Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding Information: GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file : Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

COMPORTAMENTO DAS SEMENTES DE SOJA DURANTE A FASE INICIAL DO PROCESSO DE GERMINAÇÃO

Com o objetivo de avaliar o comportamento das sementes de soja durante a fase inicial do processo de germinação, utilizaram-se sementes de um lote de soja [Glycine max (L.) Merrill], do cultivar IAC-15, que foram submetidas ao envelhecimento artificial, a 41oC, durante 0, 36 e 42 horas, obtendo-se três diferentes níveis de vigor, designados de lotes 1, 2 e 3, respectivamente. As sementes de cada lote foram submetidas ao umedecimento artificial, a 20oC e 100% de umidade relativa do ar, visando a obtenção de três diferentes teores de água (90, 110 e 130 g de água/kg). Para cada lote, foram verificadas as marchas de absorção de água e efetuadas avaliações da ocorrência de danos por embebição. Assim, sementes com 90, 110 e 130 g de água/kg foram embebidas entre camadas de folhas de papel Germitest, umedecidas com soluções de diferentes concentrações de Polietilenoglicol (PEG 6000), que simulavam os potenciais hídricos de -0,04; -0,10; -0,20 e -0,40 MPa. A análise dos dados e a interpretação dos resultados permitiram concluir que a diminuição do potencial hídrico inicial do substrato promove a redução da velocidade de hidratação das sementes; o aumento do teor de água inicial das sementes contribue para a redução da liberação de exsudatos, sob menor disponibilidade hídrica do substrato.<br>With the main purpose of studying the performance of soybean seeds during the early stage of the germination process, seeds from three soybean [Glycine max (L.) Merrill] lots of cv. IAC-15 with different levels of physiological quality were used.Three moisture levels: 90, 110 and 130g of water.kg-1 fresh weight, were obtained artificially in air 20ºC and 100% relative humidity. The rate of water uptake for each lot was measured. The imbibition damage after different periods of time was also evaluated. Seeds were placed between layers of paper towels, moistened with different polyethylene glycol solutions (PEG 6000), simulating water potentials of -0.04, -0.10, -0.20 e -0.40 MPa. The analysis and the interpretation of the results led to the following conclusions: The low water availability decreases the water uptake rate, and the increase in the water content of the seeds resulted in a reduced imbibition damage, at lowest water availability of the substrate