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

Genomic structure of the human gene for protein kinase A regulatory subunit R1-beta (PRKAR1B) on 7p22: No evidence for mutations in familial hyperaldosteronism type II in a large affected kindred

OBJECTIVE Familial hyperaldosteronism type II (FH-II) is characterized by inheritance of primary aldosteronism (PAL) but, unlike FH-I, is not glucocorticoid remediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. Analysis of two pedigrees previously demonstrated linkage of FH-II with a locus at chromosome 7p22. We sought to determine whether mutations in the exons or intron/exon boundaries in PRKAR1B (encoding protein kinase A regulatory subunit R1-beta), which resides within the linked locus, are associated with FH-II

The origin of stable halogenated compounds in volcanic gases

Background: Halogenated compounds in the atmosphere are of great environmental concern due to their demonstrated negative effect on atmospheric chemistry and climate. Detailed knowledge of the emission budgets of halogenated compounds has to be gained to understand better their specific impact on ozone chemistry and the climate. Such data are also highly relevant to guide policy decisions in connexion with international agreements about protection of the ozone layer. In selected cases, the relevance of specific emission sources for certain compounds were unclear. In this study we present new and comprehensive evidence regarding the existence and relevance of a volcanic contribution of chlorofluorocarbons (CFCs), hydrofluorocarbons (HFCs), hydrochlorofluorocarbons (HCFCs), halons (bromine containing halo(hydro)carbons), and fully fluorinated compounds (e.g. CF4 and SF6) to the atmospheric budget. Methods: In order to obtain new evidence of a volcanic origin of these compounds, we collected repeatedly, during four field campaigns covering a period of two years, gases from fumaroles discharging over a wide range of temperatures at the Nicaraguan subduction zone volcanoes Momotombo, Cerro Negro and Mombacho, and analysed them with very sensitive GC/MS systems. Results and Discussion: In most fumarolic samples certain CFCs, HFCs, HCFCs, halons, and the fully fluorinated compounds CF4 and SF6 were present above detection limits. However, these compounds occur in the fumarole gases in relative proportions characteristic for ambient air. Conclusion: This atmospheric fingerprint can be explained by variable amounts of air entering the porous volcanic edifices and successively being incorporated into the fumarolic gas discharges. Recommendation and Outlook: Our results suggest that the investigated volcanoes do not constitute a significant natural source for CFCs, HFCs, HCFCs, halons, CF4, SF6 and NF3

Global change tipping points: above- and below-ground biotic interactions in a low diversity ecosystem

Low diversity ecosystems are expected to be more vulnerable to global changes although they have received less attention than high diversity ecosystems. Addressing the present state of the Antarctic Dry Valley region by focusing on the potential global changes that may alter the coupling of above- and below-ground species and ecosystem processes is a realistic and critical need that has value beyond the Antarctic community. Presented here are suggested implications of global change on the Dry Valley terrestrial systems and how these effects might be manifested in the future