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Short-term mortality risk, which is indicative of individual frailty, serves as a marker for aging. Previous age clocks focused on predicting either chronological age or longer-term mortality. Aging clocks predicting short-term mortality are lacking and their algorithmic fairness remains unexamined. We developed a deep learning model to predict 1-year mortality using nationwide longitudinal data from the Finnish population (FinRegistry; n = 5.4 million), incorporating more than 8,000 features spanning up to 50 years. We achieved an area under the curve (AUC) of 0.944, outperforming a baseline model that included only age and sex (AUC = 0.897). The model generalized well to different causes of death (AUC > 0.800 for 45 of 50 causes), including coronavirus disease 2019, which was absent in the training data. Performance varied among demographics, with young females exhibiting the best and older males the worst results. Extensive prediction fairness analyses highlighted disparities among disadvantaged groups, posing challenges to equitable integration into public health interventions. Our model accurately identified short-term mortality risk, potentially serving as a population-wide aging marker.
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Envelhecimento , Aprendizado Profundo , Mortalidade , Humanos , Finlândia/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Mortalidade/tendências , Adulto , Idoso de 80 Anos ou mais , COVID-19/mortalidade , COVID-19/epidemiologia , Adulto Jovem , Fragilidade/mortalidade , Fragilidade/epidemiologia , AdolescenteRESUMO
Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals1,2, but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.
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Aneuploidia , Cromossomos Humanos X , Células Clonais , Leucócitos , Mosaicismo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Alelos , Doenças Autoimunes/genética , Bancos de Espécimes Biológicos , Segregação de Cromossomos/genética , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Células Clonais/metabolismo , Células Clonais/patologia , Exoma/genética , Proteínas F-Box/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Leucemia/genética , Leucócitos/metabolismo , Modelos Genéticos , Herança Multifatorial/genética , Mutação de Sentido Incorreto/genéticaRESUMO
Band structure of a semiconducting film critically determines the charge separation and transport efficiency. In antimony selenosulfide (Sb2(S,Se)3) solar cells, the hydrothermal method has achieved control of band gap width of Sb2(S,Se)3 thin film through tuning the atomic ratio of S/Se, resulting in an efficiency breakthrough towards 10 %. However, the obtained band structure exhibits an unfavorable gradient distribution in terms of carrier transport, which seriously impedes the device efficiency improvement. To solve this problem, here we develop a strategy by intentionally regulating hydrothermal temperature to control the chemical reaction kinetics between S and Se sources with Sb source. This approach enables the control over vertical distribution of S/Se atomic ratio in Sb2(S,Se)3 films, forming a favorable band structure which is conducive to carrier transport. Meanwhile, the adjusted element distribution not only ensures the uniformity of grain structure, but also increases the Se content of the films and suppress sulfur vacancy defects. Ultimately, the device delivers a high efficiency of 10.55 %, which is among the highest reported efficiency of Sb2(S,Se)3 solar cells. This study provides an effective strategy towards manipulating the element distribution in mixed-anion compound films prepared by solution-based method to optimize their optical and electrical properties.
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Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals.
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Carcinoma de Células Renais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Renais , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Humanos , Neoplasias Renais/genética , Carcinoma de Células Renais/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Estudos de Casos e Controles , População Branca/genéticaRESUMO
Antimony selenide (Sb2Se3) consists of 1D (Sb4Se6)n ribbons, along which the carriers exhibit high transport efficiency. By adjusting the deposition parameters of vacuum-deposited methods, such as evaporation temperature, chamber pressure, and vapor concentration, it is possible to grow the (Sb4Se6)n ribbons vertically or highly inclined towards the substrate, resulting in films with [hk1] orientation. However, the specific mechanisms by which these deposition parameters affect the orientation of thin films require a deeper understanding. Herein, a molecular beam epitaxy technique is developed for the preparation of highly [hk1]-oriented Sb2Se3 films, and the effect of evaporation parameters on the film orientation is investigated. It is found that the evaporation temperature can affect the decomposition degree of Sb2Se3, which in turn determines the vapor composition and film orientation. Additionally, the decomposition of Sb2Se3 related to evaporation temperature leads to significant changes in the elemental composition of the film, thereby passivating deep-level defects under Se-rich conditions. Consequently, the Sb2Se3 films with highly [hk1] orientation achieve a power conversion efficiency of 8.42% for the solar cells. This study provides new insights into the control of orientation in antimony-based chalcogenide films and points out new directions for improving the photovoltaic performance of solar cells.
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Importance: The reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQOL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the less than 15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry. Objectives: To determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); to describe military service metrics of men with SCAs; and to compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis vs matched controls. Design, Setting, and Participants: This cross-sectional study used a case-control recruitment design to select biological males enrolled in the MVP biobank in the US Veterans Administration health care system from 2011 to 2022. Cases were participants with 47,XXY syndrome or 47,XYY syndrome, matched 1:5 with controls based on sex, age, and genetic ancestry. Data were analyzed from January 2022 to December 2023. Exposure: Genomic identification of an additional X or Y chromosome. Main Outcomes and Measures: Outcomes of interest included prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index; rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; and standardized mortality ratio. Results: Of 595â¯612 genotyped males in the MVP, 862 had an additional X chromosome (47,XXY) and 747 had an extra Y chromosome (47,XYY), with the highest prevalence among men with East Asian (47,XXY: 10 of 7313 participants; 47,XYY: 14 of 7313 participants) and European (47,XXY: 725 of 427â¯143 participants; 47,XYY: 625 of 427â¯143 participants) ancestry. Mean (SD) age at assessment was 61 (12) years, at which point 636 veterans (74.X%) with 47,XXY and 745 veterans (99%) with 47,XYY remained undiagnosed. Individuals with 47,XXY and 47,XYY had similar military service history, all-cause standardized mortality ratio, and age of death compared with matched controls. Individuals with SCA, compared with controls, had higher Charlson Comorbidity Index scores (47,XXY: mean [SD], 4.30 [2.72] vs controls: mean [SD], 3.90 [2.47]; 47,XYY: mean [SD], 4.45 [2.90] vs controls: mean [SD], 3.82 [2.50]) and health care utilization (eg, median [IQR] outpatient encounters per year: 47,XXY, 22.6 [11.8-37.8] vs controls, 16.8 [9.4-28]; 47,XYY: 21.4 [12.4-33.8] vs controls: 17.0 [9.4-28.2]), while several measures of HRQOL were lower (eg, mean [SD] self-reported physical function: 47,XXY: 34.2 [12] vs control mean [SD] 37.8 [12.8]; 47,XYY: 36.3 [11.6] vs control 37.9 [12.8]). Men with a clinical diagnosis of 47,XXY, compared with individuals without a clinical diagnosis, had higher health care utilization (eg, median [IQR] encounters per year: 26.6 [14.9-43.2] vs 22.2 [11.3-36.0]) but lower Charlson Comorbidity Index scores (mean [SD]: 3.7 [2.7] vs 4.5 [4.1]). Conclusion and Relevance: In this case-control study of men with 47,XXY and 47,XYY syndromes, prevalence of SCA was comparable with estimates in the general population. While these men had successfully served in the military, they had higher morbidity and reported poorer HRQOL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics.
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Transtornos dos Cromossomos Sexuais , Veteranos , Cariótipo XYY , Masculino , Humanos , Feminino , Prevalência , Estudos de Casos e Controles , Estudos Transversais , Qualidade de Vida , Aberrações dos Cromossomos Sexuais , Aneuploidia , Morbidade , Cromossomos SexuaisRESUMO
The percentage of people without children over their lifetime is approximately 25% in men and 20% in women. Individual diseases have been linked to childlessness, mostly in women, yet we lack a comprehensive picture of the effect of early-life diseases on lifetime childlessness. We examined all individuals born in 1956-1968 (men) and 1956-1973 (women) in Finland (n = 1,035,928) and Sweden (n = 1,509,092) to the completion of their reproductive lifespan in 2018. Leveraging nationwide registers, we associated sociodemographic and reproductive information with 414 diseases across 16 categories, using a population and matched-pair case-control design of siblings discordant for childlessness (71,524 full sisters and 77,622 full brothers). The strongest associations were mental-behavioural disorders (particularly among men), congenital anomalies and endocrine-nutritional-metabolic disorders (strongest among women). We identified new associations for inflammatory and autoimmune diseases. Associations were dependent on age at onset and mediated by singlehood and education. This evidence can be used to understand how disease contributes to involuntary childlessness.
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Transtornos Mentais , Reprodução , Masculino , Criança , Humanos , Feminino , Idoso , Finlândia/epidemiologia , Suécia/epidemiologia , EscolaridadeRESUMO
Antimony sulfoselenide (Sb2(S,Se)3) is a promising light absorption material because of its high photoabsorption coefficient, appropriate band gap, superior stability, and abundant elemental storage. As an emerging solar material, hydrothermal deposition of Sb2(S,Se)3 solar cells has enabled a 10% efficiency threshold, where cadmium sulfide (CdS) is applied as an electron transport layer (ETL). The high-efficiency Sb2(S,Se)3 solar cells largely employ CdS as the ETL. In terms of efficiency improvement, there are two questions regarding the CdS substrate: (1) the high roughness of CdS grown on F-doped tin oxide glass which increases the roughness of the absorber layer and (2) the low conductivity of CdS films because of low purity of CdS film grown by chemical bath deposition. In this study, we demonstrate an effective potassium chloride (KCl) post-treatment to modify the CdS ETL for improving the Sb2(S,Se)3 solar cell efficiency. We found that KCl plays dual roles that reduce roughness and enhance conductivity of the CdS films, thus acquiring a maximum efficiency of 9.98%, which is 9.2% higher than the control device. This study provides a new method for the surface engineering of CdS layer to improve the morphological and electrical properties, which is significant for improving the performance of CdS-based thin-film solar cells.
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BACKGROUND: Novel immunisation methods against respiratory syncytial virus (RSV) are emerging, but knowledge of risk factors for severe RSV disease is insufficient for optimal targeting of interventions against them. Our aims were to identify predictors for RSV hospital admission from registry-based data and to develop and validate a clinical prediction model to guide RSV immunoprophylaxis for infants younger than 1 year. METHODS: In this model development and validation study, we studied all infants born in Finland between June 1, 1997, and May 31, 2020, and in Sweden between June 1, 2006, and May 31, 2020, along with the data for their parents and siblings. Infants were excluded if they died or were admitted to hospital for RSV within the first 7 days of life. The outcome was hospital admission due to RSV bronchiolitis during the first year of life. The Finnish study population was divided into a development dataset (born between June 1, 1997, and May 31, 2017) and a temporal hold-out validation dataset (born between June 1, 2017, and May 31, 2020). The development dataset was used for predictor discovery and selection in which we screened 1511 candidate predictors from the infants', parents', and siblings' data, and developed a logistic regression model with the 16 most important predictors. This model was then validated using the Finnish hold-out validation dataset and the Swedish dataset. FINDINGS: In total, there were 1 124 561 infants in the Finnish development dataset, 130 352 infants in the Finnish hold-out validation dataset, and 1 459 472 infants in the Swedish dataset. In addition to known predictors such as severe congenital heart defects (adjusted odds ratio 2·89, 95% CI 2·28-3·65), we confirmed some less established predictors for RSV hospital admission, most notably oesophageal malformations (3·11, 1·86-5·19) and lower complexity congenital heart defects (1·43, 1·25-1·63). The prediction model's C-statistic was 0·766 (95% CI 0·742-0·789) in Finnish data and 0·737 (0·710-0·762) in Swedish validation data. The infants in the highest decile of predicted RSV hospital admission probability had 4·5 times higher observed risk compared with others. Calibration varied according to epidemic intensity. The model's performance was similar to a machine learning (XGboost) model using all 1511 candidate predictors (C-statistic in Finland 0·771, 95% CI 0·754-0·788). The prediction model showed clinical utility in decision curve analysis and in hypothetical number needed to treat calculations for immunisation, and its C-statistic was similar across different strata of parental income. INTERPRETATION: The identified predictors and the prediction model can be used in guiding RSV immunoprophylaxis in infants, or as a basis for further immunoprophylaxis targeting tools. FUNDING: Sigrid Jusélius Foundation, European Research Council, Pediatric Research Foundation, and Academy of Finland.
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Cardiopatias Congênitas , Infecções por Vírus Respiratório Sincicial , Lactente , Criança , Humanos , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Modelos Estatísticos , Prognóstico , Vírus Sinciciais Respiratórios , Fatores de RiscoRESUMO
Importance: The reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQoL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the <15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry. Objectives: Determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); describe military service metrics of men with SCAs; compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis to matched controls. Design: Cross-sectional, case-control. Setting: United States Veterans Administration Healthcare System. Participants: Biologic males enrolled in the MVP biobank with genomic identification of an additional X or Y chromosome (cases); controls matched 1:5 on sex, age, and genetic ancestry. Main Outcomes and Measures: Prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index (CCI); rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; standardized mortality ratio (SMR). Results: An additional X or Y chromosome was present in 145 and 125 per 100,000 males in the MVP, respectively, with the highest prevalence among men with European and East Asian ancestry. At a mean age of 61±12 years, 74% of male veterans with 47,XXY and >99% with 47,XYY remained undiagnosed. Individuals with 47,XXY (n=862) and 47,XYY (n=747) had similar military service history, all-cause SMR, and age of death compared to matched controls. CCI and healthcare utilization were higher among individuals with SCA, while several measures of HRQoL were lower. Men with a clinical diagnosis of 47,XXY had higher healthcare utilization but lower comorbidity score compared to those undiagnosed. Conclusion and Relevance: One in 370 males in the MVP cohort have SCA, a prevalence comparable to estimates in the general population. While these men have successfully served in the military, they have higher morbidity and report poorer HRQoL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics. KEY POINTS: Comparable to the general population, approximately 1 in 370 male veterans have a sex chromosome aneuploidy, but most are undiagnosed.Men with X or Y chromosome aneuploidy successfully complete US miliary duty with similar service history compared to their 46,XY peers.Medical comorbidities and healthcare utilization metrics are higher in male veterans with 47,XXY and 47,XYY during aging, however life expectancy is similar to matched controls.
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Mosaic loss of the X chromosome (mLOX) is the most commonly occurring clonal somatic alteration detected in the leukocytes of women, yet little is known about its genetic determinants or phenotypic consequences. To address this, we estimated mLOX in >900,000 women across eight biobanks, identifying 10% of women with detectable X loss in approximately 2% of their leukocytes. Out of 1,253 diseases examined, women with mLOX had an elevated risk of myeloid and lymphoid leukemias and pneumonia. Genetic analyses identified 49 common variants influencing mLOX, implicating genes with established roles in chromosomal missegregation, cancer predisposition, and autoimmune diseases. Complementary exome-sequence analyses identified rare missense variants in FBXO10 which confer a two-fold increased risk of mLOX. A small fraction of these associations were shared with mosaic Y chromosome loss in men, suggesting different biological processes drive the formation and clonal expansion of sex chromosome missegregation events. Allelic shift analyses identified alleles on the X chromosome which are preferentially retained, demonstrating that variation at many loci across the X chromosome is under cellular selection. A novel polygenic score including 44 independent X chromosome allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Collectively our results support a model where germline variants predispose women to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of subsequent clonal expansion.
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High mortality and involuntary culling rates cause great economic losses to the worldwide dairy cattle industry. However, there is low emphasis on wellness traits in replacement animals (dairy calves and replacement heifers) during their development stages in modern dairy cattle breeding programs. Therefore, the main objectives of this study were to estimate genetic parameters of wellness traits in replacement cattle (replacement wellness traits) and obtain their genetic correlations with 12 cow health and longevity traits in the Chinese Holstein population. Seven replacement wellness traits were analyzed, including birth weight, survival from 3 to 60 d (Sur1), survival from 61 to 365 d (Sur2), survival from 366 d to the first calving (Sur3), calf diarrhea, calf pneumonia, and calf serum total protein (STP). Single and bivariate animal models were employed to estimate (co)variance components using the data from 189,980 Holstein cattle. The genetic correlations between replacement wellness traits and cow longevity, health traits were calculated by employing bivariate models, including 6 longevity traits and 6 health traits (clinical mastitis, metritis, ketosis, displaced abomasum, milk fever, and hoof health or hoof disease). The estimated heritabilities (± SE) were 0.335 (± 0.008), 0.088 (± 0.005), 0.166 (± 0.006), 0.102 (±0 .006), 0.048 (± 0.003), 0.063 (± 0.004), and 0.170 (± 0.019) for birth weight, Sur1, Sur2, Sur3, pneumonia, diarrhea, and STP, respectively. The majority of the genetic correlations among the 7 replacement wellness traits were negligible. The genetic correlations among Sur1, Sur2, and Sur3 ranged from 0.112 (Sur1 and Sur3) to 0.445 (Sur1 and Sur2) when fitting a linear model (estimates in the observed scale), and from 0.560 (Sur1 and Sur3) to 0.773 (Sur1 and Sur2) when fitting a threshold model (estimates in the liability scale). The genetic correlations between replacement wellness and cow longevity were low (absolute value lower than 0.30), but some of them were significantly different from zero. Compared with other replacement wellness traits, Sur3 and STP had relatively high genetic correlations with cow longevity. Replacement wellness traits are heritable and can be improved through direct genetic and genomic selection. The results from the current study will contribute for better balancing dairy cattle breeding goals to genetically improve dairy cattle wellness in the period from birth to first calving.
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Doenças dos Bovinos , Longevidade , Animais , Peso ao Nascer , Bovinos/genética , Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/genética , Diarreia/veterinária , Feminino , Lactação/genética , Longevidade/genética , LeiteRESUMO
In our previous GWAS of Chinese and Nordic dairy cattle, genes CACNB2, SLC39A12, and ZEB1 locating on BTA 13 were suggested as candidate genes for reproduction. In this study, validation of these associations was performed in an independent population with records of nine reproductive traits. More importantly, functions of these genes in the reproductive process were verified by employing the expression data of ovarian follicles. The potential variants within the three genes were firstly detected in 68 Chinese Holstein bulls, and then screened in 1,588 Chinese Holstein cows using the KASP (Kompetitive allele-specific PCR) method. There were nine variants with polymorphisms in CACNB2, five in SLC39A12, and four in ZEB1, respectively, of which one SNP was in the upstream regulatory region, two in exon region, four in downstream regulatory region, and 11 SNPs in intronic regions. Amongst the 18 variants, g.33267056T/G in CACNB2 explained the largest phenotypic variance for age at first calving (0.011%), interval from first to last insemination (0.004%), and calving ease (0.002%), while g.32751518G/A in SLC39A12 contributed the most to stillbirth in heifers (0.038%). Two haplotype blocks were constructed for CACNB2 while one each for SLC39A12 and ZEB1, which were significantly associated with five reproductive traits, including age at the first service, age at the first calving, calving ease in heifers and cows, and the interval from calving to the first insemination. We then studied the profile of gene expression in granulosa cells isolated from four developmental stages of ovarian follicles from eight dairy cows. All three genes were differentially expressed between ovarian follicles with different sizes (p < 0.05), indicating their potential roles in the reproductive process of dairy cows. This study successfully demonstrated the associations of three BTA 13 genes CACNB2, SLC39A12, and ZEB1 with reproduction and further examined their expression levels in ovarian follicles directly. These findings can be beneficial for the ongoing genomic selection program for reproductive traits which have long been considered as traits that are difficult to achieve genetic improvement due to the lack of efficient genetic markers.
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Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.
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Envelhecimento/genética , Doenças Transmissíveis/genética , Pneumonia/genética , Sepse/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Bancos de Espécimes Biológicos , Aberrações Cromossômicas , Doenças Transmissíveis/complicações , Doenças Transmissíveis/microbiologia , Doenças do Sistema Digestório/epidemiologia , Doenças do Sistema Digestório/genética , Doenças do Sistema Digestório/microbiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Pneumonia/epidemiologia , Pneumonia/microbiologia , Fatores de Risco , Sepse/epidemiologia , Sepse/microbiologia , Anormalidades Urogenitais/epidemiologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/microbiologia , Adulto JovemRESUMO
Bayesian regression models are widely used in genomic prediction for various species. By introducing the global parameter τ, which can shrink marker effects to zero, and the local parameter λ k , which can allow markers with large effects to escape from the shrinkage, we developed two novel Bayesian models, named BayesHP and BayesHE. The BayesHP model uses Horseshoe+ prior, whereas the BayesHE model assumes local parameter λ k , after a half-t distribution with an unknown degree of freedom. The performances of BayesHP and BayesHE models were compared with three classical prediction models, including GBLUP, BayesA, and BayesB, and BayesU, which also applied global-local prior (Horseshoe prior). To assess model performances for traits with various genetic architectures, simulated data and real data in cattle (milk production, health, and type traits) and mice (type and growth traits) were analyzed. The results of simulation data analysis indicated that models based on global-local priors, including BayesU, BayesHP, and BayesHE, performed better in traits with higher heritability and fewer quantitative trait locus. The results of real data analysis showed that BayesHE was optimal or suboptimal for all traits, whereas BayesHP was not superior to other classical models. For BayesHE, its flexibility to estimate hyperparameter automatically allows the model to be more adaptable to a wider range of traits. The BayesHP model, however, tended to be suitable for traits having major/large quantitative trait locus, given its nature of the "U" type-like shrinkage pattern. Our results suggested that auto-estimate the degree of freedom (e.g., BayesHE) would be a better choice other than increasing the local parameter layers (e.g., BayesHP). In this study, we introduced the global-local prior with unknown hyperparameter to Bayesian regression models for genomic prediction, which can trigger further investigations on model development.
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Due to the complexity of longevity trait in dairy cattle, two groups of trait definitions are widely used to measure longevity, either covering the full lifespan or representing only a part of it to achieve an early selection. Usually, only one group of longevity definition is used in breeding program for one population, and genetic studies on the comparisons of two groups of trait definitions are scarce. Based on the data of eight traits well representing the both groups of trait definitions, the current study investigated genetic parameters and genetic architectures of longevity in Holsteins. Heritabilities and correlations of eight longevity traits were estimated using single-trait and multi-trait animal models, with the data from 103,479 cows. Among the cows with phenotypes, 2,630 cows were genotyped with the 150K-SNP panel. A single-trait fixed and random Circuitous Probability Unification model was performed to detect candidate genes for eight longevity traits. Generally, all eight longevity traits had low heritabilities, ranging from 0.038 for total productive life and herd life to 0.090 for days from the first calving to the end of first lactation or culling. High genetic correlations were observed among the traits within the same definition group: from 0.946 to 0.997 for three traits reflecting full lifespan and from 0.666 to 0.997 for five traits reflecting partial productive life. Genetic correlations between two groups of traits ranged from 0.648 to 0.963, and increased gradually with the extension of lactations number regarding the partial productive life traits. A total of 55 SNPs located on 25 chromosomes were found genome-wide significantly associated with longevity, in which 12 SNPs were associated with more than one trait, even across traits of different definition groups. This is the first study to investigate the genetic architecture of longevity representing both full and the partial lifespan simultaneously, which will assist the selection of an appropriate trait definition for genetic improvement of longevity. Because of high genetic correlations with the full lifespan traits and higher heritability, the partial productive life trait measured as the days from the first calving to the end of the third lactation or culling could be a good alternative for early selection on longevity. The candidate genes identified by this study, such as RPRM, GRIA3, GTF2H5, CA5A, CACNA2D1, FGF10, and DNAJA3, could be used to pinpoint causative mutations for longevity and further benefit the genomic improvement of longevity in dairy cattle.
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BACKGROUND: The effect of heat stress on livestock production is a worldwide issue. Animal performance is influenced by exposure to harsh environmental conditions potentially causing genotype-by-environment interactions (G × E), especially in highproducing animals. In this context, the main objectives of this study were to (1) detect the time periods in which heifer fertility traits are more sensitive to the exposure to high environmental temperature and/or humidity, (2) investigate G × E due to heat stress in heifer fertility traits, and, (3) identify genomic regions associated with heifer fertility and heat tolerance in Holstein cattle. RESULTS: Phenotypic records for three heifer fertility traits (i.e., age at first calving, interval from first to last service, and conception rate at the first service) were collected, from 2005 to 2018, for 56,998 Holstein heifers raised in 15 herds in the Beijing area (China). By integrating environmental data, including hourly air temperature and relative humidity, the critical periods in which the heifers are more sensitive to heat stress were located in more than 30 days before the first service for age at first calving and interval from first to last service, or 10 days before and less than 60 days after the first service for conception rate. Using reaction norm models, significant G × E was detected for all three traits regarding both environmental gradients, proportion of days exceeding heat threshold, and minimum temperature-humidity index. Through single-step genome-wide association studies, PLAG1, AMHR2, SP1, KRT8, KRT18, MLH1, and EOMES were suggested as candidate genes for heifer fertility. The genes HCRTR1, AGRP, PC, and GUCY1B1 are strong candidates for association with heat tolerance. CONCLUSIONS: The critical periods in which the reproductive performance of heifers is more sensitive to heat stress are trait-dependent. Thus, detailed analysis should be conducted to determine this particular period for other fertility traits. The considerable magnitude of G × E and sire re-ranking indicates the necessity to consider G × E in dairy cattle breeding schemes. This will enable selection of more heat-tolerant animals with high reproductive efficiency under harsh climatic conditions. Lastly, the candidate genes identified to be linked with response to heat stress provide a better understanding of the underlying biological mechanisms of heat tolerance in dairy cattle.
Assuntos
Interação Gene-Ambiente , Lactação , Animais , Bovinos , China , Feminino , Fertilidade/genética , Estudo de Associação Genômica Ampla , GenômicaRESUMO
Heat stress is a major cause of welfare issues and economic losses to the worldwide dairy cattle industry. Genetic selection for heat tolerance has a great potential to positively affect the dairy industry, as the gains are permanent and cumulative over generations. Rectal temperature (RT) is hypothesized to be a good indicator trait of heat tolerance. Therefore, this study investigated the genetic architecture of RT by estimating genetic parameters, performing genome-wide association studies, and biologically validating potential candidate genes identified to be related to RT in Holstein cattle. A total of 33,013 RT records from 7,598 cows were used in this study. In addition, 1,114 cows were genotyped using the Illumina 150K Bovine BeadChip (Illumina, San Diego, CA). Rectal temperature measurements taken in the morning (AMRT) and in the afternoon (PMRT) are moderately heritable traits, with estimates of 0.09 ± 0.02 and 0.04 ± 0.01, respectively. These 2 traits are also highly genetically correlated (r = 0.90 ± 0.08). A total of 10 SNPs (located on BTA3, BTA4, BTA8, BTA13, BTA14, and BTA29) were found to be significantly associated with AMRT and PMRT. Subsequently, gene expression analyses were performed to validate the key functional genes identified (SPAG17, FAM107B, TSNARE1, RALYL, and PHRF1). This was done through in vitro exposure of peripheral blood mononuclear cells (PBMC) to different temperatures (37°C, 39°C, and 42°C). The relative mRNA expression of 2 genes, FAM107B and PHRF1, significantly changed between the control and heat stressed PBMC. In summary, RT is heritable, and enough genetic variability exists to enable genetic improvement of heat tolerance in Holstein cattle. Important genomic regions were identified and biologically validated; FAM107B and PHRF1 are the main candidate genes identified to influence heat stress response in dairy cattle.