RÉSUMÉ
BACKGROUND: Most genome wide association studies (GWAS) of plasma proteomics have focused on White individuals of European ancestry, limiting biological insight from other ancestry enriched protein quantitative loci (pQTL). METHODS: We conducted a discovery GWAS of ~3,000 plasma proteins measured by the antibody based Olink platform in 1,054 Black adults from the Jackson Heart Study (JHS), and validated our findings in the Multi-Ethnic Study of Atherosclerosis (MESA). The genetic architecture of identified pQTLs were further explored through fine mapping and admixture association analysis. Finally, using our pQTL findings, we performed a phenome wide association study (PheWAS) across two large multi-ethnic electronic health record (EHR) systems in All of Us and BioMe. RESULTS: We identified 1002 pQTLs for 925 proteins. Fine mapping and admixture analyses suggested allelic heterogeneity of the plasma proteome across diverse populations. We identified associations for variants enriched in African ancestry, many in diseases that lack precise biomarkers, including cis-pQTLs for Cathepsin L (CTSL) and Siglec-9 that were linked with sarcoidosis and non-Hodgkin's lymphoma, respectively. We found concordant associations across clinical diagnoses and laboratory measurements, elucidating disease pathways, including a cis-pQTL associated with circulating CD58, white blood cell count, and multiple sclerosis. CONCLUSIONS: Our findings emphasize the value of leveraging diverse populations to enhance biological insights from proteomics GWAS, and we have made this resource readily available as an interactive web portal.
RÉSUMÉ
Circulating metabolite levels partly reflect the state of human health and diseases, and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single study analyses. Leveraging the rich metabolomics resources generated by the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally-diverse samples. We provided recommendations for outlier and imputation handling to process metabolite data, as well as a general analytical framework. We further performed a pooled analysis following our practical recommendations and discovered 1,778 independent loci associated with 667 metabolites. Among 108 novel locus - metabolite pairs, we detected not only novel loci within previously implicated metabolite associated genes, but also novel genes (such as GAB3 and VSIG4 located in the X chromosome) that have putative roles in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, including well-known metabolic genes such as FADS2 , D2HGDH , SUGP1 , UTG2B17 , strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.
RÉSUMÉ
PREMISE: Because of its broad range in the neotropical rainforest and within tree canopies, the tank bromeliad Guzmania monostachia was investigated as a model of how varying leaf hydraulic conductance (Kleaf ) could help plants resist and recover from episodic drought. The two pathways of Kleaf , inside and outside the xylem, were also examined to determine the sites and causes of major hydraulic resistances within the leaf. METHODS: We measured leaf hydraulic conductance for plants in the field and laboratory under wet, dry, and rewetted conditions and applied physiological, anatomical, and gene expression analysis with modeling to investigate changes in Kleaf . RESULTS: After 7 d with no rain in the field or 14 days with no water in the glasshouse, Kleaf decreased by 50% yet increased to hydrated values within 4 d of tank refilling. Staining to detect embolism combined with modeling indicated that changes outside the xylem were of greater importance to Kleaf than were changes inside the xylem and were associated with changes in intercellular air spaces (aerenchyma), aquaporin expression and inhibition, and cuticular conductance. CONCLUSIONS: Low values for all conductances during drying, particularly in pathways outside the xylem, lead to hydraulic resilience for this species and may also contribute to its broad environmental tolerances.