical framework based on Yule branching processes, we gain a detailed understanding of the adaptation dynamics for this trait. Our key analytical result is an expression for the joint distribution of mutant alleles at the end of the adaptive phase. This distribution characterizes the polygenic pattern of adaptation at the underlying genotype when phenotypic adaptation has been accomplished. We find that a single compound parameter, the population-scaled background mutation rate Θbg, explains the main differences among these patterns. For a focal locus, Θbg measures the mutation rate at all redundant loci in its genetic background that offer alternative ways for adaptation. For adaptation starting from mutation-selection-drift balance, we observe different patterns in three parameter regions. Adaptation proceeds by sweeps for small Θbg ≲ 0.1, while small polygenic allele frequency shifts require large Θbg ≳ 100. In the large intermediate regime, we observe a heterogeneous pattern of partial sweeps at several interacting loci.


Assuntos
Adaptação Fisiológica/genética , Herança Multifatorial/genética , Seleção Genética/genética , Aclimatação/genética , Alelos , Evolução Biológica , Biologia Computacional/métodos , Simulação por Computador , Evolução Molecular , Frequência do Gene/genética , Genética Populacional/métodos , Modelos Genéticos , Mutação , Taxa de Mutação , Fenótipo , Locos de Características Quantitativas/genética
10.
Curr Protoc Hum Genet ; 101(1): e83, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30849219

RESUMO

With the advent of Next Generation Sequencing (NGS) technologies, whole genome and whole exome DNA sequencing has become affordable for routine genetic studies. Coupled with improved genotyping arrays and genotype imputation methodologies, it is increasingly feasible to obtain rare genetic variant information in large datasets. Such datasets allow researchers to gain a more complete understanding of the genetic architecture of complex traits caused by rare variants. State-of-the-art statistical methods for the statistical genetics analysis of sequence-based association, including efficient algorithms for association analysis in biobank-scale datasets, gene-association tests, meta-analysis, fine mapping methods that integrate functional genomic dataset, and phenome-wide association studies (PheWAS), are reviewed here. These methods are expected to be highly useful for next generation statistical genetics analysis in the era of precision medicine. © 2019 by John Wiley & Sons, Inc.


Assuntos
Predisposição Genética para Doença , Genoma Humano/genética , Herança Multifatorial/genética , Algoritmos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Exoma/métodos , Sequenciamento Completo do Genoma/métodos
11.
Nat Genet ; 51(4): 584-591, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926966

RESUMO

Polygenic risk scores (PRS) are poised to improve biomedical outcomes via precision medicine. However, the major ethical and scientific challenge surrounding clinical implementation of PRS is that those available today are several times more accurate in individuals of European ancestry than other ancestries. This disparity is an inescapable consequence of Eurocentric biases in genome-wide association studies, thus highlighting that-unlike clinical biomarkers and prescription drugs, which may individually work better in some populations but do not ubiquitously perform far better in European populations-clinical uses of PRS today would systematically afford greater improvement for European-descent populations. Early diversifying efforts show promise in leveling this vast imbalance, even when non-European sample sizes are considerably smaller than the largest studies to date. To realize the full and equitable potential of PRS, greater diversity must be prioritized in genetic studies, and summary statistics must be publically disseminated to ensure that health disparities are not increased for those individuals already most underserved.


Assuntos
Predisposição Genética para Doença/genética , Herança Multifatorial/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Disparidades em Assistência à Saúde , Humanos , Medicina de Precisão/métodos , Fatores de Risco
12.
Nat Genet ; 51(3): 431-444, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804558

RESUMO

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Dinamarca , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Herança Multifatorial/genética , Fenótipo , Fatores de Risco
13.
Gene ; 696: 113-121, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30776462

RESUMO

Multiple-allele-inherited male sterility (MAMS) is important in Chinese cabbage (Brassica rapa L. ssp. pekinensis) breeding, but the molecular mechanisms leading to male sterility are poorly understood. In this study, we cloned a novel gene, BrSKS13, that is differentially expressed in fertile and sterile flower buds of Chinese cabbage. BrSKS13 is most similar to Arabidopsis thaliana AT3G13400 (SKS13) and encodes a predicted 61.87 kDa protein with three cupredoxin superfamily conserved domains in the multicopper oxidase family. Semi-quantitative reverse-transcription PCR (sqRT-PCR) showed that expression of BrSKS13 is higher in fertile buds than in sterile buds. Quantitative RT-PCR (qRT-PCR) and in situ hybridization showed that BrSKS13 is highly expressed in fertile anthers, peaking at pollen-maturation stage VI, but is weakly expressed in other tissues and floral organs. Expression patterns of BrSKS13 promoter::GUS reporter fusions in Arabidopsis showed that the BrSKS13 promoter drives expression of the GUS gene only in anthers. The relative expression of Brsks13 in fertile buds was higher than in sterile buds for all other MAMS lines of Chinese cabbage examined. These results suggest that BrSKS13 affects pollen development. In situ hybridization analysis of flower stigmas at different times after pollination showed that BrSKS13 expression was first observed in stigmas and immature seeds at 1 h after pollination, and the signal intensity in seeds increased with increasing maturity. Compared to Col-0, A. thaliana sks13 mutant plants have shorter and fewer siliques, shriveled pollen grains, pollen tube abnormalities, and reduced seed number. The phenotype of sks13 mutant was recovered by over-expressing BrSKS13. Our results suggest that BrSKS13 affects pollen development and the pollination/fertilization process, and will enable further study of the genetic mechanisms underlying MAMS in Chinese cabbage.


Assuntos
Brassica rapa/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica de Plantas/genética , Infertilidade das Plantas/genética , Proteínas de Plantas/genética , Polinização/genética , Alelos , Arabidopsis/genética , Brassica rapa/crescimento & desenvolvimento , Fertilização/genética , Perfilação da Expressão Gênica , Herança Multifatorial/genética , Plantas Geneticamente Modificadas , Pólen/crescimento & desenvolvimento
14.
Nat Genet ; 51(3): 445-451, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30643256

RESUMO

We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (Nobs = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores. Supporting transcriptome- and methylome-wide analyses (TWAS and MWAS, respectively) uncovered an additional 17 and 75 independent loci, respectively. Bioinformatic analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABAergic interneurons are enriched in their effect on the well-being spectrum.


Assuntos
Genoma Humano/genética , Encéfalo/fisiologia , Biologia Computacional/métodos , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Interneurônios/fisiologia , Herança Multifatorial/genética , Análise Multivariada , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Transcriptoma/genética
15.
Mol Genet Genomics ; 294(3): 563-571, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30635785

RESUMO

Growth is one of the most important traits from both a physiological and economic perspective in aquaculture species. Thus, identifying the genomic regions and genes underpinning genetic variation for this trait is of particular interest in several fish species, including rainbow trout. In this work, we perform a genome-wide association study (GWAS) to identify the genomic regions associated with body weight at tagging (BWT) and at 18 months (BW18M) using a dense SNP panel (57 k) and 4596 genotyped rainbow trout from 105 full-sib families belonging to a Chilean breeding population. Analysis was performed by means of single-step GBLUP approach. Genetic variance explained by 20 adjacent SNP windows across the whole genome is reported. To further explore candidate genes, we focused on windows that explained the highest proportion of genetic variance in the top 10 chromosomes for each trait. The main window from the top 10 chromosomes was explored by BLAST using the first and last SNP position of each window to determine the target nucleotide sequence. As expected, the percentage of genetic variance explained by windows was relatively low, due to the polygenic nature of body weight. The most important genomic region for BWT and BW18M were located on chromosomes 15 and 24 and they explained 2.14% and 3.02% of the genetic variance for each trait, respectively. Candidate genes including several growth factors, genes involved in development of skeletal muscle and bone tissue and nutrient metabolism were identified within the associated regions for both traits BWT and BW18M. These results indicate that body weight is polygenic in nature in rainbow trout, with the most important loci explaining as much as 3% of the genetic variance for the trait. The genes identified here represent good candidates for further functional validation to uncover biological mechanisms underlying variation for growth in rainbow trout.


Assuntos
Peso Corporal/genética , Proteínas de Peixes/genética , Estudo de Associação Genômica Ampla/métodos , Oncorhynchus mykiss/genética , Animais , Mapeamento Cromossômico , Proteínas de Peixes/metabolismo , Genômica/métodos , Genótipo , Herança Multifatorial/genética , Oncorhynchus mykiss/crescimento & desenvolvimento , Oncorhynchus mykiss/metabolismo , Polimorfismo de Nucleotídeo Único
16.
Hum Mol Genet ; 28(7): 1212-1224, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30624610

RESUMO

Interpretation of genetic association results is difficult because signals often lack biological context. To generate hypotheses of the functional genetic etiology of complex cardiometabolic traits, we estimated the genetically determined component of gene expression from common variants using PrediXcan (1) and determined genes with differential predicted expression by trait. PrediXcan imputes tissue-specific expression levels from genetic variation using variant-level effect on gene expression in transcriptome data. To explore the value of imputed genetically regulated gene expression (GReX) models across different ancestral populations, we evaluated imputed expression levels for predictive accuracy genome-wide in RNA sequence data in samples drawn from European-ancestry and African-ancestry populations and identified substantial predictive power using European-derived models in a non-European target population. We then tested the association of GReX on 15 cardiometabolic traits including blood lipid levels, body mass index, height, blood pressure, fasting glucose and insulin, RR interval, fibrinogen level, factor VII level and white blood cell and platelet counts in 15 755 individuals across three ancestry groups, resulting in 20 novel gene-phenotype associations reaching experiment-wide significance across ancestries. In addition, we identified 18 significant novel gene-phenotype associations in our ancestry-specific analyses. Top associations were assessed for additional support via query of S-PrediXcan (2) results derived from publicly available genome-wide association studies summary data. Collectively, these findings illustrate the utility of transcriptome-based imputation models for discovery of cardiometabolic effect genes in a diverse dataset.


Assuntos
Previsões/métodos , Metaboloma/genética , Metaboloma/fisiologia , Adulto , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Mapeamento Cromossômico/métodos , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética
17.
Brain ; 142(2): 460-470, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30689776

RESUMO

Mounting evidence indicates that the polygenic basis of late-onset Alzheimer's disease can be harnessed to identify individuals at greatest risk for cognitive decline. We have previously developed and validated a polygenic hazard score comprising of 31 single nucleotide polymorphisms for predicting Alzheimer's disease dementia age of onset. In this study, we examined whether polygenic hazard scores are associated with: (i) regional tracer uptake using amyloid PET; (ii) regional volume loss using longitudinal MRI; (iii) post-mortem regional amyloid-ß protein and tau associated neurofibrillary tangles; and (iv) four common non-Alzheimer's pathologies. Even after accounting for APOE, we found a strong association between polygenic hazard scores and amyloid PET standard uptake volume ratio with the largest effects within frontal cortical regions in 980 older individuals across the disease spectrum, and longitudinal MRI volume loss within the entorhinal cortex in 607 older individuals across the disease spectrum. We also found that higher polygenic hazard scores were associated with greater rates of cognitive and clinical decline in 632 non-demented older individuals, even after controlling for APOE status, frontal amyloid PET and entorhinal cortex volume. In addition, the combined model that included polygenic hazard scores, frontal amyloid PET and entorhinal cortex volume resulted in a better fit compared to a model with only imaging markers. Neuropathologically, we found that polygenic hazard scores were associated with regional post-mortem amyloid load and neuronal neurofibrillary tangles, even after accounting for APOE, validating our imaging findings. Lastly, polygenic hazard scores were associated with Lewy body and cerebrovascular pathology. Beyond APOE, we show that in living subjects, polygenic hazard scores were associated with amyloid deposition and neurodegeneration in susceptible brain regions. Polygenic hazard scores may also be useful for the identification of individuals at the highest risk for developing multi-aetiological dementia.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Herança Multifatorial/genética , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/genética
18.
Brain ; 142(2): 471-485, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535067

RESUMO

Cognitive deficit is thought to represent, at least in part, genetic mechanisms of risk for schizophrenia, with recent evidence from statistical modelling of twin data suggesting direct causality from the former to the latter. However, earlier evidence was based on inferences from twin not molecular genetic data and it is unclear how much genetic influence 'passes through' cognition on the way to diagnosis. Thus, we included direct measurements of genetic risk (e.g. schizophrenia polygenic risk scores) in causation models to assess the extent to which cognitive deficit mediates some of the effect of polygenic risk scores on the disorder. Causal models of family data tested relationships among key variables and allowed parsing of genetic variance components. Polygenic risk scores were calculated from summary statistics from the current largest genome-wide association study of schizophrenia and were represented as a latent trait. Cognition was also modelled as a latent trait. Participants were 1313 members of 1078 families: 416 patients with schizophrenia, 290 unaffected siblings, and 607 controls. Modelling supported earlier findings that cognitive deficit has a putatively causal role in schizophrenia. In total, polygenic risk score explained 8.07% [confidence interval (CI) 5.45-10.74%] of schizophrenia risk in our sample. Of this, more than a third (2.71%, CI 2.41-3.85%) of the polygenic risk score influence was mediated through cognition paths, exceeding the direct influence of polygenic risk score on schizophrenia risk (1.43%, CI 0.46-3.08%). The remainder of the polygenic risk score influence (3.93%, CI 2.37-4.48%) reflected reciprocal causation between schizophrenia liability and cognition (e.g. mutual influences in a cyclical manner). Analysis of genetic variance components of schizophrenia liability indicated that 26.87% (CI 21.45-32.57%) was associated with cognition-related pathways not captured by polygenic risk score. The remaining variance in schizophrenia was through pathways other than cognition-related and polygenic risk score. Although our results are based on inference through statistical modelling and do not provide an absolute proof of causality, we find that cognition pathways mediate a significant part of the influence of cumulative genetic risk on schizophrenia. We estimate from our model that 33.51% (CI 27.34-43.82%) of overall genetic risk is mediated through influences on cognition, but this requires further studies and analyses as the genetics of schizophrenia becomes better characterized.


Assuntos
Cognição/fisiologia , Predisposição Genética para Doença/genética , Herança Multifatorial/genética , Esquizofrenia/genética , Transdução de Sinais/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Esquizofrenia/diagnóstico , Adulto Jovem
19.
Artigo em Inglês | MEDLINE | ID: mdl-30559312

RESUMO

Over the past decade, a focus on de novo mutations has rapidly accelerated gene discovery in autism spectrum disorder (ASD), intellectual disability (ID), and other neurodevelopmental disorders (NDDs). However, recent studies suggest that only a minority of cases are attributable to de novo mutations, and instead these disorders often result from an accumulation of various forms of genetic risk. Consequently, we adopted an inclusive approach to investigate the genetic risk contributing to a case of male monozygotic twins with ASD and ID. At the time of the study, the probands were 7 yr old and largely nonverbal. Medical records indicated a history of motor delays, sleep difficulties, and significant cognitive deficits. Through whole-genome sequencing of the probands and their parents, we uncovered elevated common polygenic risk, a coding de novo point mutation in CENPE, an ultra-rare homozygous regulatory variant in ANK3, inherited rare variants in NRXN3, and a maternally inherited X-linked deletion situated in a noncoding regulatory region between ZNF81 and ZNF182 Although each of these genes has been directly or indirectly associated with NDDs, evidence suggests that no single variant adequately explains the probands' phenotype. Instead, we propose that the probands' condition is due to the confluence of multiple rare variants in the context of a high-risk genetic background. This case emphasizes the multifactorial nature of genetic risk underlying most instances of NDDs and aligns with the "female protective model" of ASD.


Assuntos
Transtorno Autístico/genética , Deficiência Intelectual/genética , Adulto , Anquirinas/genética , Transtorno do Espectro Autista/genética , Criança , Proteínas Cromossômicas não Histona/genética , Família , Feminino , Genes Ligados ao Cromossomo X , Predisposição Genética para Doença/genética , Humanos , Masculino , Herança Multifatorial/genética , Mutação , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Fatores de Risco , Gêmeos Monozigóticos , Sequenciamento Completo do Genoma/métodos
20.
Genet Epidemiol ; 42(7): 636-647, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30156736

RESUMO

Complex traits can share a substantial proportion of their polygenic heritability. However, genome-wide polygenic correlations between pairs of traits can mask heterogeneity in their shared polygenic effects across loci. We propose a novel method (weighted maximum likelihood-regional polygenic correlation [RPC]) to evaluate polygenic correlation between two complex traits in small genomic regions using summary association statistics. Our method tests for evidence that the polygenic effect at a given region affects two traits concurrently. We show through simulations that our method is well calibrated, powerful, and more robust to misspecification of linkage disequilibrium than other methods under a polygenic model. As small genomic regions are more likely to harbor specific genetic effects, our method is ideal to identify heterogeneity in shared polygenic correlation across regions. We illustrate the usefulness of our method by addressing two questions related to cardiometabolic traits. First, we explored how RPC can inform on the strong epidemiological association between high-density lipoprotein cholesterol and coronary artery disease (CAD), suggesting a key role for triglycerides metabolism. Second, we investigated the potential role of PPARγ activators in the prevention of CAD. Our results provide a compelling argument that shared heritability between complex traits is highly heterogeneous across loci.


Assuntos
Desequilíbrio de Ligação/genética , Herança Multifatorial/genética , HDL-Colesterol/genética , Simulação por Computador , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Loci Gênicos , Genoma Humano , Estudo de Associação Genômica Ampla , Haplótipos/genética , Humanos , Modelos Genéticos , PPAR gama/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Tiazolidinedionas/uso terapêutico
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