{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T18:15:58Z","timestamp":1791483358612,"version":"4.3.4"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT092830M"],"award-info":[{"award-number":["WT092830M"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT088806"],"award-info":[{"award-number":["WT088806"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT102215\/2\/13\/2"],"award-info":[{"award-number":["WT102215\/2\/13\/2"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G1001357"],"award-info":[{"award-number":["G1001357"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["102215\/2\/13\/2"],"award-info":[{"award-number":["102215\/2\/13\/2"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UK Medical Research Council Integrative Epidemiology Unit","award":["MC_UU_00011\/1"],"award-info":[{"award-number":["MC_UU_00011\/1"]}]},{"name":"UK Medical Research Council Integrative Epidemiology Unit","award":["MC_UU_00011\/4"],"award-info":[{"award-number":["MC_UU_00011\/4"]}]},{"name":"British Heart Foundation and Diabetes UK","award":["SBF006\\1117"],"award-info":[{"award-number":["SBF006\\1117"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The protein \u03b1-Klotho acts as transmembrane co-receptor for fibroblast growth factor 23 (FGF23) and is a key regulator of phosphate homeostasis. However, \u03b1-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a genome-wide association study (GWAS) meta-analysis followed by Mendelian randomization (MR) of circulating \u03b1-Klotho levels.<\/jats:p>\n               <jats:p>Plasma \u03b1-Klotho levels were measured by enzyme-linked immunosorbent assay (ELISA) in the Ludwigshafen Risk and Cardiovascular Health and Avon Longitudinal Study of Parents and Children (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts.<\/jats:p>\n               <jats:p>Six signals at five loci were associated with circulating \u03b1-Klotho levels at genome-wide significance (P\u2009&amp;lt;\u20095\u2009\u00d7\u200910\u22128), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained &amp;gt;9% of the variation in circulating \u03b1-Klotho levels. MR analyses revealed no causal relationships between \u03b1-Klotho and renal function, FGF23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes followed by targeted MR suggested causal effects of liability of Crohn\u2019s disease risk [Inverse variance weighted (IVW) beta\u2009=\u20090.059 (95% confidence interval 0.026, 0.093)] and low-density lipoprotein cholesterol levels [\u22120.198 (\u22120.332, \u22120.063)] on \u03b1-Klotho.<\/jats:p>\n               <jats:p>Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on \u03b1-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on \u03b1-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively. Significance statement: \u03b1-Klotho as a transmembrane protein is well investigated along the endocrine FGF23-\u03b1-Klotho pathway. However, the role of the circulating form of \u03b1-Klotho, which is generated by cleavage of transmembrane \u03b1-Klotho, remains incompletely understood. Genetic analyses might help to elucidate novel regulatory and functional mechanisms. The identification of genetic factors related to circulating \u03b1-Klotho further enables MR to examine causal relationships with other factors. The findings from the first GWAS meta-analysis of circulating \u03b1-Klotho levels identified six genome-wide significant signals across five genes. Given the function of two of the genes identified, B4GALNT3 and CHST9, it is tempting to speculate that post-translational modification significantly contributes to genetic influences on \u03b1-Klotho levels, presumably by affecting protein turnover and stability.<\/jats:p>","DOI":"10.1093\/hmg\/ddab263","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T19:20:09Z","timestamp":1631733609000},"page":"792-802","source":"Crossref","is-referenced-by-count":24,"title":["GWAS meta-analysis followed by Mendelian randomization revealed potential control mechanisms for circulating \u03b1-Klotho levels"],"prefix":"10.1093","volume":"31","author":[{"given":"Ingrid","family":"Gergei","sequence":"first","affiliation":[{"name":"Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), University Medical Center, Medical Faculty Mannheim, University of Heidelberg, Mannheim 69117, Germany"},{"name":"Therapeutic Area Cardiovascular Medicine, Boehringer Ingelheim International GmbH, Ingelheim 06877, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6623-6839","authenticated-orcid":false,"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK"},{"name":"Population Health Science, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till F M","family":"Andlauer","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Psychiatry, Munich 80804, Germany"},{"name":"Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich 80333, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Brandenburg","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Nephrology, Rhein-Maas Klinikum W\u00fcrselen, W\u00fcrselen 52146, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazanin","family":"Mirza-Schreiber","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen, Neuherberg 85764, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertram","family":"M\u00fcller-Myhsok","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Psychiatry, Munich 80804, Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy), Munich 2145, Germany"},{"name":"Institute of Translational Medicine, University of Liverpool, Liverpool 11341, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard K","family":"Kr\u00e4mer","sequence":"additional","affiliation":[{"name":"Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), University Medical Center, Medical Faculty Mannheim, University of Heidelberg, Mannheim 69117, Germany"},{"name":"European Center for Angioscience ECAS, Medical Faculty Mannheim, University of Heidelberg, Mannheim 69117, Germany"},{"name":"Center for Preventive Medicine and Digital Health Baden-W\u00fcrttemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim 69117, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Richard","sequence":"additional","affiliation":[{"name":"Department of Human Evolutionary Biology, Harvard University, Cambridge 02138, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Falk","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Mov\u00e9rare-Skrtic","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Sahlgrenska Osteoporosis Centre, CBAR, Institute of Medicine, Gothenburg 41296, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claes","family":"Ohlsson","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Sahlgrenska Osteoporosis Centre, CBAR, Institute of Medicine, Gothenburg 41296, Sweden"},{"name":"Department of Drug Treatment, Region V\u00e4stra G\u00f6taland, Sahlgrenska University Hospital, Gothenburg 7163, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Davey Smith","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK"},{"name":"Population Health Science, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winfried","family":"M\u00e4rz","sequence":"additional","affiliation":[{"name":"Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), University Medical Center, Medical Faculty Mannheim, University of Heidelberg, Mannheim 69117, Germany"},{"name":"SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim 24496, Germany"},{"name":"Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8010, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Voelkl","sequence":"additional","affiliation":[{"name":"Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz 4040, Austria"},{"name":"Department of Nephrology and Medical Intensive Care, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Berlin 10117, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin 10623, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan H","family":"Tobias","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK"},{"name":"Musculoskeletal Research Unit, Translational Health, Learning and Research Building, Level 1 , Southmead Hospital, Bristol BS10 5NB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,9,20]]},"reference":[{"key":"2022030413193756400_ref1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s11684-019-0711-y","article-title":"The FGF metabolic 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Genet."},{"key":"2022030413193756400_ref14","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1003062","article-title":"Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: a multivariable Mendelian randomisation analysis","volume":"17","author":"Richardson","year":"2020","journal-title":"PLoS Med."},{"key":"2022030413193756400_ref15","doi-asserted-by":"crossref","first-page":"47534","DOI":"10.1074\/jbc.M308857200","article-title":"Molecular cloning and characterization of a novel human beta 1,4-N-acetylgalactosaminyltransferase, beta 4GalNAc-T3, responsible for the synthesis of N,N'-diacetyllactosediamine, galNAc beta 1-4GlcNAc","volume":"278","author":"Sato","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2022030413193756400_ref16","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1002\/jbmr.3803","article-title":"Mendelian randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures","volume":"34","author":"Zheng","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"2022030413193756400_ref17","doi-asserted-by":"crossref","first-page":"4037","DOI":"10.1210\/jc.2006-0305","article-title":"The role of mutant UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis","volume":"91","author":"Garringer","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2022030413193756400_ref18","doi-asserted-by":"crossref","first-page":"29204","DOI":"10.1074\/jbc.M112.371880","article-title":"Peptide-specific transfer of N-acetylgalactosamine to O-linked glycans by the glycosyltransferases \u03b21,4-N-acetylgalactosaminyl transferase 3 (\u03b24GalNAc-T3) and \u03b24GalNAc-T4","volume":"287","author":"Fiete","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2022030413193756400_ref19","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1073\/pnas.89.1.334","article-title":"Circulatory half-life but not interaction with the lutropin\/chorionic gonadotropin receptor is modulated by sulfation of bovine lutropin oligosaccharides","volume":"89","author":"Baenziger","year":"1992","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2022030413193756400_ref20","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/0092-8674(91)90287-9","article-title":"A hepatic reticuloendothelial cell receptor specific for SO4-4GalNAc beta 1,4GlcNAc beta 1,2Man alpha that mediates rapid clearance of lutropin","volume":"67","author":"Fiete","year":"1991","journal-title":"Cell"},{"key":"2022030413193756400_ref21","doi-asserted-by":"crossref","first-page":"11256","DOI":"10.1073\/pnas.94.21.11256","article-title":"The macrophage\/endothelial cell mannose receptor cDNA encodes a protein that binds oligosaccharides terminating with SO4-4-GalNAcbeta1,4GlcNAcbeta or Man at independent sites","volume":"94","author":"Fiete","year":"1997","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2022030413193756400_ref22","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1073\/pnas.95.5.2089","article-title":"A cysteine-rich domain of the \u2018mannose\u2019 receptor mediates GalNAc-4-SO4 binding","volume":"95","author":"Fiete","year":"1998","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2022030413193756400_ref23","doi-asserted-by":"crossref","first-page":"17052","DOI":"10.1074\/jbc.M101027200","article-title":"The mannose\/N-acetylgalactosamine-4-SO4 receptor displays greater specificity for multivalent than monovalent ligands","volume":"276","author":"Roseman","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2022030413193756400_ref24","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/nsb832","article-title":"The structural basis for specificity in human ABO(H) blood group biosynthesis","volume":"9","author":"Patenaude","year":"2002","journal-title":"Nat. Struct. Biol."},{"key":"2022030413193756400_ref25","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1056\/NEJMoa2020283","article-title":"Genomewide association study of severe Covid-19 with respiratory failure","volume":"383","author":"The Severe Covid-19 GWAS Group","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"2022030413193756400_ref26","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1007\/s000180050038","article-title":"Endothelial dysfunction in the Klotho mouse and downregulation of Klotho gene expression in various animal models of vascular and metabolic diseases","volume":"57","author":"Nagai","year":"2000","journal-title":"Cell. Mol. Life Sci."},{"key":"2022030413193756400_ref27","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0083713","article-title":"Hyperlipidemia-associated renal damage decreases Klotho expression in kidneys from ApoE knockout mice","volume":"8","author":"Sastre","year":"2013","journal-title":"PLoS One"},{"key":"2022030413193756400_ref28","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.2337\/db10-1262","article-title":"Klotho depletion contributes to increased inflammation in kidney of the db\/db mouse model of diabetes via RelA (serine)536 phosphorylation","volume":"60","author":"Zhao","year":"2011","journal-title":"Diabetes"},{"key":"2022030413193756400_ref29","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1053\/j.gastro.2009.12.002","article-title":"Tumor necrosis factor and interferon-gamma down-regulate Klotho in mice with colitis","volume":"138","author":"Thurston","year":"2010","journal-title":"Gastroenterology"},{"key":"2022030413193756400_ref30","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1681\/ASN.2010101073","article-title":"The inflammatory cytokines TWEAK and TNFalpha reduce renal klotho expression through NFkappaB","volume":"22","author":"Moreno","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"2022030413193756400_ref31","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.18632\/aging.102734","article-title":"Association between serum levels of Klotho and inflammatory cytokines in cardiovascular disease: a case-control study","volume":"12","author":"Martin-Nunez","year":"2020","journal-title":"Aging"},{"key":"2022030413193756400_ref32","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1126\/science.1135245","article-title":"A genome-wide association study identifies IL23R as an inflammatory bowel disease gene","volume":"314","author":"Duerr","year":"2006","journal-title":"Science"},{"key":"2022030413193756400_ref33","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/ckj\/sfz085","article-title":"Performance of soluble Klotho assays in clinical samples of kidney disease","volume":"13","author":"Neyra","year":"2019","journal-title":"Clin. Kidney J."},{"key":"2022030413193756400_ref34","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1517\/14622416.2.1.S1","article-title":"Rationale and design of the LURIC study--a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease","volume":"2","author":"Winkelmann","year":"2001","journal-title":"Pharmacogenomics"},{"key":"2022030413193756400_ref35","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"2022030413193756400_ref36","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.1501678","article-title":"Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation","volume":"2","author":"Andlauer","year":"2016","journal-title":"Sci. Adv."},{"key":"2022030413193756400_ref37","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1038\/ng.2354","article-title":"Fast and accurate genotype imputation in genome-wide association studies through pre-phasing","volume":"44","author":"Howie","year":"2012","journal-title":"Nat. Genet."},{"key":"2022030413193756400_ref38","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1000529","article-title":"A flexible and accurate genotype imputation method for the next generation of genome-wide association studies","volume":"5","author":"Howie","year":"2009","journal-title":"PLoS Genet."},{"key":"2022030413193756400_ref39","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/nmeth.2307","article-title":"Improved whole-chromosome phasing for disease and population genetic studies","volume":"10","author":"Delaneau","year":"2013","journal-title":"Nat. Methods"},{"key":"2022030413193756400_ref40","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/ije\/dys064","article-title":"Cohort Profile: the \u2018children of the 90s\u2019--the index offspring of the Avon Longitudinal Study of Parents and Children","volume":"42","author":"Boyd","year":"2013","journal-title":"Int. J. Epidemiol."},{"key":"2022030413193756400_ref41","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/ije\/dys066","article-title":"Cohort Profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort","volume":"42","author":"Fraser","year":"2013","journal-title":"Int. J. Epidemiol."},{"key":"2022030413193756400_ref42","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.bbrc.2010.06.110","article-title":"Establishment of sandwich ELISA for soluble alpha-Klotho measurement: age-dependent change of soluble alpha-Klotho levels in healthy subjects","volume":"398","author":"Yamazaki","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2022030413193756400_ref43","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1023\/A:1008868325009","article-title":"Maternally expressed PGK-Cre transgene as a tool for early and uniform activation of the Cre site-specific recombinase","volume":"7","author":"Lallemand","year":"1998","journal-title":"Transgenic Res."},{"key":"2022030413193756400_ref44","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1093\/ndt\/gfu291","article-title":"The demonstration of \u03b1Klotho deficiency in human chronic kidney disease with a novel synthetic antibody","volume":"30","author":"Barker","year":"2014","journal-title":"Nephrol. Dial. Transplant."},{"key":"2022030413193756400_ref45","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1093\/bioinformatics\/btq340","article-title":"METAL: fast and efficient meta-analysis of genomewide association scans","volume":"26","author":"Willer","year":"2010","journal-title":"Bioinformatics"},{"key":"2022030413193756400_ref46","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/ng.3211","article-title":"LD score regression distinguishes confounding from polygenicity in genome-wide association studies","volume":"47","author":"Bulik-Sullivan","year":"2015","journal-title":"Nat. Genet."},{"key":"2022030413193756400_ref47","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/ng.3406","article-title":"An atlas of genetic correlations across human diseases and traits","volume":"47","author":"Bulik-Sullivan","year":"2015","journal-title":"Nat. Genet."},{"key":"2022030413193756400_ref48","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1093\/bioinformatics\/btw613","article-title":"LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis","volume":"33","author":"Zheng","year":"2016","journal-title":"Bioinformatics"},{"key":"2022030413193756400_ref49","doi-asserted-by":"crossref","first-page":"R89","DOI":"10.1093\/hmg\/ddu328","article-title":"Mendelian randomization: genetic anchors for causal inference in epidemiological studies","volume":"23","author":"Davey Smith","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"2022030413193756400_ref50","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"2022030413193756400_ref51","first-page":"1961","article-title":"Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic","volume":"45","author":"Bowden","year":"2016","journal-title":"Int. J. Epidemiol."},{"key":"2022030413193756400_ref52","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption","volume":"46","author":"Hartwig","year":"2017","journal-title":"Int. J. Epidemiol."},{"key":"2022030413193756400_ref53","doi-asserted-by":"crossref","DOI":"10.1093\/gigascience\/giy090","article-title":"PhenoSpD: an integrated toolkit for phenotypic correlation estimation and multiple testing correction using GWAS summary statistics","volume":"7","author":"Zheng","year":"2018","journal-title":"Gigascience"},{"key":"2022030413193756400_ref54","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/ije\/dyy262","article-title":"An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings","volume":"48","author":"Sanderson","year":"2019","journal-title":"Int. J. Epidemiol."},{"key":"2022030413193756400_ref55","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nature24277","article-title":"Genetic effects on gene expression across human tissues","volume":"550","author":"Battle","year":"2017","journal-title":"Nature"},{"key":"2022030413193756400_ref56","article-title":"Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis","author":"V\u00f5sa","year":"2018","journal-title":"bioRxiv"},{"key":"2022030413193756400_ref57","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1101\/gr.137323.112","article-title":"Annotation of functional variation in personal genomes using RegulomeDB","volume":"22","author":"Boyle","year":"2012","journal-title":"Genome Res."},{"key":"2022030413193756400_ref58","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1004383","article-title":"Bayesian test for colocalisation between pairs of genetic association studies using summary statistics","volume":"10","author":"Giambartolomei","year":"2014","journal-title":"PLoS Genet."},{"key":"2022030413193756400_ref59","doi-asserted-by":"crossref","first-page":"D794","DOI":"10.1093\/nar\/gkx1081","article-title":"The Encyclopedia of DNA elements (ENCODE): data portal update","volume":"46","author":"Davis","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2022030413193756400_ref60","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1093\/bib\/bbs038","article-title":"The UCSC genome browser and associated tools","volume":"14","author":"Kuhn","year":"2013","journal-title":"Brief. 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