A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Via Peters
  • Asrani, S. K., Devarbhavi, H., Eaton, J. & Kamath, P. S. Burden of liver diseases in the world. J. Hepatol. 70, 151–171 (2019).

    PubMed 
    Article 

    Google Scholar
     

  • Younossi, Z., Anstee, Q. M. & Marietti, M. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15, 11–20 (2018).

    PubMed 
    Article 

    Google Scholar
     

  • Estes, C., Razavi, H., Loomba, R., Younossi, Z. & Sanyal, A. J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 67, 123–133 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Carr, R. M., Oranu, A. & Khungar, V. Nonalcoholic fatty liver disease: pathophysiology and management. Gastroenterol. Clin. North Am. 45, 639–652 (2016).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Chalasani, N. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67, 328–357 (2018).

    PubMed 
    Article 

    Google Scholar
     

  • Sookoian, S. & Pirola, C. J. Genetic predisposition in nonalcoholic fatty liver disease. Clin. Mol. Hepatol. 23, 1–12 (2017).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Chambers, J. C. et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat. Genet. 43, 1131–1138 (2011).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Speliotes, E. K. et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 7, e1001324 (2011).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Emdin, C. A. et al. A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease. PLoS Genet. 16, e1008629 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Anstee, Q. M. et al. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort. J. Hepatol. 73, 505–515 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Gaziano, J. M. et al. Million Veteran Program: a mega-biobank to study genetic influences on health and disease. J. Clin. Epidemiol. 70, 214–223 (2016).

    PubMed 
    Article 

    Google Scholar
     

  • Husain, N. et al. Nonalcoholic fatty liver disease (NAFLD) in the Veterans Administration population: development and validation of an algorithm for NAFLD using automated data. Aliment Pharm. Ther. 40, 949–954 (2014).

    CAS 
    Article 

    Google Scholar
     

  • Serper, M. et al. Validating a non-invasive non-alcoholic fatty liver phenotype in the Million Veteran Program. PLoS One 15, e0237430 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • de Vries, P. S. et al. Multiancestry genome-wide association study of lipid levels incorporating gene-alcohol interactions. Am. J. Epidemiol. 188, 1033–1054 (2019).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Kozlitina, J. et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46, 352–356 (2014).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Abul-Husn, N. S. et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N. Engl. J. Med. 378, 1096–1106 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Young, K. A. et al. Genome-wide association study identifies loci for liver enzyme concentrations in Mexican Americans: the GUARDIAN Consortium. Obes. (Silver Spring) 27, 1331–1337 (2019).

    CAS 
    Article 

    Google Scholar
     

  • Namjou, B. et al. GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network. BMC Med. 17, 135 (2019).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Chalasani, N. et al. Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Gastroenterology 139, 1567–1576 (2010). 1576 e1-6.

    PubMed 
    Article 

    Google Scholar
     

  • Chen, V. L. et al. Genome-wide association study of serum liver enzymes implicates diverse metabolic and liver pathology. Nat. Commun. 12, 816 (2021).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Pazoki, R. et al. Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes. Nat. Commun. 12, 2579 (2021).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Stephens, C. R. et al. The impact of education and age on metabolic disorders. Front Public Health 8, 180 (2020).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Wakefield, J. Bayes factors for genome-wide association studies: comparison with P-values. Genet. Epidemiol. 33, 79–86 (2009).

    PubMed 
    Article 

    Google Scholar
     

  • Baxter, M. et al. Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes. J. Hepatol. 62, 581–589 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Brancale, J. & Vilarinho, S. A single cell gene expression atlas of 28 human livers. J. Hepatol. 75, 219–220 (2021).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Goldstein, J. A. et al. LabWAS: novel findings and study design recommendations from a meta-analysis of clinical labs in two independent biobanks. PLoS Genet. 16, e1009077 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Sliz, E. et al. NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects. Hum. Mol. Genet 27, 2214–2223 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Stender, S. et al. Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride. Hepatology 67, 2182–2195 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Mehta, M. B. et al. Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis. J. Biol. Chem. 292, 10444–10454 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Brouwers, M., Jacobs, C., Bast, A., Stehouwer, C. D. A. & Schaper, N. C. Modulation of glucokinase regulatory protein: a double-edged sword? Trends Mol. Med. 21, 583–594 (2015).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Fagerberg, L. et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol. Cell Proteom. 13, 397–406 (2014).

    CAS 
    Article 

    Google Scholar
     

  • Duff, M. O. et al. Genome-wide identification of zero nucleotide recursive splicing in Drosophila. Nature 521, 376–379 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Jamialahmadi, O. et al. Exome-wide association study on alanine aminotransferase identifies sequence variants in the GPAM and APOE associated with fatty liver disease. Gastroenterology 160, 1634–1646 e7 (2021).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Hammond, L. E. et al. Mitochondrial glycerol-3-phosphate acyltransferase-deficient mice have reduced weight and liver triacylglycerol content and altered glycerolipid fatty acid composition. Mol. Cell. Biol. 22, 8204–8214 (2002).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Cuchel, M. et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N. Engl. J. Med. 356, 148–156 (2007).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Soubeyrand, S., Martinuk, A. & McPherson, R. TRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha. Sci. Rep. 7, 5574 (2017).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Laudadio, I. et al. A feedback loop between the liver-enriched transcription factor network and miR-122 controls hepatocyte differentiation. Gastroenterology 142, 119–129 (2012).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Kim, J. Y., Han, Y. H., Nam, M. W., Kim, H. J. & Lee, M. O. RORalpha suppresses interleukin-6-mediated hepatic acute phase response. Sci. Rep. 9, 11798 (2019).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Laatsch, A. et al. Low density lipoprotein receptor-related protein 1 dependent endosomal trapping and recycling of apolipoprotein E. PLoS One 7, e29385 (2012).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Musso, G., Cassader, M., Paschetta, E. & Gambino, R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med. 177, 633–640 (2017).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Ratziu, V. et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 51, 445–453 (2010).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Cusi, K. et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann. Intern Med. 165, 305–315 (2016).

    PubMed 
    Article 

    Google Scholar
     

  • Tilg, H., Adolph, T. E. & Moschen, A. R. Multiple parallel hits hypothesis in nonalcoholic fatty liver disease: revisited after a decade. Hepatology 73, 833–842 (2021).

    PubMed 
    Article 

    Google Scholar
     

  • Hamada, M., Tsunakawa, Y., Jeon, H., Yadav, M. K. & Takahashi, S. Role of MafB in macrophages. Exp. Anim. 69, 1–10 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Klarin, D. et al. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program. Nat. Genet. 50, 1514–1523 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Stoffel, W. et al. Obesity resistance and deregulation of lipogenesis in Delta6-fatty acid desaturase (FADS2) deficiency. EMBO Rep. 15, 110–120 (2014).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Mirea, A. M., Tack, C. J., Chavakis, T., Joosten, L. A. B. & Toonen, E. J. M. IL-1 family cytokine pathways underlying NAFLD: towards new treatment strategies. Trends Mol. Med. 24, 458–471 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Miao, Z. et al. Identification of 90 NAFLD GWAS loci and establishment of NAFLD PRS and causal role of NAFLD in coronary artery disease. HGG Adv. 3, 100056 (2022).

    PubMed 

    Google Scholar
     

  • Kranzler, H. R. et al. Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations. Nat. Commun. 10, 1499 (2019).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Justice, A. C. et al. AUDIT-C and ICD codes as phenotypes for harmful alcohol use: association with ADH1B polymorphisms in two US populations. Addiction 113, 2214–2224 (2018).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Hutchinson, A., Watson, H. & Wallace, C. Improving the coverage of credible sets in Bayesian genetic fine-mapping. PLoS Comput. Biol. 16, e1007829 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • MacLean, M. T. et al. Quantification of abdominal fat from computed tomography using deep learning and its association with electronic health records in an academic biobank. J. Am. Med. Inform. Assoc. 28, 1178–1187 (2021).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Haas, M. E. et al. Machine learning enables new insights into genetic contributions to liver fat accumulation. Cell Genom. 1, 100066 (2021).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Wattacheril, J. et al. Genome-wide associations related to hepatic histology in nonalcoholic fatty liver disease in Hispanic boys. J. Pediatr. 190, 100–107 (2017).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Patton, H. M. et al. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology 135, 1961–1971 (2008).

    PubMed 
    Article 

    Google Scholar
     

  • Lin, H. J. et al. Home use of a compact, 12lead ECG recording system for newborns. J. Electrocardiol. 53, 89–94 (2019).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Weinshilboum, R. M. & Wang, L. Pharmacogenomics: precision medicine and drug response. Mayo Clin. Proc. 92, 1711–1722 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Simon, J. A. et al. Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) study. Am. J. Cardiol. 97, 843–850 (2006).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Hardy, T. et al. The European NAFLD Registry: a real-world longitudinal cohort study of nonalcoholic fatty liver disease. Contemp. Clin. Trials 98, 106175 (2020).

    PubMed 
    Article 

    Google Scholar
     

  • Angulo, P. et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389–397 (2015).

    PubMed 
    Article 

    Google Scholar
     

  • Dewey, F. E. et al. Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. Science 354, aaf6814 (2016).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • Harrison, S. A. et al. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials. J. Hepatol. 73, 26–39 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Roden, D. M. et al. Development of a large-scale de-identified DNA biobank to enable personalized medicine. Clin. Pharmacol. Ther. 84, 362–369 (2008).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Roadmap Epigenomics Consortium et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).

    Article 
    CAS 

    Google Scholar
     

  • Andersson, R. et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455–461 (2014).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Finucane, H. K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Finucane, H. K. et al. Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nat. Genet. 50, 621–629 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • CARDIoGRAMplusC4D Consortium et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat. Genet. 45, 25–33 (2013).

    Article 
    CAS 

    Google Scholar
     

  • Fehrmann, R. S. et al. Gene expression analysis identifies global gene dosage sensitivity in cancer. Nat. Genet. 47, 115–125 (2015).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Cahoy, J. D. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Heng, T. S. & Painter, M. W., Immunological Genome Project Consortium. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Pers, T. H. et al. Biological interpretation of genome-wide association studies using predicted gene functions. Nat. Commun. 6, 5890 (2015).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Schmidt, E. M. et al. GREGOR: evaluating global enrichment of trait-associated variants in epigenomic features using a systematic, data-driven approach. Bioinformatics 31, 2601–2606 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • McLaren, W. et al. The ensembl variant effect predictor. Genome Biol. 17, 122 (2016).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 1000 Genomes Project Consortium et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).

    Article 
    CAS 

    Google Scholar
     

  • GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).

    Article 
    CAS 

    Google Scholar
     

  • Chesi, A. et al. Genome-scale Capture-C promoter interactions implicate effector genes at GWAS loci for bone mineral density. Nat. Commun. 10, 1260 (2019).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Pashos, E. E. et al. Large, diverse population cohorts of hiPSCs and derived hepatocyte-like cells reveal functional genetic variation at blood lipid-associated loci. Cell Stem Cell 20, 558–570 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Caliskan, M. et al. Genetic and epigenetic fine mapping of complex trait associated loci in the human liver. Am. J. Hum. Genet 105, 89–107 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Wingett, S. et al. HiCUP: pipeline for mapping and processing Hi-C data. F1000Res 4, 1310 (2015).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Cairns, J. et al. CHiCAGO: robust detection of DNA looping interactions in Capture Hi-C data. Genome Biol. 17, 127 (2016).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Szklarczyk, D. et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47, D607–D613 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Gagliano Taliun, S. A. et al. Exploring and visualizing large-scale genetic associations by using PheWeb. Nat. Genet. 52, 550–552 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Denny, J. C. et al. PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations. Bioinformatics 26, 1205–1210 (2010).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Loh, P. R. et al. Reference-based phasing using the Haplotype Reference Consortium panel. Nat. Genet. 48, 1443–1448 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Zhou, W. et al. Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat. Genet. 50, 1335–1341 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Elsworth, B. et al. The MRC IEU OpenGWAS data infrastructure. Preprint at bioRxiv, https://doi.org/10.1101/2020.08.10.244293 (2020).

  • Shin, S. et al. CREB mediates the insulinotropic and anti-apoptotic effects of GLP-1 signaling in adult mouse beta-cells. Mol. Metab. 3, 803–812 (2014).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Kettunen, J. et al. Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA. Nat. Commun. 7, 11122 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Hemani, G. et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife 7, e34408 (2018).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Sun, B. B. et al. Genomic atlas of the human plasma proteome. Nature 558, 73–79 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Giri, A. et al. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. Nat. Genet. 51, 51–62 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Pulit, S. L. et al. Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry. Hum. Mol. Genet 28, 166–174 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Teumer, A. et al. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. Nat. Commun. 10, 4130 (2019).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Tin, A. et al. Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. Nat. Genet. 51, 1459–1474 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Wuttke, M. et al. A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nat. Genet. 51, 957–972 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Astle, W. J. et al. The allelic landscape of human blood cell trait variation and links to common complex disease. Cell 167, 1415–1429 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Guo, H. et al. Integration of disease association and eQTL data using a Bayesian colocalisation approach highlights six candidate causal genes in immune-mediated diseases. Hum. Mol. Genet 24, 3305–3313 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Lambert, S. A. et al. The human transcription factors. Cell 175, 598–599 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Garcia-Alonso, L., Holland, C. H., Ibrahim, M. M., Turei, D. & Saez-Rodriguez, J. Benchmark and integration of resources for the estimation of human transcription factor activities. Genome Res. 29, 1363–1375 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Turei, D., Korcsmaros, T. & Saez-Rodriguez, J. OmniPath: guidelines and gateway for literature-curated signaling pathway resources. Nat. Methods 13, 966–967 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Ceccarelli, F., Turei, D., Gabor, A. & Saez-Rodriguez, J. Bringing data from curated pathway resources to Cytoscape with OmniPath. Bioinformatics 36, 2632–2633 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • https://www.nature.com/articles/s41588-022-01078-z

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