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1.
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
2.
Lancet Oncol ; 21(10): 1378-1386, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002439

RESUMO

BACKGROUND: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. METHODS: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10-4 p=5 × 10-5 p=5 × 10-6 p=5 × 10-7, and p=5 × 10-8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. FINDINGS: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10-5) showed the strongest association with gastric cancer risk (p=7·56 × 10-10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (ptrend<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10-4) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (ptrend<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56). INTERPRETATION: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.


Assuntos
Predisposição Genética para Doença/genética , Estilo de Vida Saudável , Neoplasias Gástricas/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , China/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/psicologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/psicologia
3.
PLoS One ; 15(9): e0239144, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32946477

RESUMO

In genome-wide association studies (GWAS), a wide variety of analysis tools have been designed, leading to various formats of GWAS data. How to convert a dataset in non-PLINK format into PLINK format to use its powerful analysis performance, or to convert a dataset in PLINK format into the format of other analysis tools, is a problem that needs to be faced and solved. To address this issue, we developed a tool called coPLINK, a complementary tool to PLINK, to cooperate with PLINK to implement the conversions of GWAS data formats and to provide some additional functions, such as data files comparison. The tool can implement mutual conversions not only between an existing data format and PLINK PED/BED, but also between a user-defined data format and PLINK PED. The usage and performance of the tool are similar to PLINK. The characteristics of the conversions of existing data formats and user-defined formats make it be a good assistant to PLINK or other tools and, have good potential for GWAS studies or other works.


Assuntos
Biologia Computacional/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Técnicas de Genotipagem/métodos , Software , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Interpretação Estatística de Dados , Conjuntos de Dados como Assunto , Estudos de Viabilidade , Técnicas de Genotipagem/estatística & dados numéricos , Humanos , Polimorfismo de Nucleotídeo Único
4.
Nat Commun ; 11(1): 3861, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737316

RESUMO

Integrating results from genome-wide association studies (GWASs) and gene expression studies through transcriptome-wide association study (TWAS) has the potential to shed light on the causal molecular mechanisms underlying disease etiology. Here, we present a probabilistic Mendelian randomization (MR) method, PMR-Egger, for TWAS applications. PMR-Egger relies on a MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and is scalable to hundreds of thousands of individuals. In simulations, PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust under various types of model misspecifications, is more powerful than existing TWAS/MR approaches, and can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank.


Assuntos
Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Análise da Randomização Mendeliana/estatística & dados numéricos , Modelos Genéticos , Transcriptoma , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Simulação por Computador , Bases de Dados Factuais , Gastroenteropatias/diagnóstico , Gastroenteropatias/genética , Gastroenteropatias/patologia , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Funções Verossimilhança , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Herança Multifatorial , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia
5.
PLoS One ; 15(8): e0237657, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817676

RESUMO

The majority of genome-wide association studies (GWAS) loci are not annotated to known genes in the human genome, which renders biological interpretations difficult. Transcriptome-wide association studies (TWAS) associate complex traits with genotype-based prediction of gene expression deriving from expression quantitative loci(eQTL) studies, thus improving the interpretability of GWAS findings. However, these results can sometimes suffer from a high false positive rate, because predicted expression of different genes may be highly correlated due to linkage disequilibrium between eQTL. We propose a novel statistical method, Gene Score Regression (GSR), to detect causal gene sets for complex traits while accounting for gene-to-gene correlations. We consider non-causal genes that are highly correlated with the causal genes will also exhibit a high marginal association with the complex trait. Consequently, by regressing on the marginal associations of complex traits with the sum of the gene-to-gene correlations in each gene set, we can assess the amount of variance of the complex traits explained by the predicted expression of the genes in each gene set and identify plausible causal gene sets. GSR can operate either on GWAS summary statistics or observed gene expression. Therefore, it may be widely applied to annotate GWAS results and identify the underlying biological pathways. We demonstrate the high accuracy and computational efficiency of GSR compared to state-of-the-art methods through simulations and real data applications. GSR is openly available at https://github.com/li-lab-mcgill/GSR.


Assuntos
Estudo de Associação Genômica Ampla/estatística & dados numéricos , Anotação de Sequência Molecular , Herança Multifatorial/genética , Transcriptoma/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Genoma Humano/genética , Genótipo , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas
6.
PLoS Genet ; 16(6): e1008855, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32542026

RESUMO

Traditional univariate genome-wide association studies generate false positives and negatives due to difficulties distinguishing associated variants from variants with spurious nonzero effects that do not directly influence the trait. Recent efforts have been directed at identifying genes or signaling pathways enriched for mutations in quantitative traits or case-control studies, but these can be computationally costly and hampered by strict model assumptions. Here, we present gene-ε, a new approach for identifying statistical associations between sets of variants and quantitative traits. Our key insight is that enrichment studies on the gene-level are improved when we reformulate the genome-wide SNP-level null hypothesis to identify spurious small-to-intermediate SNP effects and classify them as non-causal. gene-ε efficiently identifies enriched genes under a variety of simulated genetic architectures, achieving greater than a 90% true positive rate at 1% false positive rate for polygenic traits. Lastly, we apply gene-ε to summary statistics derived from six quantitative traits using European-ancestry individuals in the UK Biobank, and identify enriched genes that are in biologically relevant pathways.


Assuntos
Estudo de Associação Genômica Ampla/estatística & dados numéricos , Modelos Genéticos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Interpretação Estatística de Dados , Bases de Dados Genéticas/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Reino Unido
7.
Nat Genet ; 52(6): 626-633, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424349

RESUMO

Disease variants identified by genome-wide association studies (GWAS) tend to overlap with expression quantitative trait loci (eQTLs), but it remains unclear whether this overlap is driven by gene expression levels 'mediating' genetic effects on disease. Here, we introduce a new method, mediated expression score regression (MESC), to estimate disease heritability mediated by the cis genetic component of gene expression levels. We applied MESC to GWAS summary statistics for 42 traits (average N = 323,000) and cis-eQTL summary statistics for 48 tissues from the Genotype-Tissue Expression (GTEx) consortium. Averaging across traits, only 11 ± 2% of heritability was mediated by assayed gene expression levels. Expression-mediated heritability was enriched in genes with evidence of selective constraint and genes with disease-appropriate annotations. Our results demonstrate that assayed bulk tissue eQTLs, although disease relevant, cannot explain the majority of disease heritability.


Assuntos
Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Locos de Características Quantitativas , Calibragem , Estudo de Associação Genômica Ampla/métodos , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Análise de Regressão
8.
PLoS Genet ; 16(5): e1008747, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32407400

RESUMO

Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during pregnancy. Data included 1,849 pregnant women from four race/ethnic groups recruited through the NICHD Fetal Growth Studies. We identified a novel genome-wide significant association of rs746039 [G] (ITPR1) with reduced fetal weight from 24 to 33 weeks gestation (P<5x10-8; log10BF>6). Additional tests revealed that the SNP was associated with head circumference (P = 4.85x10-8), but not with abdominal circumference or humerus/femur lengths. Conditional analysis in an independent sample of mother-offspring pairs replicated the findings and showed that the effect was more likely maternal but not fetal. Trans-ethnic approaches successfully narrowed down the haplotype block that contained the 99% credible set of SNPs associated with head circumference. We further demonstrated that decreased placental expression of ITPR1 was correlated with increased placental epigenetic age acceleration, a risk factor for reduced fetal growth, among male fetuses (r = -0.4, P = 0.01). Finally, genetic risk score composed of known maternal SNPs implicated in birthweight among Europeans was associated with fetal weight from mid-gestation onwards among Whites only. The present study sheds new light on the role of common maternal genetic variants in the inositol receptor signaling pathway on fetal growth from late second trimester to early third trimester. Clinical Trial Registration: ClinicalTrials.gov, NCT00912132.


Assuntos
Grupos Étnicos/genética , Grupos Étnicos/estatística & dados numéricos , Desenvolvimento Fetal/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Receptores de Inositol 1,4,5-Trifosfato/genética , Gravidez , Adulto , Comparação Transcultural , Feminino , Peso Fetal/etnologia , Peso Fetal/genética , Loci Gênicos , Estudo de Associação Genômica Ampla/métodos , Idade Gestacional , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez/etnologia , Gravidez/genética , Gravidez/estatística & dados numéricos , Adulto Jovem
9.
PLoS Genet ; 16(5): e1008766, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32365090

RESUMO

Complex traits are known to be influenced by a combination of environmental factors and rare and common genetic variants. However, detection of such multivariate associations can be compromised by low statistical power and confounding by population structure. Linear mixed effects models (LMM) can account for correlations due to relatedness but have not been applicable in high-dimensional (HD) settings where the number of fixed effect predictors greatly exceeds the number of samples. False positives or false negatives can result from two-stage approaches, where the residuals estimated from a null model adjusted for the subjects' relationship structure are subsequently used as the response in a standard penalized regression model. To overcome these challenges, we develop a general penalized LMM with a single random effect called ggmix for simultaneous SNP selection and adjustment for population structure in high dimensional prediction models. We develop a blockwise coordinate descent algorithm with automatic tuning parameter selection which is highly scalable, computationally efficient and has theoretical guarantees of convergence. Through simulations and three real data examples, we show that ggmix leads to more parsimonious models compared to the two-stage approach or principal component adjustment with better prediction accuracy. Our method performs well even in the presence of highly correlated markers, and when the causal SNPs are included in the kinship matrix. ggmix can be used to construct polygenic risk scores and select instrumental variables in Mendelian randomization studies. Our algorithms are available in an R package available on CRAN (https://cran.r-project.org/package=ggmix).


Assuntos
Algoritmos , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Animais , Simulação por Computador , Cruzamentos Genéticos , Genética Populacional/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Leishmania tropica/genética , Leishmaniose Cutânea/genética , Modelos Lineares , Camundongos , Camundongos Endogâmicos , Herança Multifatorial/genética , Mycobacterium bovis , Dinâmica Populacional , Tamanho da Amostra , Software , Tuberculose/genética , Tuberculose/patologia
10.
PLoS Genet ; 16(5): e1008749, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453742

RESUMO

Indonesia is the world's fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10.55% of tested genes are differentially expressed between the islands of Sumba and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.80% of genes correlating with nearby promoter CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia's tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by fine-scale environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.


Assuntos
Metilação de DNA , Grupos Étnicos/genética , Interação Gene-Ambiente , Transcriptoma , Ilhas de CpG , Meio Ambiente , Epigênese Genética/fisiologia , Grupos Étnicos/estatística & dados numéricos , Perfilação da Expressão Gênica/estatística & dados numéricos , Genética Populacional , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genômica/métodos , Humanos , Indonésia/epidemiologia , Ilhas/epidemiologia , Ilhas do Pacífico/epidemiologia , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA-Seq
11.
PLoS Genet ; 16(5): e1008612, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32427991

RESUMO

Estimating the polygenicity (proportion of causally associated single nucleotide polymorphisms (SNPs)) and discoverability (effect size variance) of causal SNPs for human traits is currently of considerable interest. SNP-heritability is proportional to the product of these quantities. We present a basic model, using detailed linkage disequilibrium structure from a reference panel of 11 million SNPs, to estimate these quantities from genome-wide association studies (GWAS) summary statistics. We apply the model to diverse phenotypes and validate the implementation with simulations. We find model polygenicities (as a fraction of the reference panel) ranging from ≃ 2 × 10-5 to ≃ 4 × 10-3, with discoverabilities similarly ranging over two orders of magnitude. A power analysis allows us to estimate the proportions of phenotypic variance explained additively by causal SNPs reaching genome-wide significance at current sample sizes, and map out sample sizes required to explain larger portions of additive SNP heritability. The model also allows for estimating residual inflation (or deflation from over-correcting of z-scores), and assessing compatibility of replication and discovery GWAS summary statistics.


Assuntos
Estudos de Associação Genética , Heterogeneidade Genética , Padrões de Herança/fisiologia , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Simulação por Computador , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Genética Populacional , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Heterozigoto , Humanos , Desequilíbrio de Ligação , Herança Multifatorial , Distribuição Normal , Fenótipo , Característica Quantitativa Herdável
12.
Sci Rep ; 10(1): 7879, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398702

RESUMO

Large genome-wide association studies (GWAS) have increased our knowledge of the genetic risk factors of rheumatoid arthritis (RA). However, little is known about genetic susceptibility in populations with a large admixture of Amerindian ancestry. The aim of the present study was to test the generalizability of previously reported RA loci in a Latin American (LA) population with admixed ancestry. We selected 128 single nucleotide polymorphisms (SNPs) in linkage equilibrium, with high association to RA in multiple populations of non-Amerindian origin. Genotyping of 118 SNPs was performed in 313 RA patients/487 healthy control subjects by mid-density arrays of polymerase chain reaction (PCR). Some of the identified associations were validated in an additional cohort (250 cases/290 controls). One marker, the SNP rs2451258, located upstream of T Cell Activation RhoGTPase Activating Protein (TAGAP) gene, showed significant association with RA (p = 5 × 10-3), whereas 18 markers exhibited suggestive associations (p < 0.05). Haplotype testing showed association of some groups of adjacent SNPs around the signal transducer and activator of transcription 4 (STAT4) gene (p = 9.82 × 10-3 to 2.04 × 10-3) with RA. Our major finding was little replication of previously reported genetic associations with RA. These results suggest that performing GWAS and admixture mapping in LA populations has the potential to reveal novel loci associated with RA. This in turn might help to gain insight into the 'pathogenomics' of this disease and to explore trans-population differences for RA in general.


Assuntos
Artrite Reumatoide/genética , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Artrite Reumatoide/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Estudos de Associação Genética/estatística & dados numéricos , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genótipo , Humanos , América Latina , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
PLoS Genet ; 16(5): e1008619, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32369493

RESUMO

Coalescent simulations are widely used to examine the effects of evolution and demographic history on the genetic makeup of populations. Thanks to recent progress in algorithms and data structures, simulators such as the widely-used msprime now provide genome-wide simulations for millions of individuals. However, this software relies on classic coalescent theory and its assumptions that sample sizes are small and that the region being simulated is short. Here we show that coalescent simulations of long regions of the genome exhibit large biases in identity-by-descent (IBD), long-range linkage disequilibrium (LD), and ancestry patterns, particularly when the sample size is large. We present a Wright-Fisher extension to msprime, and show that it produces more realistic distributions of IBD, LD, and ancestry proportions, while also addressing more subtle biases of the coalescent. Further, these extensions are more computationally efficient than state-of-the-art coalescent simulations when simulating long regions, including whole-genome data. For shorter regions, efficiency can be maintained via a hybrid model which simulates the recent past under the Wright-Fisher model and uses coalescent simulations in the distant past.


Assuntos
Algoritmos , Sequência de Bases/fisiologia , Genética Populacional/métodos , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Estudos de Coortes , Simulação por Computador , Evolução Molecular , Genoma/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Desequilíbrio de Ligação , Recombinação Genética/fisiologia , Tamanho da Amostra
14.
Nat Med ; 26(4): 542-548, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32251405

RESUMO

While polygenic risk scores (PRSs) are poised to be translated into clinical practice through prediction of inborn health risks1, a strategy to utilize genetics to prioritize modifiable risk factors driving heath outcome is warranted2. To this end, we investigated the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (ntotal = 675,898; BioBank Japan (n = 179,066), UK Biobank (n = 361,194) and FinnGen (n = 135,638)). In contrast to observational studies, in which discerning the cause-and-effect can be difficult, PRSs could help to identify the driver biomarkers affecting human lifespan. A high systolic blood pressure PRS was trans-ethnically associated with a shorter lifespan (hazard ratio = 1.03[1.02-1.04], Pmeta = 3.9 × 10-13) and parental lifespan (hazard ratio = 1.06[1.06-1.07], P = 2.0 × 10-86). The obesity PRS showed distinct effects on lifespan in Japanese and European individuals (Pheterogeneity = 9.5 × 10-8 for BMI). The causal effect of blood pressure and obesity on lifespan was further supported by Mendelian randomization studies. Beyond genotype-phenotype associations, our trans-biobank study offers a new value of PRSs in prioritization of risk factors that could be potential targets of medical treatment to improve population health.


Assuntos
Bancos de Espécimes Biológicos/estatística & dados numéricos , Marcadores Genéticos , Estudo de Associação Genômica Ampla/métodos , Longevidade/genética , Herança Multifatorial/genética , Adulto , Fatores Etários , Idoso , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Finlândia/epidemiologia , Marcadores Genéticos/genética , Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Hipertensão/genética , Hipertensão/mortalidade , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/mortalidade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Reino Unido/epidemiologia
15.
Med Sci (Paris) ; 36(2): 181-184, 2020 Feb.
Artigo em Francês | MEDLINE | ID: mdl-32129759

RESUMO

Evidence for a "homosexuality gene" was claimed in the early 1990's on the basis of linkage studies that, by current criteria, were woefully underpowered. Indeed, follow up studies gave contradictory results. Genome-wide association studies, and very large databases with detailed genetic and phenotypic data, have made possible a re-examination of this issue. While modest heritability (ca. 0.3) for homosexuality is confirmed, no major locus is found and the genetic influence appears extremely polygenic. Thus, there is no single gene, or even small set of genes, that have a strong influence on homosexuality.


Assuntos
Marcadores Genéticos , Homossexualidade/fisiologia , Padrões de Herança/genética , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla/história , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Estudo de Associação Genômica Ampla/tendências , História do Século XX , História do Século XXI , Homossexualidade/estatística & dados numéricos , Humanos , Masculino , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Prevalência
16.
Clin Interv Aging ; 15: 185-193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32103921

RESUMO

Background: Alzheimer's disease is a devastating neurodegenerative disorder. Its worldwide prevalence is over 24 million and is expected to double by 2040. Finding ways to prevent its cognitive decline is urgent. Methods: A two-sample Mendelian randomization study was performed instrumenting glutamine, which is abundant in blood, capable of crossing the blood-brain barrier, and involved in a metabolic cycle with glutamate in the brain. Results: The results reveal a protective effect of circulating glutamine against Alzheimer's disease (inverse-variance weighted method, odds ratio per 1-standard deviation increase in circulating glutamine = 0.83; 95% CI 0.71, 0.97; P = 0.02). Conclusion: These findings lend credence to the emerging story supporting the modifiability of glutamine/glutamate metabolism for the prevention of cognitive decline. More circulating glutamine might mean that more substrate is available during times of stress, acting as a neuroprotectant. Modifications to exogenous glutamine may be worth exploring in future efforts to prevent and/or treat Alzheimer's disease.


Assuntos
Doença de Alzheimer , Barreira Hematoencefálica/fisiologia , Encéfalo/metabolismo , Disfunção Cognitiva/prevenção & controle , Glutamina , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/metabolismo , Cognição/fisiologia , Feminino , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Glutamina/sangue , Glutamina/genética , Glutamina/metabolismo , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Fármacos Neuroprotetores/metabolismo , Receptores de Glutamato/metabolismo
17.
BMC Med Genet ; 21(1): 40, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093658

RESUMO

BACKGROUND: Sarcopenia is a skeletal muscle disease of clinical importance that occurs commonly in old age and in various disease sub-categories. Widening the scope of knowledge of the genetics of muscle mass and strength is important because it may allow to identify patients with an increased risk to develop a specific musculoskeletal disease or condition such as sarcopenia based on genetic markers. METHODS: We used bioinformatics tools to identify gene loci responsible for regulating muscle strength and lean mass, which can then be a target for downstream lab experimentation validation. Single nuclear polymorphisms (SNPs) associated with various disease traits of muscles and specific genes were chosen according to their muscle phenotype association p-value, as traditionally done in Genome Wide Association Studies, GWAS. We've developed and applied a combination of expression quantitative trait loci (eQTLs) and GWAS summary information, to prioritize causative SNP and point out the unique genes associated in the tissues of interest (muscle). RESULTS: We found NUDT3 and KLF5 for lean mass and HLA-DQB1-AS1 for hand grip strength as candidate genes to target for these phenotypes. The associated regulatory SNPs are rs464553, rs1028883 and rs3129753 respectively. CONCLUSION: Transcriptome Wide Association Studies, TWAS, approaches of combining GWAS and eQTL summary statistics proved helpful in statistically prioritizing genes and their associated SNPs for the disease phenotype of study, in this case, Sarcopenia. Potentially regulatory SNPs associated with these genes, and the genes further prioritized by a scoring system, can be then wet lab verified, depending on the phenotype it is hypothesized to affect.


Assuntos
Hidrolases Anidrido Ácido/genética , Força da Mão , Fatores de Transcrição Kruppel-Like/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Sarcopenia/genética , Magreza/genética , Composição Corporal/genética , Perfilação da Expressão Gênica , Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Cadeias beta de HLA-DQ/genética , Humanos , Desequilíbrio de Ligação , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/metabolismo , Tamanho do Órgão/genética , Fenótipo , Locos de Características Quantitativas , Projetos de Pesquisa , Sarcopenia/complicações , Sarcopenia/epidemiologia , Magreza/complicações , Magreza/epidemiologia
18.
J Atheroscler Thromb ; 27(1): 71-99, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31142690

RESUMO

AIM: Studies have suggested that genetic and environmental factors do not account for all risks and mechanisms of intracranial atherosclerotic stenosis (ICAS). DNA methylation may play a role in the progression of ICAS. METHODS: DNA methylation profiles of peripheral blood leucocytes from 7 patients with early-onset ICAS and 7 perfectly matched controls were interrogated for the first time using the Illumina Infinium Human MethylationEPIC BeadChip. Afterward, functional analysis for differentially methylated genes was conducted. In addition, pyrosequencing verification was performed in an independent cohort comprising 21 patients with early-onset ICAS and 21 age- and gender-matched controls. RESULTS: A total of 318 cytosine-phosphate-guanine sites were found to be differentially methylated based on the established standards. Functional analysis annotated differentially methylated sites to atherosclerosis-related processes and pathways, such as the negative regulation of hydrolase activity (GO 0051346), type II diabetes mellitus (KEGG hsa04930), and the insulin signaling pathway (KEGG hsa04910). In addition, a differentially methylated site was also validated, cg22443212 in gene Rnf213, which showed significant hypermethylation in patients with early-onset ICAS compared with controls 59.56% (49.77%, 88.55%) vs. 44.65% (25.07%, 53.21%), respectively; P=0.010). Receiver operating characteristic curve analysis showed that the area under the curve value of cg22443212 was 0.744 (95% confidence interval, 0.586-0.866; P=0.002). CONCLUSIONS: We revealed that altered DNA methylation may play a role in the occurrence and development of ICAS. These results provided new epigenetic insights into ICAS.


Assuntos
Ilhas de CpG/genética , Metilação de DNA/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Arteriosclerose Intracraniana , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
J Steroid Biochem Mol Biol ; 196: 105516, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31678109

RESUMO

Vitamin D deficiency is a public health concern associated with, but not limited to, skeletal anomalies, chronic diseases, immune conditions, and cancer, among others. Hypovitaminosis D is mainly associated with environmental and lifestyle factors that affect sunlight exposure. However, genetic factors also influence 25-hydroxyvitamin D (25[OH]D) serum concentration. Although there is available information of genes with clear biological relevance or markers identified by Genome-Wide Association Studies, an overall view and screening tool to identify known genetic causes of altered serum levels of 25(OH)D is lacking. Moreover, there are no studies including the total genetic evidence associated with abnormal serum concentration of 25(OH)D. Therefore, we conducted a de-novo systematic literature review to propose a set of genes comprehensive of all genetic variants reported to be associated with deficiency of vitamin D. Abstracts retrieved from PubMed search were organized by gene and curated one-by-one using the PubTerm web tool. The genes identified were classified according to the type of genetic evidence associated with serum 25(OH)D levels and were also compared with the few commonly screened genes related to vitamin D status. This strategy allowed the identification of 35 genes associated with serum 25(OH)D concentrations, 27 (75%) of which are not commercially available and are not, therefore, analyzed in clinical practice for genetic counseling, nor are they sufficiently studied for research purposes. Functional analysis of the genes identified confirmed their role in vitamin D pathways and diseases. Thus, the list of genes is an important source to understand the genetic determinants of 25(OH)D levels. To further support our findings, we provide a map of the reported functional variants and SNPs not included in ClinVar, minor allelic frequencies, SNP effect sizes, associated diseases, and an integrated overview of the biological role of the genes. In conclusion, we identified a comprehensive candidate list of genes associated with serum 25(OH)D concentrations, most of which are not commercially available, but would prove of importance in clinical practice in screening for patients that should respond to supplementation because of alterations in absorption, patients that would have little benefit because alterations in the downstream metabolism of vitamin D, and to study non-responsiveness to supplementation with vitamin D.


Assuntos
Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Redes e Vias Metabólicas/genética , Deficiência de Vitamina D/genética , Vitamina D/metabolismo , Bases de Dados Genéticas/estatística & dados numéricos , Estudos de Associação Genética/métodos , Genética Populacional , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Polimorfismo de Nucleotídeo Único , Vitamina D/administração & dosagem , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/epidemiologia
20.
Nat Genet ; 51(12): 1749-1755, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768069

RESUMO

The genome-wide association study (GWAS) has been widely used as an experimental design to detect associations between genetic variants and a phenotype. Two major confounding factors, population stratification and relatedness, could potentially lead to inflated GWAS test statistics and hence to spurious associations. Mixed linear model (MLM)-based approaches can be used to account for sample structure. However, genome-wide association (GWA) analyses in biobank samples such as the UK Biobank (UKB) often exceed the capability of most existing MLM-based tools especially if the number of traits is large. Here, we develop an MLM-based tool (fastGWA) that controls for population stratification by principal components and for relatedness by a sparse genetic relationship matrix for GWA analyses of biobank-scale data. We demonstrate by extensive simulations that fastGWA is reliable, robust and highly resource-efficient. We then apply fastGWA to 2,173 traits on array-genotyped and imputed samples from 456,422 individuals and to 2,048 traits on whole-exome-sequenced samples from 46,191 individuals in the UKB.


Assuntos
Estudo de Associação Genômica Ampla/estatística & dados numéricos , Modelos Lineares , Bancos de Espécimes Biológicos , Índice de Massa Corporal , Interpretação Estatística de Dados , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Software , Reino Unido , Sequenciamento Completo do Exoma
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