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1.
medRxiv ; 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39252935

RESUMEN

While respiratory diseases such as COPD and asthma share many risk factors, most studies investigate them in insolation and in predominantly European ancestry populations. Here, we conducted the most powerful multi-trait and -ancestry genetic analysis of respiratory diseases and auxiliary traits to date. Our approach improves the power of genetic discovery across traits and ancestries, identifying 44 novel loci associated with lung function in individuals of East Asian ancestry. Using these results, we developed PRSxtra (cross TRait and Ancestry), a multi-trait and -ancestry polygenic risk score approach that leverages shared components of heritable risk via pleiotropic effects. PRSxtra significantly improved the prediction of asthma, COPD, and lung cancer compared to trait- and ancestry-matched PRS in a multi-ancestry cohort from the All of Us Research Program, especially in diverse populations. PRSxtra identified individuals in the top decile with over four-fold odds of asthma and COPD compared to the first decile. Our results present a new framework for multi-trait and -ancestry studies of respiratory diseases to improve genetic discovery and polygenic prediction.

2.
Psychol Med ; : 1-9, 2024 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-39282852

RESUMEN

BACKGROUND: Major depressive disorder (MDD) is the leading cause of disability globally, with moderate heritability and well-established socio-environmental risk factors. Genetic studies have been mostly restricted to European settings, with polygenic scores (PGS) demonstrating low portability across diverse global populations. METHODS: This study examines genetic architecture, polygenic prediction, and socio-environmental correlates of MDD in a family-based sample of 10 032 individuals from Nepal with array genotyping data. We used genome-based restricted maximum likelihood to estimate heritability, applied S-LDXR to estimate the cross-ancestry genetic correlation between Nepalese and European samples, and modeled PGS trained on a GWAS meta-analysis of European and East Asian ancestry samples. RESULTS: We estimated the narrow-sense heritability of lifetime MDD in Nepal to be 0.26 (95% CI 0.18-0.34, p = 8.5 × 10-6). Our analysis was underpowered to estimate the cross-ancestry genetic correlation (rg = 0.26, 95% CI -0.29 to 0.81). MDD risk was associated with higher age (beta = 0.071, 95% CI 0.06-0.08), female sex (beta = 0.160, 95% CI 0.15-0.17), and childhood exposure to potentially traumatic events (beta = 0.050, 95% CI 0.03-0.07), while neither the depression PGS (beta = 0.004, 95% CI -0.004 to 0.01) or its interaction with childhood trauma (beta = 0.007, 95% CI -0.01 to 0.03) were strongly associated with MDD. CONCLUSIONS: Estimates of lifetime MDD heritability in this Nepalese sample were similar to previous European ancestry samples, but PGS trained on European data did not predict MDD in this sample. This may be due to differences in ancestry-linked causal variants, differences in depression phenotyping between the training and target data, or setting-specific environmental factors that modulate genetic effects. Additional research among under-represented global populations will ensure equitable translation of genomic findings.

4.
bioRxiv ; 2024 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-39149254

RESUMEN

Recent studies have demonstrated that polygenic risk scores (PRS) trained on multi-ancestry data can improve prediction accuracy in groups historically underrepresented in genomic studies, but the availability of linked health and genetic data from large-scale diverse cohorts representative of a wide spectrum of human diversity remains limited. To address this need, the All of Us research program (AoU) generated whole-genome sequences of 245,388 individuals who collectively reflect the diversity of the USA. Leveraging this resource and another widely-used population-scale biobank, the UK Biobank (UKB) with a half million participants, we developed PRS trained on multi-ancestry and multi-biobank data with up to ~750,000 participants for 32 common, complex traits and diseases across a range of genetic architectures. We then compared effects of ancestry, PRS methodology, and genetic architecture on PRS accuracy across a held out subset of ancestrally diverse AoU participants. Due to the more heterogeneous study design of AoU, we found lower heritability on average compared to UKB (0.075 vs 0.165), which limited the maximal achievable PRS accuracy in AoU. Overall, we found that the increased diversity of AoU significantly improved PRS performance in some participants in AoU, especially underrepresented individuals, across multiple phenotypes. Notably, maximizing sample size by combining discovery data across AoU and UKB is not the optimal approach for predicting some phenotypes in African ancestry populations; rather, using data from only AoU for these traits resulted in the greatest accuracy. This was especially true for less polygenic traits with large ancestry-enriched effects, such as neutrophil count (R 2: 0.055 vs. 0.035 using AoU vs. cross-biobank meta-analysis, respectively, because of e.g. DARC). Lastly, we calculated individual-level PRS accuracies rather than grouping by continental ancestry, a critical step towards interpretability in precision medicine. Individualized PRS accuracy decays linearly as a function of ancestry divergence, but the slope was smaller using multi-ancestry GWAS compared to using European GWAS. Our results highlight the potential of biobanks with more balanced representations of human diversity to facilitate more accurate PRS for the individuals least represented in genomic studies.

5.
Artículo en Inglés | MEDLINE | ID: mdl-38954848

RESUMEN

Food literacy is a growing area of interest given its potential to support healthy and sustainable diets. Most existing food literacy measures focus on nutrition and food skills but fail to address food systems and socio-environmental aspects of food literacy. Further, measures developed and tested in the Canadian context are lacking. The objective of this project was to develop and test the validity and reliability of a brief self-administered measure, in French and English, designed to assess multiple dimensions of food literacy among adults living in Canada. The 23-item Canadian Food Literacy Measure was developed through an iterative process that included assessment of face and content validity through expert review (n=20) and cognitive interviews (n=20), and construct validity and reliability, i.e., internal consistency through an online survey (n=154). The results indicate that the measure is well understood by both English- and French-speaking adults. The measure's construct validity is demonstrated by the observed differences in total scores in hypothesized directions by gender (p=0.003), age (p=0.007), education level (p=0.002), health literacy (p<0.001) and smoking status (p=0.001) and the significant positive correlation (r = 0.29; p=0.002) between total scores and fruit and vegetable intake. The measure also has high internal consistency with a Cronbach's coefficient alpha of 0.80. This measure can be used in surveillance studies to provide insight into the food literacy of adults living in Canada and in epidemiologic research that aims to explore how food literacy is associated with a variety of health outcomes.

6.
Nat Commun ; 15(1): 5007, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38866767

RESUMEN

Polygenic scores (PGSs) offer the ability to predict genetic risk for complex diseases across the life course; a key benefit over short-term prediction models. To produce risk estimates relevant to clinical and public health decision-making, it is important to account for varying effects due to age and sex. Here, we develop a novel framework to estimate country-, age-, and sex-specific estimates of cumulative incidence stratified by PGS for 18 high-burden diseases. We integrate PGS associations from seven studies in four countries (N = 1,197,129) with disease incidences from the Global Burden of Disease. PGS has a significant sex-specific effect for asthma, hip osteoarthritis, gout, coronary heart disease and type 2 diabetes (T2D), with all but T2D exhibiting a larger effect in men. PGS has a larger effect in younger individuals for 13 diseases, with effects decreasing linearly with age. We show for breast cancer that, relative to individuals in the bottom 20% of polygenic risk, the top 5% attain an absolute risk for screening eligibility 16.3 years earlier. Our framework increases the generalizability of results from biobank studies and the accuracy of absolute risk estimates by appropriately accounting for age- and sex-specific PGS effects. Our results highlight the potential of PGS as a screening tool which may assist in the early prevention of common diseases.


Asunto(s)
Predisposición Genética a la Enfermedad , Herencia Multifactorial , Humanos , Masculino , Femenino , Herencia Multifactorial/genética , Incidencia , Persona de Mediana Edad , Adulto , Anciano , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiología , Factores de Riesgo , Medición de Riesgo/métodos , Carga Global de Enfermedades , Factores Sexuales , Factores de Edad
7.
Nat Commun ; 15(1): 4874, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38849341

RESUMEN

Evidence for adaptation of human skin color to regional ultraviolet radiation suggests shared and distinct genetic variants across populations. However, skin color evolution and genetics in East Asians are understudied. We quantified skin color in 48,433 East Asians using image analysis and identified associated genetic variants and potential causal genes for skin color as well as their polygenic interplay with sun exposure. This genome-wide association study (GWAS) identified 12 known and 11 previously unreported loci and SNP-based heritability was 23-24%. Potential causal genes were determined through the identification of nonsynonymous variants, colocalization with gene expression in skin tissues, and expression levels in melanocytes. Genomic loci associated with pigmentation in East Asians substantially diverged from European populations, and we detected signatures of polygenic adaptation. This large GWAS for objectively quantified skin color in an East Asian population improves understanding of the genetic architecture and polygenic adaptation of skin color and prioritizes potential causal genes.


Asunto(s)
Estudio de Asociación del Genoma Completo , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Pigmentación de la Piel , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adaptación Fisiológica/genética , Mapeo Cromosómico , Herencia Multifactorial/genética , Sitios de Carácter Cuantitativo/genética , Pigmentación de la Piel/genética , Rayos Ultravioleta , Pueblos del Este de Asia
8.
Genome Res ; 34(5): 796-809, 2024 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-38749656

RESUMEN

Underrepresented populations are often excluded from genomic studies owing in part to a lack of resources supporting their analyses. The 1000 Genomes Project (1kGP) and Human Genome Diversity Project (HGDP), which have recently been sequenced to high coverage, are valuable genomic resources because of the global diversity they capture and their open data sharing policies. Here, we harmonized a high-quality set of 4094 whole genomes from 80 populations in the HGDP and 1kGP with data from the Genome Aggregation Database (gnomAD) and identified over 153 million high-quality SNVs, indels, and SVs. We performed a detailed ancestry analysis of this cohort, characterizing population structure and patterns of admixture across populations, analyzing site frequency spectra, and measuring variant counts at global and subcontinental levels. We also show substantial added value from this data set compared with the prior versions of the component resources, typically combined via liftOver and variant intersection; for example, we catalog millions of new genetic variants, mostly rare, compared with previous releases. In addition to unrestricted individual-level public release, we provide detailed tutorials for conducting many of the most common quality-control steps and analyses with these data in a scalable cloud-computing environment and publicly release this new phased joint callset for use as a haplotype resource in phasing and imputation pipelines. This jointly called reference panel will serve as a key resource to support research of diverse ancestry populations.


Asunto(s)
Bases de Datos Genéticas , Genoma Humano , Humanos , Proyecto Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Variación Genética , Genómica/métodos
9.
Explor Res Clin Soc Pharm ; 14: 100442, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38707788

RESUMEN

Introduction: In the dynamic landscape of healthcare, pharmacists play a critical role in ensuring the well-being of communities, and having solid professional organisations to support pharmacists is essential in crucial activities, including continuing education, advocacy and establishing service standards. Eight pharmacy organisations play vital roles in representing pharmacists in various sectors and collectively contribute to developing, regulating, and promoting the pharmacy profession in Australia. However, a notable lack of female representation in these organisations' leadership roles has led to an increased focus on gender balance and equity. Objective: To determine if the gender distribution in pharmacy leadership aligns with the pharmacy workforce in Australia (64% women) and how it has changed in the five years since our last study on the issue. Setting: Australia. Method: Eight key Australian pharmacy organisations were identified. The website for each organisation was accessed, and data were recorded for their 2023 boards/committees/councils based on annual reports. Data recorded include name, number of males, number of females, and the gender of the president/chair of each board/committee/council. Results: Data were obtained for 340 separate professional committee members from the eight organisations (including state/territory branches) in 2023. Gender balance in pharmacy organisations has increased significantly since 2018, with women's representation in leadership positions now at 58% (47% 2018). Conclusion: Gender equity within Australian pharmacy professional organisations has significantly progressed.

10.
Biofactors ; 2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38733572

RESUMEN

Several neuropeptides present in bone tissues, produced by nerve fibers and bone cells, have been reported to play a role in regulating the fine-tuning of osteoblast and osteoclast functions to maintain bone homeostasis. This study aims to characterize the influence of the neuropeptide vasoactive intestinal peptide (VIP) on the differentiation process of human mesenchymal stem cells (MSCs) into osteoblasts and on their anabolic function. We describe the mRNA and protein expression profile of VIP and its receptors in MSCs as they differentiate into osteoblasts, suggesting the presence of an autocrine signaling pathway in these cells. Our findings reveal that VIP enhances the expression of early osteoblast markers in MSCs under osteogenic differentiation and favors both bone matrix formation and proper cytoskeletal reorganization. Finally, our data suggest that VIP could be exerting a direct modulatory role on the osteoblast to osteoclast signaling by downregulating the receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio. These results highlight the potential of VIP as an osteoinductive differentiation factor, emerging as a key molecule in the maintenance of human bone homeostasis.

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