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1.
PLoS Genet ; 16(9): e1008780, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925905

RESUMO

Genome-Wide Association Studies (GWAS) in large human cohorts have identified thousands of loci associated with complex traits and diseases. For identifying the genes and gene-associated variants that underlie complex traits in livestock, especially where sample sizes are limiting, it may help to integrate the results of GWAS for equivalent traits in humans as prior information. In this study, we sought to investigate the usefulness of results from a GWAS on human height as prior information for identifying the genes and gene-associated variants that affect stature in cattle, using GWAS summary data on samples sizes of 700,000 and 58,265 for humans and cattle, respectively. Using Fisher's exact test, we observed a significant proportion of cattle stature-associated genes (30/77) that are also associated with human height (odds ratio = 5.1, p = 3.1e-10). Result of randomized sampling tests showed that cattle orthologs of human height-associated genes, hereafter referred to as candidate genes (C-genes), were more enriched for cattle stature GWAS signals than random samples of genes in the cattle genome (p = 0.01). Randomly sampled SNPs within the C-genes also tend to explain more genetic variance for cattle stature (up to 13.2%) than randomly sampled SNPs within random cattle genes (p = 0.09). The most significant SNPs from a cattle GWAS for stature within the C-genes did not explain more genetic variance for cattle stature than the most significant SNPs within random cattle genes (p = 0.87). Altogether, our findings support previous studies that suggest a similarity in the genetic regulation of height across mammalian species. However, with the availability of a powerful GWAS for stature that combined data from 8 cattle breeds, prior information from human-height GWAS does not seem to provide any additional benefit with respect to the identification of genes and gene-associated variants that affect stature in cattle.


Assuntos
Estatura/genética , Bovinos/genética , Estudo de Associação Genômica Ampla/métodos , Animais , Cruzamento/métodos , Bases de Dados Genéticas , Variação Genética/genética , Humanos , Gado/genética , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
2.
Genet Sel Evol ; 52(1): 51, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32842956

RESUMO

BACKGROUND: Temperament traits are of high importance across species. In humans, temperament or personality traits correlate with psychological traits and psychiatric disorders. In cattle, they impact animal welfare, product quality and human safety, and are therefore of direct commercial importance. We hypothesized that genetic factors that contribute to variation in temperament among individuals within a species will be shared between humans and cattle. Using imputed whole-genome sequence data from 9223 beef cattle from three cohorts, a series of genome-wide association studies was undertaken on cattle flight time, a temperament phenotype measured as the time taken for an animal to cover a short-fixed distance after release from an enclosure. We also investigated the association of cattle temperament with polymorphisms in bovine orthologs of risk genes for neuroticism, schizophrenia, autism spectrum disorders (ASD), and developmental delay disorders in humans. RESULTS: Variants with the strongest associations were located in the bovine orthologous region that is involved in several behavioural and cognitive disorders in humans. These variants were also partially validated in independent cattle cohorts. Genes in these regions (BARHL2, NDN, SNRPN, MAGEL2, ABCA12, KIFAP3, TOPAZ1, FZD3, UBE3A, and GABRA5) were enriched for the GO term neuron migration and were differentially expressed in brain and pituitary tissues in humans. Moreover, variants within 100 kb of ASD susceptibility genes were associated with cattle temperament and explained 6.5% of the total additive genetic variance in the largest cattle cohort. The ASD genes with the most significant associations were GABRB3 and CUL3. Using the same 100 kb window, a weak association was found with polymorphisms in schizophrenia risk genes and no association with polymorphisms in neuroticism and developmental delay disorders risk genes. CONCLUSIONS: Our analysis showed that genes identified in a meta-analysis of cattle temperament contribute to neuron development functions and are differentially expressed in human brain tissues. Furthermore, some ASD susceptibility genes are associated with cattle temperament. These findings provide evidence that genetic control of temperament might be shared between humans and cattle and highlight the potential for future analyses to leverage results between species.

3.
Genet Sel Evol ; 52(1): 28, 2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32460805

RESUMO

BACKGROUND: In tropically-adapted beef heifers, application of genomic prediction for age at puberty has been limited due to low prediction accuracies. Our aim was to investigate novel methods of pre-selecting whole-genome sequence (WGS) variants and alternative analysis methodologies; including genomic best linear unbiased prediction (GBLUP) with multiple genomic relationship matrices (MGRM) and Bayesian (BayesR) analyses, to determine if prediction accuracy for age at puberty can be improved. METHODS: Genotypes and phenotypes were obtained from two research herds. In total, 868 Brahman and 960 Tropical Composite heifers were recorded in the first population and 3695 Brahman, Santa Gertrudis and Droughtmaster heifers were recorded in the second population. Genotypes were imputed to 23 million whole-genome sequence variants. Eight strategies were used to pre-select variants from genome-wide association study (GWAS) results using conditional or joint (COJO) analyses. Pre-selected variants were included in three models, GBLUP with a single genomic relationship matrix (SGRM), GBLUP MGRM and BayesR. Five-way cross-validation was used to test the effect of marker panel density (6 K, 50 K and 800 K), analysis model, and inclusion of pre-selected WGS variants on prediction accuracy. RESULTS: In all tested scenarios, prediction accuracies for age at puberty were highest in BayesR analyses. The addition of pre-selected WGS variants had little effect on the accuracy of prediction when BayesR was used. The inclusion of WGS variants that were pre-selected using a meta-analysis with COJO analyses by chromosome, fitted in a MGRM model, had the highest prediction accuracies in the GBLUP analyses, regardless of marker density. When the low-density (6 K) panel was used, the prediction accuracy of GBLUP was equal (0.42) to that with the high-density panel when only six additional sequence variants (identified using meta-analysis COJO by chromosome) were included. CONCLUSIONS: While BayesR consistently outperforms other methods in terms of prediction accuracies, reasonable improvements in accuracy can be achieved when using GBLUP and low-density panels with the inclusion of a relatively small number of highly relevant WGS variants.


Assuntos
Bovinos/genética , Genômica/métodos , Maturidade Sexual/genética , Animais , Teorema de Bayes , Cruzamento , Feminino , Genoma/genética , Estudo de Associação Genômica Ampla , Genótipo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Maturidade Sexual/fisiologia , Sequenciamento Completo do Genoma/métodos
4.
Int J Methods Psychiatr Res ; 28(4): e1801, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31568635

RESUMO

OBJECTIVE: The collection and use of ordinal variables are common in many psychological and psychiatric studies. Although the models for continuous variables have similarities to those for ordinal variables, there are advantages when a model developed for modeling ordinal data is used such as avoiding "floor" and "ceiling" effects and avoiding to assign scores, as it happens in continuous models, which can produce results sensitive to the score assigned. This paper introduces and focuses on the application of the ordered stereotype model, which was developed for modeling ordinal outcomes and is not so popular as other models such as linear regression and proportional odds models. This paper aims to compare the performance of the ordered stereotype model with other more commonly used models among researchers and practitioners. METHODS: This article compares the performance of the stereotype model against the proportional odd and linear regression models, with three, four, and five levels of ordinal categories and sample sizes 100, 500, and 1000. This paper also discusses the problem of treating ordinal responses as continuous using a simulation study. The trend odds model is also presented in the application. RESULTS: Three types of models were fitted in one real-life example, including ordered stereotype, proportional odds, and trend odds models. They reached similar conclusions in terms of the significance of covariates. The simulation study evaluated the performance of the ordered stereotype model under four cases. The performance varies depending on the scenarios. CONCLUSIONS: The method presented can be applied to several areas of psychiatry dealing with ordinal outcomes. One of the main advantages of this model is that it breaks with the assumption of levels of the ordinal response are equally spaced, which might be not true.


Assuntos
Transtornos Mentais/diagnóstico , Modelos Estatísticos , Psicometria/métodos , Adulto , Humanos , Adulto Jovem
5.
Genet Sel Evol ; 51(1): 29, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221081

RESUMO

BACKGROUND: Selection of cattle that are less sensitive to environmental variation in unfavorable environments and more adapted to harsh conditions is of primary importance for tropical beef cattle production systems. Understanding the genetic background of sensitivity to environmental variation is necessary for developing strategies and tools to increase efficiency and sustainability of beef production. We evaluated the degree of sensitivity of beef cattle performance to environmental variation, at the animal and molecular marker levels (412 K single nucleotide polymorphisms), by fitting and comparing the results of different reaction norm models (RNM), using a comprehensive dataset of Nellore cattle raised under diverse environmental conditions. RESULTS: Heteroscedastic RNM (with different residual variances for environmental level) provided better fit than homoscedastic RNM. In addition, spline and quadratic RNM outperformed linear RNM, which suggests the existence of a nonlinear genetic component affecting the performance of Nellore cattle. This nonlinearity indicates that within-animal sensitivity depends on the environmental gradient (EG) level and that animals may present different patterns of sensitivity according to the range of environmental variations. The spline RNM showed that sensitivity to environmental variation from harsh to average EG is lowly correlated with sensitivity from average to good EG, at both the animal and molecular marker levels. Although the genomic regions that affect sensitivity in harsher environments were not the same as those associated with less challenging environments, the candidate genes within those regions participate in common biological processes such as those related to inflammatory and immune response. Some plausible candidate genes were identified. CONCLUSIONS: Sensitivity of tropical beef cattle to environmental variation is not continuous along the environmental gradient, which implies that animals that are less sensitive to harsher conditions are not necessarily less responsive to variations in better environmental conditions, and vice versa. The same pattern was observed at the molecular marker level, i.e. genomic regions and, consequently, candidate genes associated with sensitivity to harsh conditions were not the same as those associated with sensitivity to less challenging conditions.


Assuntos
Bovinos/genética , Interação Gene-Ambiente , Animais , Feminino , Estudo de Associação Genômica Ampla/veterinária , Masculino , Polimorfismo de Nucleotídeo Único , Clima Tropical , Ganho de Peso/genética
6.
Aust N Z J Public Health ; 37(3): 218-25, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23731103

RESUMO

AIM: Cancer burden measured in disability adjusted life years (DALYs) captures survival and disability impacts of incident cancers. In this paper, we estimate the prospective burden of disease arising from 27 cancer sites diagnosed in 2006, by sex and ethnicity; and determine how its distribution differs from that for incidence rates alone. METHODS: Using a prospective approach, Markov and cancer disease models were used to estimate DALYs with inputs of population counts, incidence and excess mortality rates, disability weights, and background mortality. DALYs were discounted at 3.5% per year. RESULTS: The age standardised Maori:non-Maori incidence rate ratios were 1.00 for males and 1.19 for females, whereas for DALYs they were greater at 1.42 for males and 1.68 for females. The total burden of cancer for 2006 incident cases (i.e. not age standardised) was estimated to be approximately 127,000 DALYs. Breast (27%), lung (14%) and colorectal (13%) cancers for females and lung (16%), colorectal (14%), and prostate (16%) cancers for males were the top contributors. By ethnicity, Maori experienced a substantially higher burden from lung cancer (around 25% for both sexes). CONCLUSIONS: Due to Maori both having higher rates of cancers with a worse survival (e.g. lung cancer), and tending to have worse survival for each cancer site, ethnic disparities in the age-standardised DALY burden were greater than those for incidence (rate ratios of 1.52 and 1.07 respectively, sexes pooled).


Assuntos
Expectativa de Vida/etnologia , Neoplasias/mortalidade , Anos de Vida Ajustados por Qualidade de Vida , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Efeitos Psicossociais da Doença , Pessoas com Deficiência/psicologia , Pessoas com Deficiência/estatística & dados numéricos , Feminino , Disparidades nos Níveis de Saúde , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/etnologia , Neoplasias/psicologia , Nova Zelândia/epidemiologia , Vigilância da População , Estudos Prospectivos , Sensibilidade e Especificidade , Taxa de Sobrevida , Adulto Jovem
7.
Int J Cancer ; 131(6): E974-82, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22419246

RESUMO

Relative survival and excess mortality approaches are commonly used to estimate and compare net survival from cancer. These approaches are based on the assumption that the underlying (non-cancer) mortality rate of cancer patients is the same as that of the general population. This assumption is likely to be violated particularly in the context of smoking-related cancers. The magnitude of this bias has not been estimated. The objective of this article is to estimate the bias in relative survival ratios (RSRs) and excess mortality rate ratios (EMRRs) from using total population compared to correct subpopulation specific life-tables. Analyses were conducted on 1996-2001 linked census-cancer data (including smoking status) for people with lung and bladder cancer, using sex-specific (standard practice), sex- and ethnic-specific, sex- and smoking-specific and sex-, ethnic- and smoking-specific life-tables. Five-year RSRs using sex-specific life-tables, compared to fully stratified life-tables, were underestimated by 10-25% for current smoking and Maori populations. For example, the current smoker male bladder cancer RSR was 0.700 for sex-specific life-tables, compared to 0.838 for fully stratified life-tables. Similarly, EMRRs comparing current to never smokers and Maori to non-Maori were overestimated using sex-specific life-tables only: modestly only for lung cancer, but markedly for bladder cancer. For example, the EMRR comparing current to never smokers with bladder cancer in a fully adjusted regression model was 1.475 when using sex-specific life-tables only, but reduced to 1.098 when using fully stratified life-tables. Substantial bias can occur when estimating relative cancer survival across subpopulations if non-matching life-tables are used.


Assuntos
Tábuas de Vida , Neoplasias Pulmonares/mortalidade , Fumar/efeitos adversos , Neoplasias da Bexiga Urinária/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Viés , Feminino , Humanos , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Neoplasias da Bexiga Urinária/etnologia
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