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O'Connor, Luke

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O'Connor

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Luke

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O'Connor, Luke

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2019 - 20202

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Author's Publications: search.filters.isAuthorOfPublication.21f7cf12-5535-4f92-9461-5d27f2cb7718

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    Quantifying Genetic Effects on Disease Mediated by Assayed Gene Expression Levels
    (Springer Science and Business Media LLC, 2020-05-18) Yao, Doug; O'Connor, Luke; Price, Alkes; Gusev, Alexander
    Disease variants identified by genome-wide association studies (GWAS) tend to overlap with expression quantitative trait loci (eQTLs), but it remains unclear whether this overlap is driven by gene expression levels ‘mediating’ genetic effects on disease. Here, we introduce a new method, mediated expression score regression (MESC), to estimate disease heritability mediated by the cis genetic component of gene expression levels. We applied MESC to GWAS summary statistics for 42 traits (average N = 323,000) and cis-eQTL summary statistics for 48 tissues from the Genotype-Tissue Expression (GTEx) consortium. Averaging across traits, only 11 ± 2% of heritability was mediated by assayed gene expression levels. Expression-mediated heritability was enriched in genes with evidence of selective constraint and genes with disease-appropriate annotations. Our results demonstrate that assayed bulk tissue eQTLs, although disease relevant, cannot explain the majority of disease heritability.
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    Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
    (Springer Science and Business Media LLC, 2019-10) Tin, Adrienne; Marten, Jonathan; Halperin Kuhns, Victoria L.; Li, Yong; Wuttke, Matthias; Kirsten, Holger; Sieber, Karsten B.; Qiu, Chengxiang; Gorski, Mathias; Yu, Zhi; Giri, Ayush; Sveinbjornsson, Gardar; Li, Man; Chu, Audrey Y.; Hoppmann, Anselm; O'Connor, Luke; Prins, Bram; Nutile, Teresa; Noce, Damia; Akiyama, Masato; Cocca, Massimiliano; Ghasemi, Sahar; van der Most, Peter J.; Horn, Katrin; Xu, Yizhe; Fuchsberger, Christian; Sedaghat, Sanaz; Afaq, Saima; Amin, Najaf; Ärnlöv, Johan; Bakker, Stephan J. L.; Bansal, Nisha; Baptista, Daniela; Bergmann, Sven; Biggs, Mary L.; Biino, Ginevra; Boerwinkle, Eric; Bottinger, Erwin P.; Boutin, Thibaud S.; Brumat, Marco; Burkhardt, Ralph; Campana, Eric; Campbell, Archie; Campbell, Harry; Carroll, Robert J.; Catamo, Eulalia; Chambers, John C.; Ciullo, Marina; Concas, Maria Pina; Coresh, Josef; Corre, Tanguy; Cusi, Daniele; Felicita, Sala Cinzia; de Borst, Martin H.; De Grandi, Alessandro; de Mutsert, Renée; de Vries, Aiko P. J.; Delgado, Graciela; Demirkan, Ayşe; Devuyst, Olivier; Dittrich, Katalin; Eckardt, Kai-Uwe; Ehret, Georg; Endlich, Karlhans; Evans, Michele K.; Gansevoort, Ron T.; Gasparini, Paolo; Giedraitis, Vilmantas; Gieger, Christian; Girotto, Giorgia; Gögele, Martin; Gordon, Scott D.; Gudbjartsson, Daniel F.; Gudnason, Vilmundur; Haller, Toomas; Hamet, Pavel; Harris, Tamara B.; Hayward, Caroline; Hicks, Andrew A.; Hofer, Edith; Holm, Hilma; Huang, Wei; Hutri-Kähönen, Nina; Hwang, Shih-Jen; Ikram, M. Arfan; Lewis, Raychel M.; Ingelsson, Erik; Jakobsdottir, Johanna; Jonsdottir, Ingileif; Jonsson, Helgi; Joshi, Peter K.; Josyula, Navya Shilpa; Jung, Bettina; Kähönen, Mika; Kamatani, Yoichiro; Kanai, Masahiro; Kerr, Shona M.; Kiess, Wieland; Kleber, Marcus E.; Koenig, Wolfgang; Kooner, Jaspal S.; Körner, Antje; Kovacs, Peter; Krämer, Bernhard K.; Kronenberg, Florian; Kubo, Michiaki; Kühnel, Brigitte; La Bianca, Martina; Lange, Leslie A.; Lehne, Benjamin; Lehtimäki, Terho; Liu, Jun; Loeffler, Markus; Loos, Ruth J. F.; Lyytikäinen, Leo-Pekka; Magi, Reedik; Mahajan, Anubha; Martin, Nicholas G.; März, Winfried; Mascalzoni, Deborah; Matsuda, Koichi; Meisinger, Christa; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; O'Donnell, Christopher; Wilson, Otis D.; Gaziano, John; Mishra, Pashupati P.; Mohlke, Karen L.; Mononen, Nina; Montgomery, Grant W.; Mook-Kanamori, Dennis O.; Müller-Nurasyid, Martina; Nadkarni, Girish N.; Nalls, Mike A.; Nauck, Matthias; Nikus, Kjell; Ning, Boting; Nolte, Ilja M.; Noordam, Raymond; O’Connell, Jeffrey R.; Olafsson, Isleifur; Padmanabhan, Sandosh; Penninx, Brenda W. J. H.; Perls, Thomas; Peters, Annette; Pirastu, Mario; Pirastu, Nicola; Pistis, Giorgio; Polasek, Ozren; Ponte, Belen; Porteous, David J.; Poulain, Tanja; Preuss, Michael H.; Rabelink, Ton J.; Raffield, Laura M.; Raitakari, Olli T.; Rettig, Rainer; Rheinberger, Myriam; Rice, Kenneth M.; Rizzi, Federica; Robino, Antonietta; Rudan, Igor; Krajcoviechova, Alena; Cifkova, Renata; Rueedi, Rico; Ruggiero, Daniela; Ryan, Kathleen A.; Saba, Yasaman; Salvi, Erika; Schmidt, Helena; Schmidt, Reinhold; Shaffer, Christian M.; Smith, Albert V.; Smith, Blair H.; Spracklen, Cassandra N.; Strauch, Konstantin; Stumvoll, Michael; Sulem, Patrick; Tajuddin, Salman M.; Teren, Andrej; Thiery, Joachim; Thio, Chris H. L.; Thorsteinsdottir, Unnur; Toniolo, Daniela; Tönjes, Anke; Tremblay, Johanne; Uitterlinden, André G.; Vaccargiu, Simona; van der Harst, Pim; van Duijn, Cornelia M.; Verweij, Niek; Völker, Uwe; Vollenweider, Peter; Waeber, Gerard; Waldenberger, Melanie; Whitfield, John B.; Wild, Sarah H.; Wilson, James F.; Yang, Qiong; Zhang, Weihua; Zonderman, Alan B.; Bochud, Murielle; Wilson, James G.; Pendergrass, Sarah A.; Ho, Kevin; Parsa, Afshin; Pramstaller, Peter P.; Psaty, Bruce M.; Böger, Carsten A.; Snieder, Harold; Butterworth, Adam S.; Okada, Yukinori; Edwards, Todd L.; Stefansson, Kari; Susztak, Katalin; Scholz, Markus; Heid, Iris M.; Hung, Adriana M.; Teumer, Alexander; Pattaro, Cristian; Woodward, Owen M.; Vitart, Veronique; Köttgen, Anna
    Elevated serum urate levels cause gout and correlate with cardio-metabolic diseases via poorly understood mechanisms. We performed a trans-ethnic genome-wide association study of serum urate among 457,690 individuals, identifying 183 loci (147 novel) that improve prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardio-metabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci, and co-localization with gene expression in 47 tissues implicated kidney and liver as main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A trans-activated the promoter of the major urate transporter ABCG2 in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional co-regulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardio-metabolic traits.