%0 Journal Article %J Diabetes Care %D 2015 %T Gene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits. %A Dashti, Hassan S %A Follis, Jack L %A Smith, Caren E %A Tanaka, Toshiko %A Garaulet, Marta %A Gottlieb, Daniel J %A Hruby, Adela %A Jacques, Paul F %A Kiefte-de Jong, Jessica C %A Lamon-Fava, Stefania %A Scheer, Frank A J L %A Bartz, Traci M %A Kovanen, Leena %A Wojczynski, Mary K %A Frazier-Wood, Alexis C %A Ahluwalia, Tarunveer S %A Perälä, Mia-Maria %A Jonsson, Anna %A Muka, Taulant %A Kalafati, Ioanna P %A Mikkilä, Vera %A Ordovas, Jose M %K Adult %K Alleles %K Blood Glucose %K Circadian Rhythm Signaling Peptides and Proteins %K Cohort Studies %K Diabetes Mellitus, Type 2 %K Diet, Fat-Restricted %K European Continental Ancestry Group %K Fasting %K Female %K Gene-Environment Interaction %K Humans %K Insulin Resistance %K Male %K Middle Aged %K Multicenter Studies as Topic %K Observational Studies as Topic %K Phenotype %K Polymorphism, Single Nucleotide %K Sleep %K Waist Circumference %X

OBJECTIVE: Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations.

RESEARCH DESIGN AND METHODS: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

RESULTS: We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m(2) higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (≥7 to <9 h).

CONCLUSIONS: Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet—specifically higher carbohydrate and lower fat composition—and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants.

%B Diabetes Care %V 38 %P 1456-66 %8 2015 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/26084345?dopt=Abstract %R 10.2337/dc14-2709 %0 Journal Article %J Hum Mol Genet %D 2016 %T A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. %A de Vries, Paul S %A Chasman, Daniel I %A Sabater-Lleal, Maria %A Chen, Ming-Huei %A Huffman, Jennifer E %A Steri, Maristella %A Tang, Weihong %A Teumer, Alexander %A Marioni, Riccardo E %A Grossmann, Vera %A Hottenga, Jouke J %A Trompet, Stella %A Müller-Nurasyid, Martina %A Zhao, Jing Hua %A Brody, Jennifer A %A Kleber, Marcus E %A Guo, Xiuqing %A Wang, Jie Jin %A Auer, Paul L %A Attia, John R %A Yanek, Lisa R %A Ahluwalia, Tarunveer S %A Lahti, Jari %A Venturini, Cristina %A Tanaka, Toshiko %A Bielak, Lawrence F %A Joshi, Peter K %A Rocanin-Arjo, Ares %A Kolcic, Ivana %A Navarro, Pau %A Rose, Lynda M %A Oldmeadow, Christopher %A Riess, Helene %A Mazur, Johanna %A Basu, Saonli %A Goel, Anuj %A Yang, Qiong %A Ghanbari, Mohsen %A Willemsen, Gonneke %A Rumley, Ann %A Fiorillo, Edoardo %A de Craen, Anton J M %A Grotevendt, Anne %A Scott, Robert %A Taylor, Kent D %A Delgado, Graciela E %A Yao, Jie %A Kifley, Annette %A Kooperberg, Charles %A Qayyum, Rehan %A Lopez, Lorna M %A Berentzen, Tina L %A Räikkönen, Katri %A Mangino, Massimo %A Bandinelli, Stefania %A Peyser, Patricia A %A Wild, Sarah %A Trégouët, David-Alexandre %A Wright, Alan F %A Marten, Jonathan %A Zemunik, Tatijana %A Morrison, Alanna C %A Sennblad, Bengt %A Tofler, Geoffrey %A de Maat, Moniek P M %A de Geus, Eco J C %A Lowe, Gordon D %A Zoledziewska, Magdalena %A Sattar, Naveed %A Binder, Harald %A Völker, Uwe %A Waldenberger, Melanie %A Khaw, Kay-Tee %A McKnight, Barbara %A Huang, Jie %A Jenny, Nancy S %A Holliday, Elizabeth G %A Qi, Lihong %A Mcevoy, Mark G %A Becker, Diane M %A Starr, John M %A Sarin, Antti-Pekka %A Hysi, Pirro G %A Hernandez, Dena G %A Jhun, Min A %A Campbell, Harry %A Hamsten, Anders %A Rivadeneira, Fernando %A McArdle, Wendy L %A Slagboom, P Eline %A Zeller, Tanja %A Koenig, Wolfgang %A Psaty, Bruce M %A Haritunians, Talin %A Liu, Jingmin %A Palotie, Aarno %A Uitterlinden, André G %A Stott, David J %A Hofman, Albert %A Franco, Oscar H %A Polasek, Ozren %A Rudan, Igor %A Morange, Pierre-Emmanuel %A Wilson, James F %A Kardia, Sharon L R %A Ferrucci, Luigi %A Spector, Tim D %A Eriksson, Johan G %A Hansen, Torben %A Deary, Ian J %A Becker, Lewis C %A Scott, Rodney J %A Mitchell, Paul %A März, Winfried %A Wareham, Nick J %A Peters, Annette %A Greinacher, Andreas %A Wild, Philipp S %A Jukema, J Wouter %A Boomsma, Dorret I %A Hayward, Caroline %A Cucca, Francesco %A Tracy, Russell %A Watkins, Hugh %A Reiner, Alex P %A Folsom, Aaron R %A Ridker, Paul M %A O'Donnell, Christopher J %A Smith, Nicholas L %A Strachan, David P %A Dehghan, Abbas %X

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

%B Hum Mol Genet %V 25 %P 358-70 %8 2016 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26561523?dopt=Abstract %R 10.1093/hmg/ddv454 %0 Journal Article %J Nat Commun %D 2016 %T A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. %A Ried, Janina S %A Jeff M, Janina %A Chu, Audrey Y %A Bragg-Gresham, Jennifer L %A van Dongen, Jenny %A Huffman, Jennifer E %A Ahluwalia, Tarunveer S %A Cadby, Gemma %A Eklund, Niina %A Eriksson, Joel %A Esko, Tõnu %A Feitosa, Mary F %A Goel, Anuj %A Gorski, Mathias %A Hayward, Caroline %A Heard-Costa, Nancy L %A Jackson, Anne U %A Jokinen, Eero %A Kanoni, Stavroula %A Kristiansson, Kati %A Kutalik, Zoltán %A Lahti, Jari %A Luan, Jian'an %A Mägi, Reedik %A Mahajan, Anubha %A Mangino, Massimo %A Medina-Gómez, Carolina %A Monda, Keri L %A Nolte, Ilja M %A Perusse, Louis %A Prokopenko, Inga %A Qi, Lu %A Rose, Lynda M %A Salvi, Erika %A Smith, Megan T %A Snieder, Harold %A Stančáková, Alena %A Ju Sung, Yun %A Tachmazidou, Ioanna %A Teumer, Alexander %A Thorleifsson, Gudmar %A van der Harst, Pim %A Walker, Ryan W %A Wang, Sophie R %A Wild, Sarah H %A Willems, Sara M %A Wong, Andrew %A Zhang, Weihua %A Albrecht, Eva %A Couto Alves, Alexessander %A Bakker, Stephan J L %A Barlassina, Cristina %A Bartz, Traci M %A Beilby, John %A Bellis, Claire %A Bergman, Richard N %A Bergmann, Sven %A Blangero, John %A Blüher, Matthias %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Bruinenberg, Marcel %A Campbell, Harry %A Chen, Yii-Der Ida %A Chiang, Charleston W K %A Chines, Peter S %A Collins, Francis S %A Cucca, Fracensco %A Cupples, L Adrienne %A D'Avila, Francesca %A de Geus, Eco J C %A Dedoussis, George %A Dimitriou, Maria %A Döring, Angela %A Eriksson, Johan G %A Farmaki, Aliki-Eleni %A Farrall, Martin %A Ferreira, Teresa %A Fischer, Krista %A Forouhi, Nita G %A Friedrich, Nele %A Gjesing, Anette Prior %A Glorioso, Nicola %A Graff, Mariaelisa %A Grallert, Harald %A Grarup, Niels %A Gräßler, Jürgen %A Grewal, Jagvir %A Hamsten, Anders %A Harder, Marie Neergaard %A Hartman, Catharina A %A Hassinen, Maija %A Hastie, Nicholas %A Hattersley, Andrew Tym %A Havulinna, Aki S %A Heliövaara, Markku %A Hillege, Hans %A Hofman, Albert %A Holmen, Oddgeir %A Homuth, Georg %A Hottenga, Jouke-Jan %A Hui, Jennie %A Husemoen, Lise Lotte %A Hysi, Pirro G %A Isaacs, Aaron %A Ittermann, Till %A Jalilzadeh, Shapour %A James, Alan L %A Jørgensen, Torben %A Jousilahti, Pekka %A Jula, Antti %A Marie Justesen, Johanne %A Justice, Anne E %A Kähönen, Mika %A Karaleftheri, Maria %A Tee Khaw, Kay %A Keinanen-Kiukaanniemi, Sirkka M %A Kinnunen, Leena %A Knekt, Paul B %A Koistinen, Heikki A %A Kolcic, Ivana %A Kooner, Ishminder K %A Koskinen, Seppo %A Kovacs, Peter %A Kyriakou, Theodosios %A Laitinen, Tomi %A Langenberg, Claudia %A Lewin, Alexandra M %A Lichtner, Peter %A Lindgren, Cecilia M %A Lindström, Jaana %A Linneberg, Allan %A Lorbeer, Roberto %A Lorentzon, Mattias %A Luben, Robert %A Lyssenko, Valeriya %A Männistö, Satu %A Manunta, Paolo %A Leach, Irene Mateo %A McArdle, Wendy L %A McKnight, Barbara %A Mohlke, Karen L %A Mihailov, Evelin %A Milani, Lili %A Mills, Rebecca %A Montasser, May E %A Morris, Andrew P %A Müller, Gabriele %A Musk, Arthur W %A Narisu, Narisu %A Ong, Ken K %A Oostra, Ben A %A Osmond, Clive %A Palotie, Aarno %A Pankow, James S %A Paternoster, Lavinia %A Penninx, Brenda W %A Pichler, Irene %A Pilia, Maria G %A Polasek, Ozren %A Pramstaller, Peter P %A Raitakari, Olli T %A Rankinen, Tuomo %A Rao, D C %A Rayner, Nigel W %A Ribel-Madsen, Rasmus %A Rice, Treva K %A Richards, Marcus %A Ridker, Paul M %A Rivadeneira, Fernando %A Ryan, Kathy A %A Sanna, Serena %A Sarzynski, Mark A %A Scholtens, Salome %A Scott, Robert A %A Sebert, Sylvain %A Southam, Lorraine %A Sparsø, Thomas Hempel %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen %A Stolk, Ronald P %A Strauch, Konstantin %A Stringham, Heather M %A Swertz, Morris A %A Swift, Amy J %A Tönjes, Anke %A Tsafantakis, Emmanouil %A van der Most, Peter J %A van Vliet-Ostaptchouk, Jana V %A Vandenput, Liesbeth %A Vartiainen, Erkki %A Venturini, Cristina %A Verweij, Niek %A Viikari, Jorma S %A Vitart, Veronique %A Vohl, Marie-Claude %A Vonk, Judith M %A Waeber, Gérard %A Widen, Elisabeth %A Willemsen, Gonneke %A Wilsgaard, Tom %A Winkler, Thomas W %A Wright, Alan F %A Yerges-Armstrong, Laura M %A Hua Zhao, Jing %A Zillikens, M Carola %A Boomsma, Dorret I %A Bouchard, Claude %A Chambers, John C %A Chasman, Daniel I %A Cusi, Daniele %A Gansevoort, Ron T %A Gieger, Christian %A Hansen, Torben %A Hicks, Andrew A %A Hu, Frank %A Hveem, Kristian %A Jarvelin, Marjo-Riitta %A Kajantie, Eero %A Kooner, Jaspal S %A Kuh, Diana %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Metspalu, Andres %A Njølstad, Inger %A Ohlsson, Claes %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Pedersen, Oluf %A Perola, Markus %A Peters, Annette %A Psaty, Bruce M %A Puolijoki, Hannu %A Rauramaa, Rainer %A Rudan, Igor %A Salomaa, Veikko %A Schwarz, Peter E H %A Shudiner, Alan R %A Smit, Jan H %A Sørensen, Thorkild I A %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Tremblay, Angelo %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A Völker, Uwe %A Vollenweider, Peter %A Wareham, Nicholas J %A Watkins, Hugh %A Wilson, James F %A Zeggini, Eleftheria %A Abecasis, Goncalo R %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A van Duijn, Cornelia M %A Fox, Caroline %A Groop, Leif C %A Heid, Iris M %A Hunter, David J %A Kaplan, Robert C %A McCarthy, Mark I %A North, Kari E %A O'Connell, Jeffrey R %A Schlessinger, David %A Thorsteinsdottir, Unnur %A Strachan, David P %A Frayling, Timothy %A Hirschhorn, Joel N %A Müller-Nurasyid, Martina %A Loos, Ruth J F %K Anthropometry %K Body Size %K Genome-Wide Association Study %K Genotype %K Humans %K Models, Genetic %K Principal Component Analysis %X

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

%B Nat Commun %V 7 %P 13357 %8 2016 11 23 %G eng %R 10.1038/ncomms13357 %0 Journal Article %J J Am Soc Nephrol %D 2016 %T SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. %A Li, Man %A Li, Yong %A Weeks, Olivia %A Mijatovic, Vladan %A Teumer, Alexander %A Huffman, Jennifer E %A Tromp, Gerard %A Fuchsberger, Christian %A Gorski, Mathias %A Lyytikäinen, Leo-Pekka %A Nutile, Teresa %A Sedaghat, Sanaz %A Sorice, Rossella %A Tin, Adrienne %A Yang, Qiong %A Ahluwalia, Tarunveer S %A Arking, Dan E %A Bihlmeyer, Nathan A %A Böger, Carsten A %A Carroll, Robert J %A Chasman, Daniel I %A Cornelis, Marilyn C %A Dehghan, Abbas %A Faul, Jessica D %A Feitosa, Mary F %A Gambaro, Giovanni %A Gasparini, Paolo %A Giulianini, Franco %A Heid, Iris %A Huang, Jinyan %A Imboden, Medea %A Jackson, Anne U %A Jeff, Janina %A Jhun, Min A %A Katz, Ronit %A Kifley, Annette %A Kilpeläinen, Tuomas O %A Kumar, Ashish %A Laakso, Markku %A Li-Gao, Ruifang %A Lohman, Kurt %A Lu, Yingchang %A Mägi, Reedik %A Malerba, Giovanni %A Mihailov, Evelin %A Mohlke, Karen L %A Mook-Kanamori, Dennis O %A Robino, Antonietta %A Ruderfer, Douglas %A Salvi, Erika %A Schick, Ursula M %A Schulz, Christina-Alexandra %A Smith, Albert V %A Smith, Jennifer A %A Traglia, Michela %A Yerges-Armstrong, Laura M %A Zhao, Wei %A Goodarzi, Mark O %A Kraja, Aldi T %A Liu, Chunyu %A Wessel, Jennifer %A Boerwinkle, Eric %A Borecki, Ingrid B %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Braga, Daniele %A Brandslund, Ivan %A Brody, Jennifer A %A Campbell, Archie %A Carey, David J %A Christensen, Cramer %A Coresh, Josef %A Crook, Errol %A Curhan, Gary C %A Cusi, Daniele %A de Boer, Ian H %A de Vries, Aiko P J %A Denny, Joshua C %A Devuyst, Olivier %A Dreisbach, Albert W %A Endlich, Karlhans %A Esko, Tõnu %A Franco, Oscar H %A Fulop, Tibor %A Gerhard, Glenn S %A Glümer, Charlotte %A Gottesman, Omri %A Grarup, Niels %A Gudnason, Vilmundur %A Harris, Tamara B %A Hayward, Caroline %A Hocking, Lynne %A Hofman, Albert %A Hu, Frank B %A Husemoen, Lise Lotte N %A Jackson, Rebecca D %A Jørgensen, Torben %A Jørgensen, Marit E %A Kähönen, Mika %A Kardia, Sharon L R %A König, Wolfgang %A Kooperberg, Charles %A Kriebel, Jennifer %A Launer, Lenore J %A Lauritzen, Torsten %A Lehtimäki, Terho %A Levy, Daniel %A Linksted, Pamela %A Linneberg, Allan %A Liu, Yongmei %A Loos, Ruth J F %A Lupo, Antonio %A Meisinger, Christine %A Melander, Olle %A Metspalu, Andres %A Mitchell, Paul %A Nauck, Matthias %A Nürnberg, Peter %A Orho-Melander, Marju %A Parsa, Afshin %A Pedersen, Oluf %A Peters, Annette %A Peters, Ulrike %A Polasek, Ozren %A Porteous, David %A Probst-Hensch, Nicole M %A Psaty, Bruce M %A Qi, Lu %A Raitakari, Olli T %A Reiner, Alex P %A Rettig, Rainer %A Ridker, Paul M %A Rivadeneira, Fernando %A Rossouw, Jacques E %A Schmidt, Frank %A Siscovick, David %A Soranzo, Nicole %A Strauch, Konstantin %A Toniolo, Daniela %A Turner, Stephen T %A Uitterlinden, André G %A Ulivi, Sheila %A Velayutham, Dinesh %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Wang, Jie Jin %A Weir, David R %A Witte, Daniel %A Kuivaniemi, Helena %A Fox, Caroline S %A Franceschini, Nora %A Goessling, Wolfram %A Köttgen, Anna %A Chu, Audrey Y %X

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

%B J Am Soc Nephrol %8 2016 Dec 05 %G eng %R 10.1681/ASN.2016020131 %0 Journal Article %J PLoS One %D 2017 %T Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study. %A de Vries, Paul S %A Sabater-Lleal, Maria %A Chasman, Daniel I %A Trompet, Stella %A Ahluwalia, Tarunveer S %A Teumer, Alexander %A Kleber, Marcus E %A Chen, Ming-Huei %A Wang, Jie Jin %A Attia, John R %A Marioni, Riccardo E %A Steri, Maristella %A Weng, Lu-Chen %A Pool, Rene %A Grossmann, Vera %A Brody, Jennifer A %A Venturini, Cristina %A Tanaka, Toshiko %A Rose, Lynda M %A Oldmeadow, Christopher %A Mazur, Johanna %A Basu, Saonli %A Frånberg, Mattias %A Yang, Qiong %A Ligthart, Symen %A Hottenga, Jouke J %A Rumley, Ann %A Mulas, Antonella %A de Craen, Anton J M %A Grotevendt, Anne %A Taylor, Kent D %A Delgado, Graciela E %A Kifley, Annette %A Lopez, Lorna M %A Berentzen, Tina L %A Mangino, Massimo %A Bandinelli, Stefania %A Morrison, Alanna C %A Hamsten, Anders %A Tofler, Geoffrey %A de Maat, Moniek P M %A Draisma, Harmen H M %A Lowe, Gordon D %A Zoledziewska, Magdalena %A Sattar, Naveed %A Lackner, Karl J %A Völker, Uwe %A McKnight, Barbara %A Huang, Jie %A Holliday, Elizabeth G %A McEvoy, Mark A %A Starr, John M %A Hysi, Pirro G %A Hernandez, Dena G %A Guan, Weihua %A Rivadeneira, Fernando %A McArdle, Wendy L %A Slagboom, P Eline %A Zeller, Tanja %A Psaty, Bruce M %A Uitterlinden, André G %A de Geus, Eco J C %A Stott, David J %A Binder, Harald %A Hofman, Albert %A Franco, Oscar H %A Rotter, Jerome I %A Ferrucci, Luigi %A Spector, Tim D %A Deary, Ian J %A März, Winfried %A Greinacher, Andreas %A Wild, Philipp S %A Cucca, Francesco %A Boomsma, Dorret I %A Watkins, Hugh %A Tang, Weihong %A Ridker, Paul M %A Jukema, Jan W %A Scott, Rodney J %A Mitchell, Paul %A Hansen, Torben %A O'Donnell, Christopher J %A Smith, Nicholas L %A Strachan, David P %A Dehghan, Abbas %X

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

%B PLoS One %V 12 %P e0167742 %8 2017 %G eng %N 1 %R 10.1371/journal.pone.0167742 %0 Journal Article %J Am J Hum Genet %D 2018 %T Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. %A Ligthart, Symen %A Vaez, Ahmad %A Võsa, Urmo %A Stathopoulou, Maria G %A de Vries, Paul S %A Prins, Bram P %A van der Most, Peter J %A Tanaka, Toshiko %A Naderi, Elnaz %A Rose, Lynda M %A Wu, Ying %A Karlsson, Robert %A Barbalic, Maja %A Lin, Honghuang %A Pool, Rene %A Zhu, Gu %A Mace, Aurelien %A Sidore, Carlo %A Trompet, Stella %A Mangino, Massimo %A Sabater-Lleal, Maria %A Kemp, John P %A Abbasi, Ali %A Kacprowski, Tim %A Verweij, Niek %A Smith, Albert V %A Huang, Tao %A Marzi, Carola %A Feitosa, Mary F %A Lohman, Kurt K %A Kleber, Marcus E %A Milaneschi, Yuri %A Mueller, Christian %A Huq, Mahmudul %A Vlachopoulou, Efthymia %A Lyytikäinen, Leo-Pekka %A Oldmeadow, Christopher %A Deelen, Joris %A Perola, Markus %A Zhao, Jing Hua %A Feenstra, Bjarke %A Amini, Marzyeh %A Lahti, Jari %A Schraut, Katharina E %A Fornage, Myriam %A Suktitipat, Bhoom %A Chen, Wei-Min %A Li, Xiaohui %A Nutile, Teresa %A Malerba, Giovanni %A Luan, Jian'an %A Bak, Tom %A Schork, Nicholas %A del Greco M, Fabiola %A Thiering, Elisabeth %A Mahajan, Anubha %A Marioni, Riccardo E %A Mihailov, Evelin %A Eriksson, Joel %A Ozel, Ayse Bilge %A Zhang, Weihua %A Nethander, Maria %A Cheng, Yu-Ching %A Aslibekyan, Stella %A Ang, Wei %A Gandin, Ilaria %A Yengo, Loic %A Portas, Laura %A Kooperberg, Charles %A Hofer, Edith %A Rajan, Kumar B %A Schurmann, Claudia %A den Hollander, Wouter %A Ahluwalia, Tarunveer S %A Zhao, Jing %A Draisma, Harmen H M %A Ford, Ian %A Timpson, Nicholas %A Teumer, Alexander %A Huang, Hongyan %A Wahl, Simone %A Liu, Yongmei %A Huang, Jie %A Uh, Hae-Won %A Geller, Frank %A Joshi, Peter K %A Yanek, Lisa R %A Trabetti, Elisabetta %A Lehne, Benjamin %A Vozzi, Diego %A Verbanck, Marie %A Biino, Ginevra %A Saba, Yasaman %A Meulenbelt, Ingrid %A O'Connell, Jeff R %A Laakso, Markku %A Giulianini, Franco %A Magnusson, Patrik K E %A Ballantyne, Christie M %A Hottenga, Jouke Jan %A Montgomery, Grant W %A Rivadineira, Fernando %A Rueedi, Rico %A Steri, Maristella %A Herzig, Karl-Heinz %A Stott, David J %A Menni, Cristina %A Frånberg, Mattias %A St Pourcain, Beate %A Felix, Stephan B %A Pers, Tune H %A Bakker, Stephan J L %A Kraft, Peter %A Peters, Annette %A Vaidya, Dhananjay %A Delgado, Graciela %A Smit, Johannes H %A Großmann, Vera %A Sinisalo, Juha %A Seppälä, Ilkka %A Williams, Stephen R %A Holliday, Elizabeth G %A Moed, Matthijs %A Langenberg, Claudia %A Räikkönen, Katri %A Ding, Jingzhong %A Campbell, Harry %A Sale, Michèle M %A Chen, Yii-der I %A James, Alan L %A Ruggiero, Daniela %A Soranzo, Nicole %A Hartman, Catharina A %A Smith, Erin N %A Berenson, Gerald S %A Fuchsberger, Christian %A Hernandez, Dena %A Tiesler, Carla M T %A Giedraitis, Vilmantas %A Liewald, David %A Fischer, Krista %A Mellström, Dan %A Larsson, Anders %A Wang, Yunmei %A Scott, William R %A Lorentzon, Matthias %A Beilby, John %A Ryan, Kathleen A %A Pennell, Craig E %A Vuckovic, Dragana %A Balkau, Beverly %A Concas, Maria Pina %A Schmidt, Reinhold %A Mendes de Leon, Carlos F %A Bottinger, Erwin P %A Kloppenburg, Margreet %A Paternoster, Lavinia %A Boehnke, Michael %A Musk, A W %A Willemsen, Gonneke %A Evans, David M %A Madden, Pamela A F %A Kähönen, Mika %A Kutalik, Zoltán %A Zoledziewska, Magdalena %A Karhunen, Ville %A Kritchevsky, Stephen B %A Sattar, Naveed %A Lachance, Genevieve %A Clarke, Robert %A Harris, Tamara B %A Raitakari, Olli T %A Attia, John R %A van Heemst, Diana %A Kajantie, Eero %A Sorice, Rossella %A Gambaro, Giovanni %A Scott, Robert A %A Hicks, Andrew A %A Ferrucci, Luigi %A Standl, Marie %A Lindgren, Cecilia M %A Starr, John M %A Karlsson, Magnus %A Lind, Lars %A Li, Jun Z %A Chambers, John C %A Mori, Trevor A %A de Geus, Eco J C N %A Heath, Andrew C %A Martin, Nicholas G %A Auvinen, Juha %A Buckley, Brendan M %A de Craen, Anton J M %A Waldenberger, Melanie %A Strauch, Konstantin %A Meitinger, Thomas %A Scott, Rodney J %A McEvoy, Mark %A Beekman, Marian %A Bombieri, Cristina %A Ridker, Paul M %A Mohlke, Karen L %A Pedersen, Nancy L %A Morrison, Alanna C %A Boomsma, Dorret I %A Whitfield, John B %A Strachan, David P %A Hofman, Albert %A Vollenweider, Peter %A Cucca, Francesco %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Spector, Tim D %A Hamsten, Anders %A Zeller, Tanja %A Uitterlinden, André G %A Nauck, Matthias %A Gudnason, Vilmundur %A Qi, Lu %A Grallert, Harald %A Borecki, Ingrid B %A Rotter, Jerome I %A März, Winfried %A Wild, Philipp S %A Lokki, Marja-Liisa %A Boyle, Michael %A Salomaa, Veikko %A Melbye, Mads %A Eriksson, Johan G %A Wilson, James F %A Penninx, Brenda W J H %A Becker, Diane M %A Worrall, Bradford B %A Gibson, Greg %A Krauss, Ronald M %A Ciullo, Marina %A Zaza, Gianluigi %A Wareham, Nicholas J %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Murray, Sarah S %A Pramstaller, Peter P %A Bandinelli, Stefania %A Heinrich, Joachim %A Ingelsson, Erik %A Deary, Ian J %A Mägi, Reedik %A Vandenput, Liesbeth %A van der Harst, Pim %A Desch, Karl C %A Kooner, Jaspal S %A Ohlsson, Claes %A Hayward, Caroline %A Lehtimäki, Terho %A Shuldiner, Alan R %A Arnett, Donna K %A Beilin, Lawrence J %A Robino, Antonietta %A Froguel, Philippe %A Pirastu, Mario %A Jess, Tine %A Koenig, Wolfgang %A Loos, Ruth J F %A Evans, Denis A %A Schmidt, Helena %A Smith, George Davey %A Slagboom, P Eline %A Eiriksdottir, Gudny %A Morris, Andrew P %A Psaty, Bruce M %A Tracy, Russell P %A Nolte, Ilja M %A Boerwinkle, Eric %A Visvikis-Siest, Sophie %A Reiner, Alex P %A Gross, Myron %A Bis, Joshua C %A Franke, Lude %A Franco, Oscar H %A Benjamin, Emelia J %A Chasman, Daniel I %A Dupuis, Josée %A Snieder, Harold %A Dehghan, Abbas %A Alizadeh, Behrooz Z %X

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

%B Am J Hum Genet %V 103 %P 691-706 %8 2018 Nov 01 %G eng %N 5 %R 10.1016/j.ajhg.2018.09.009 %0 Journal Article %J Nat Commun %D 2018 %T Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. %A Teumer, Alexander %A Chaker, Layal %A Groeneweg, Stefan %A Li, Yong %A Di Munno, Celia %A Barbieri, Caterina %A Schultheiss, Ulla T %A Traglia, Michela %A Ahluwalia, Tarunveer S %A Akiyama, Masato %A Appel, Emil Vincent R %A Arking, Dan E %A Arnold, Alice %A Astrup, Arne %A Beekman, Marian %A Beilby, John P %A Bekaert, Sofie %A Boerwinkle, Eric %A Brown, Suzanne J %A De Buyzere, Marc %A Campbell, Purdey J %A Ceresini, Graziano %A Cerqueira, Charlotte %A Cucca, Francesco %A Deary, Ian J %A Deelen, Joris %A Eckardt, Kai-Uwe %A Ekici, Arif B %A Eriksson, Johan G %A Ferrrucci, Luigi %A Fiers, Tom %A Fiorillo, Edoardo %A Ford, Ian %A Fox, Caroline S %A Fuchsberger, Christian %A Galesloot, Tessel E %A Gieger, Christian %A Gögele, Martin %A De Grandi, Alessandro %A Grarup, Niels %A Greiser, Karin Halina %A Haljas, Kadri %A Hansen, Torben %A Harris, Sarah E %A van Heemst, Diana %A den Heijer, Martin %A Hicks, Andrew A %A den Hollander, Wouter %A Homuth, Georg %A Hui, Jennie %A Ikram, M Arfan %A Ittermann, Till %A Jensen, Richard A %A Jing, Jiaojiao %A Jukema, J Wouter %A Kajantie, Eero %A Kamatani, Yoichiro %A Kasbohm, Elisa %A Kaufman, Jean-Marc %A Kiemeney, Lambertus A %A Kloppenburg, Margreet %A Kronenberg, Florian %A Kubo, Michiaki %A Lahti, Jari %A Lapauw, Bruno %A Li, Shuo %A Liewald, David C M %A Lim, Ee Mun %A Linneberg, Allan %A Marina, Michela %A Mascalzoni, Deborah %A Matsuda, Koichi %A Medenwald, Daniel %A Meisinger, Christa %A Meulenbelt, Ingrid %A De Meyer, Tim %A Meyer zu Schwabedissen, Henriette E %A Mikolajczyk, Rafael %A Moed, Matthijs %A Netea-Maier, Romana T %A Nolte, Ilja M %A Okada, Yukinori %A Pala, Mauro %A Pattaro, Cristian %A Pedersen, Oluf %A Petersmann, Astrid %A Porcu, Eleonora %A Postmus, Iris %A Pramstaller, Peter P %A Psaty, Bruce M %A Ramos, Yolande F M %A Rawal, Rajesh %A Redmond, Paul %A Richards, J Brent %A Rietzschel, Ernst R %A Rivadeneira, Fernando %A Roef, Greet %A Rotter, Jerome I %A Sala, Cinzia F %A Schlessinger, David %A Selvin, Elizabeth %A Slagboom, P Eline %A Soranzo, Nicole %A Sørensen, Thorkild I A %A Spector, Timothy D %A Starr, John M %A Stott, David J %A Taes, Youri %A Taliun, Daniel %A Tanaka, Toshiko %A Thuesen, Betina %A Tiller, Daniel %A Toniolo, Daniela %A Uitterlinden, André G %A Visser, W Edward %A Walsh, John P %A Wilson, Scott G %A Wolffenbuttel, Bruce H R %A Yang, Qiong %A Zheng, Hou-Feng %A Cappola, Anne %A Peeters, Robin P %A Naitza, Silvia %A Völzke, Henry %A Sanna, Serena %A Köttgen, Anna %A Visser, Theo J %A Medici, Marco %X

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

%B Nat Commun %V 9 %P 4455 %8 2018 10 26 %G eng %N 1 %R 10.1038/s41467-018-06356-1 %0 Journal Article %J Wellcome Open Res %D 2018 %T Meta-analysis of exome array data identifies six novel genetic loci for lung function. %A Jackson, Victoria E %A Latourelle, Jeanne C %A Wain, Louise V %A Smith, Albert V %A Grove, Megan L %A Bartz, Traci M %A Obeidat, Ma'en %A Province, Michael A %A Gao, Wei %A Qaiser, Beenish %A Porteous, David J %A Cassano, Patricia A %A Ahluwalia, Tarunveer S %A Grarup, Niels %A Li, Jin %A Altmaier, Elisabeth %A Marten, Jonathan %A Harris, Sarah E %A Manichaikul, Ani %A Pottinger, Tess D %A Li-Gao, Ruifang %A Lind-Thomsen, Allan %A Mahajan, Anubha %A Lahousse, Lies %A Imboden, Medea %A Teumer, Alexander %A Prins, Bram %A Lyytikäinen, Leo-Pekka %A Eiriksdottir, Gudny %A Franceschini, Nora %A Sitlani, Colleen M %A Brody, Jennifer A %A Bossé, Yohan %A Timens, Wim %A Kraja, Aldi %A Loukola, Anu %A Tang, Wenbo %A Liu, Yongmei %A Bork-Jensen, Jette %A Justesen, Johanne M %A Linneberg, Allan %A Lange, Leslie A %A Rawal, Rajesh %A Karrasch, Stefan %A Huffman, Jennifer E %A Smith, Blair H %A Davies, Gail %A Burkart, Kristin M %A Mychaleckyj, Josyf C %A Bonten, Tobias N %A Enroth, Stefan %A Lind, Lars %A Brusselle, Guy G %A Kumar, Ashish %A Stubbe, Beate %A Kähönen, Mika %A Wyss, Annah B %A Psaty, Bruce M %A Heckbert, Susan R %A Hao, Ke %A Rantanen, Taina %A Kritchevsky, Stephen B %A Lohman, Kurt %A Skaaby, Tea %A Pisinger, Charlotta %A Hansen, Torben %A Schulz, Holger %A Polasek, Ozren %A Campbell, Archie %A Starr, John M %A Rich, Stephen S %A Mook-Kanamori, Dennis O %A Johansson, Asa %A Ingelsson, Erik %A Uitterlinden, André G %A Weiss, Stefan %A Raitakari, Olli T %A Gudnason, Vilmundur %A North, Kari E %A Gharib, Sina A %A Sin, Don D %A Taylor, Kent D %A O'Connor, George T %A Kaprio, Jaakko %A Harris, Tamara B %A Pederson, Oluf %A Vestergaard, Henrik %A Wilson, James G %A Strauch, Konstantin %A Hayward, Caroline %A Kerr, Shona %A Deary, Ian J %A Barr, R Graham %A de Mutsert, Renée %A Gyllensten, Ulf %A Morris, Andrew P %A Ikram, M Arfan %A Probst-Hensch, Nicole %A Gläser, Sven %A Zeggini, Eleftheria %A Lehtimäki, Terho %A Strachan, David P %A Dupuis, Josée %A Morrison, Alanna C %A Hall, Ian P %A Tobin, Martin D %A London, Stephanie J %X

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2·8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

%B Wellcome Open Res %V 3 %P 4 %8 2018 %G eng %R 10.12688/wellcomeopenres.12583.3 %0 Journal Article %J Nat Commun %D 2018 %T Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. %A Wyss, Annah B %A Sofer, Tamar %A Lee, Mi Kyeong %A Terzikhan, Natalie %A Nguyen, Jennifer N %A Lahousse, Lies %A Latourelle, Jeanne C %A Smith, Albert Vernon %A Bartz, Traci M %A Feitosa, Mary F %A Gao, Wei %A Ahluwalia, Tarunveer S %A Tang, Wenbo %A Oldmeadow, Christopher %A Duan, Qing %A de Jong, Kim %A Wojczynski, Mary K %A Wang, Xin-Qun %A Noordam, Raymond %A Hartwig, Fernando Pires %A Jackson, Victoria E %A Wang, Tianyuan %A Obeidat, Ma'en %A Hobbs, Brian D %A Huan, Tianxiao %A Gui, Hongsheng %A Parker, Margaret M %A Hu, Donglei %A Mogil, Lauren S %A Kichaev, Gleb %A Jin, Jianping %A Graff, Mariaelisa %A Harris, Tamara B %A Kalhan, Ravi %A Heckbert, Susan R %A Paternoster, Lavinia %A Burkart, Kristin M %A Liu, Yongmei %A Holliday, Elizabeth G %A Wilson, James G %A Vonk, Judith M %A Sanders, Jason L %A Barr, R Graham %A de Mutsert, Renée %A Menezes, Ana Maria Baptista %A Adams, Hieab H H %A van den Berge, Maarten %A Joehanes, Roby %A Levin, Albert M %A Liberto, Jennifer %A Launer, Lenore J %A Morrison, Alanna C %A Sitlani, Colleen M %A Celedón, Juan C %A Kritchevsky, Stephen B %A Scott, Rodney J %A Christensen, Kaare %A Rotter, Jerome I %A Bonten, Tobias N %A Wehrmeister, Fernando César %A Bossé, Yohan %A Xiao, Shujie %A Oh, Sam %A Franceschini, Nora %A Brody, Jennifer A %A Kaplan, Robert C %A Lohman, Kurt %A McEvoy, Mark %A Province, Michael A %A Rosendaal, Frits R %A Taylor, Kent D %A Nickle, David C %A Williams, L Keoki %A Burchard, Esteban G %A Wheeler, Heather E %A Sin, Don D %A Gudnason, Vilmundur %A North, Kari E %A Fornage, Myriam %A Psaty, Bruce M %A Myers, Richard H %A O'Connor, George %A Hansen, Torben %A Laurie, Cathy C %A Cassano, Patricia A %A Sung, Joohon %A Kim, Woo Jin %A Attia, John R %A Lange, Leslie %A Boezen, H Marike %A Thyagarajan, Bharat %A Rich, Stephen S %A Mook-Kanamori, Dennis O %A Horta, Bernardo Lessa %A Uitterlinden, André G %A Im, Hae Kyung %A Cho, Michael H %A Brusselle, Guy G %A Gharib, Sina A %A Dupuis, Josée %A Manichaikul, Ani %A London, Stephanie J %X

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

%B Nat Commun %V 9 %P 2976 %8 2018 Jul 30 %G eng %N 1 %R 10.1038/s41467-018-05369-0 %0 Journal Article %J Nat Genet %D 2019 %T A catalog of genetic loci associated with kidney function from analyses of a million individuals. %A Wuttke, Matthias %A Li, Yong %A Li, Man %A Sieber, Karsten B %A Feitosa, Mary F %A Gorski, Mathias %A Tin, Adrienne %A Wang, Lihua %A Chu, Audrey Y %A Hoppmann, Anselm %A Kirsten, Holger %A Giri, Ayush %A Chai, Jin-Fang %A Sveinbjornsson, Gardar %A Tayo, Bamidele O %A Nutile, Teresa %A Fuchsberger, Christian %A Marten, Jonathan %A Cocca, Massimiliano %A Ghasemi, Sahar %A Xu, Yizhe %A Horn, Katrin %A Noce, Damia %A van der Most, Peter J %A Sedaghat, Sanaz %A Yu, Zhi %A Akiyama, Masato %A Afaq, Saima %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boehnke, Michael %A Boerwinkle, Eric %A Boissel, Mathilde %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brenner, Hermann %A Brumat, Marco %A Burkhardt, Ralph %A Butterworth, Adam S %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Canouil, Mickaël %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Chee, Miao-Ling %A Chee, Miao-Li %A Chen, Xu %A Cheng, Ching-Yu %A Cheng, Yurong %A Christensen, Kaare %A Cifkova, Renata %A Ciullo, Marina %A Concas, Maria Pina %A Cook, James P %A Coresh, Josef %A Corre, Tanguy %A Sala, Cinzia Felicita %A Cusi, Daniele %A Danesh, John %A Daw, E Warwick %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Degenhardt, Frauke %A Delgado, Graciela %A Demirkan, Ayse %A Di Angelantonio, Emanuele %A Dittrich, Katalin %A Divers, Jasmin %A Dorajoo, Rajkumar %A Eckardt, Kai-Uwe %A Ehret, Georg %A Elliott, Paul %A Endlich, Karlhans %A Evans, Michele K %A Felix, Janine F %A Foo, Valencia Hui Xian %A Franco, Oscar H %A Franke, Andre %A Freedman, Barry I %A Freitag-Wolf, Sandra %A Friedlander, Yechiel %A Froguel, Philippe %A Gansevoort, Ron T %A Gao, He %A Gasparini, Paolo %A Gaziano, J Michael %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Giulianini, Franco %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hartman, Catharina A %A Hayward, Caroline %A Hellwege, Jacklyn N %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hofer, Edith %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Indridason, Olafur S %A Ingelsson, Erik %A Ising, Marcus %A Jaddoe, Vincent W V %A Jakobsdottir, Johanna %A Jonas, Jost B %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kammerer, Candace M %A Kanai, Masahiro %A Kastarinen, Mika %A Kerr, Shona M %A Khor, Chiea-Chuen %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Kraja, Aldi T %A Krajcoviechova, Alena %A Kramer, Holly %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A Kuokkanen, Mikko %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lange, Leslie A %A Langefeld, Carl D %A Lee, Jeannette Jen-Mai %A Lehne, Benjamin %A Lehtimäki, Terho %A Lieb, Wolfgang %A Lim, Su-Chi %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Jun %A Liu, Jianjun %A Loeffler, Markus %A Loos, Ruth J F %A Lucae, Susanne %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Magnusson, Patrik K E %A Mahajan, Anubha %A Martin, Nicholas G %A Martins, Jade %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Metspalu, Andres %A Mikaelsdottir, Evgenia K %A Milaneschi, Yuri %A Miliku, Kozeta %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey %A O'Donoghue, Michelle L %A Olafsson, Isleifur %A Oldehinkel, Albertine J %A Orho-Melander, Marju %A Ouwehand, Willem H %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Palsson, Runolfur %A Penninx, Brenda W J H %A Perls, Thomas %A Perola, Markus %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Podgornaia, Anna I %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Pramstaller, Peter P %A Preuss, Michael H %A Prins, Bram P %A Province, Michael A %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Reilly, Dermot F %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Ridker, Paul M %A Rivadeneira, Fernando %A Rizzi, Federica %A Roberts, David J %A Robino, Antonietta %A Rossing, Peter %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Sabanayagam, Charumathi %A Salomaa, Veikko %A Salvi, Erika %A Saum, Kai-Uwe %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Schupf, Nicole %A Shaffer, Christian M %A Shi, Yuan %A Smith, Albert V %A Smith, Blair H %A Soranzo, Nicole %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Svensson, Per O %A Szymczak, Silke %A Tai, E-Shyong %A Tajuddin, Salman M %A Tan, Nicholas Y Q %A Taylor, Kent D %A Teren, Andrej %A Tham, Yih-Chung %A Thiery, Joachim %A Thio, Chris H L %A Thomsen, Hauke %A Thorleifsson, Gudmar %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Tzoulaki, Ioanna %A Uitterlinden, André G %A Vaccargiu, Simona %A van Dam, Rob M %A van der Harst, Pim %A van Duijn, Cornelia M %A Velez Edward, Digna R %A Verweij, Niek %A Vogelezang, Suzanne %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Wallentin, Lars %A Wang, Ya Xing %A Wang, Chaolong %A Waterworth, Dawn M %A Bin Wei, Wen %A White, Harvey %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Wojczynski, Mary K %A Wong, Charlene %A Wong, Tien-Yin %A Xu, Liang %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Weihua %A Zonderman, Alan B %A Rotter, Jerome I %A Bochud, Murielle %A Psaty, Bruce M %A Vitart, Veronique %A Wilson, James G %A Dehghan, Abbas %A Parsa, Afshin %A Chasman, Daniel I %A Ho, Kevin %A Morris, Andrew P %A Devuyst, Olivier %A Akilesh, Shreeram %A Pendergrass, Sarah A %A Sim, Xueling %A Böger, Carsten A %A Okada, Yukinori %A Edwards, Todd L %A Snieder, Harold %A Stefansson, Kari %A Hung, Adriana M %A Heid, Iris M %A Scholz, Markus %A Teumer, Alexander %A Köttgen, Anna %A Pattaro, Cristian %K Chromosome Mapping %K European Continental Ancestry Group %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Inheritance Patterns %K Kidney Function Tests %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Renal Insufficiency, Chronic %K Uromodulin %X

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

%B Nat Genet %V 51 %P 957-972 %8 2019 06 %G eng %N 6 %R 10.1038/s41588-019-0407-x %0 Journal Article %J Am J Hypertens %D 2019 %T Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group. %A Irvin, Marguerite R %A Sitlani, Colleen M %A Floyd, James S %A Psaty, Bruce M %A Bis, Joshua C %A Wiggins, Kerri L %A Whitsel, Eric A %A Stürmer, Til %A Stewart, James %A Raffield, Laura %A Sun, Fangui %A Liu, Ching-Ti %A Xu, Hanfei %A Cupples, Adrienne L %A Tanner, Rikki M %A Rossing, Peter %A Smith, Albert %A Zilhão, Nuno R %A Launer, Lenore J %A Noordam, Raymond %A Rotter, Jerome I %A Yao, Jie %A Li, Xiaohui %A Guo, Xiuqing %A Limdi, Nita %A Sundaresan, Aishwarya %A Lange, Leslie %A Correa, Adolfo %A Stott, David J %A Ford, Ian %A Jukema, J Wouter %A Gudnason, Vilmundur %A Mook-Kanamori, Dennis O %A Trompet, Stella %A Palmas, Walter %A Warren, Helen R %A Hellwege, Jacklyn N %A Giri, Ayush %A O'donnell, Christopher %A Hung, Adriana M %A Edwards, Todd L %A Ahluwalia, Tarunveer S %A Arnett, Donna K %A Avery, Christy L %K Aged %K Antihypertensive Agents %K Black or African American %K Blood Pressure %K Case-Control Studies %K DNA (Cytosine-5-)-Methyltransferases %K DNA Methyltransferase 3A %K DNA-Binding Proteins %K Drug Resistance %K Dystrophin-Associated Proteins %K Europe %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Middle Aged %K Myosin Heavy Chains %K Myosin Type V %K Neuropeptides %K Pharmacogenetics %K Pharmacogenomic Variants %K Polymorphism, Single Nucleotide %K Risk Assessment %K Risk Factors %K Transcription Factors %K United States %K White People %X

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

%B Am J Hypertens %V 32 %P 1146-1153 %8 2019 Nov 15 %G eng %N 12 %R 10.1093/ajh/hpz150 %0 Journal Article %J Eur J Epidemiol %D 2020 %T Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood. %A Zheng, Yan %A Huang, Tao %A Wang, Tiange %A Mei, Zhendong %A Sun, Zhonghan %A Zhang, Tao %A Ellervik, Christina %A Chai, Jin-Fang %A Sim, Xueling %A van Dam, Rob M %A Tai, E-Shyong %A Koh, Woon-Puay %A Dorajoo, Rajkumar %A Saw, Seang-Mei %A Sabanayagam, Charumathi %A Wong, Tien Yin %A Gupta, Preeti %A Rossing, Peter %A Ahluwalia, Tarunveer S %A Vinding, Rebecca K %A Bisgaard, Hans %A Bønnelykke, Klaus %A Wang, Yujie %A Graff, Mariaelisa %A Voortman, Trudy %A van Rooij, Frank J A %A Hofman, Albert %A van Heemst, Diana %A Noordam, Raymond %A Estampador, Angela C %A Varga, Tibor V %A Enzenbach, Cornelia %A Scholz, Markus %A Thiery, Joachim %A Burkhardt, Ralph %A Orho-Melander, Marju %A Schulz, Christina-Alexandra %A Ericson, Ulrika %A Sonestedt, Emily %A Kubo, Michiaki %A Akiyama, Masato %A Zhou, Ang %A Kilpeläinen, Tuomas O %A Hansen, Torben %A Kleber, Marcus E %A Delgado, Graciela %A McCarthy, Mark %A Lemaitre, Rozenn N %A Felix, Janine F %A Jaddoe, Vincent W V %A Wu, Ying %A Mohlke, Karen L %A Lehtimäki, Terho %A Wang, Carol A %A Pennell, Craig E %A Schunkert, Heribert %A Kessler, Thorsten %A Zeng, Lingyao %A Willenborg, Christina %A Peters, Annette %A Lieb, Wolfgang %A Grote, Veit %A Rzehak, Peter %A Koletzko, Berthold %A Erdmann, Jeanette %A Munz, Matthias %A Wu, Tangchun %A He, Meian %A Yu, Caizheng %A Lecoeur, Cécile %A Froguel, Philippe %A Corella, Dolores %A Moreno, Luis A %A Lai, Chao-Qiang %A Pitkänen, Niina %A Boreham, Colin A %A Ridker, Paul M %A Rosendaal, Frits R %A de Mutsert, Renée %A Power, Chris %A Paternoster, Lavinia %A Sørensen, Thorkild I A %A Tjønneland, Anne %A Overvad, Kim %A Djoussé, Luc %A Rivadeneira, Fernando %A Lee, Nanette R %A Raitakari, Olli T %A Kähönen, Mika %A Viikari, Jorma %A Langhendries, Jean-Paul %A Escribano, Joaquin %A Verduci, Elvira %A Dedoussis, George %A König, Inke %A Balkau, Beverley %A Coltell, Oscar %A Dallongeville, Jean %A Meirhaeghe, Aline %A Amouyel, Philippe %A Gottrand, Frédéric %A Pahkala, Katja %A Niinikoski, Harri %A Hyppönen, Elina %A März, Winfried %A Mackey, David A %A Gruszfeld, Dariusz %A Tucker, Katherine L %A Fumeron, Frédéric %A Estruch, Ramon %A Ordovas, Jose M %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Mozaffarian, Dariush %A Psaty, Bruce M %A North, Kari E %A Chasman, Daniel I %A Qi, Lu %X

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

%B Eur J Epidemiol %V 35 %P 685-697 %8 2020 Jul %G eng %N 7 %R 10.1007/s10654-020-00638-z %0 Journal Article %J Kidney Int %D 2020 %T Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. %A Gorski, Mathias %A Jung, Bettina %A Li, Yong %A Matias-Garcia, Pamela R %A Wuttke, Matthias %A Coassin, Stefan %A Thio, Chris H L %A Kleber, Marcus E %A Winkler, Thomas W %A Wanner, Veronika %A Chai, Jin-Fang %A Chu, Audrey Y %A Cocca, Massimiliano %A Feitosa, Mary F %A Ghasemi, Sahar %A Hoppmann, Anselm %A Horn, Katrin %A Li, Man %A Nutile, Teresa %A Scholz, Markus %A Sieber, Karsten B %A Teumer, Alexander %A Tin, Adrienne %A Wang, Judy %A Tayo, Bamidele O %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Bakker, Stephan J L %A Banas, Bernhard %A Bansal, Nisha %A Biggs, Mary L %A Boerwinkle, Eric %A Bottinger, Erwin P %A Brenner, Hermann %A Carroll, Robert J %A Chalmers, John %A Chee, Miao-Li %A Chee, Miao-Ling %A Cheng, Ching-Yu %A Coresh, Josef %A de Borst, Martin H %A Degenhardt, Frauke %A Eckardt, Kai-Uwe %A Endlich, Karlhans %A Franke, Andre %A Freitag-Wolf, Sandra %A Gampawar, Piyush %A Gansevoort, Ron T %A Ghanbari, Mohsen %A Gieger, Christian %A Hamet, Pavel %A Ho, Kevin %A Hofer, Edith %A Holleczek, Bernd %A Xian Foo, Valencia Hui %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Josyula, Navya Shilpa %A Kähönen, Mika %A Khor, Chiea-Chuen %A Koenig, Wolfgang %A Kramer, Holly %A Krämer, Bernhard K %A Kuhnel, Brigitte %A Lange, Leslie A %A Lehtimäki, Terho %A Lieb, Wolfgang %A Loos, Ruth J F %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A O'Donoghue, Michelle L %A Orho-Melander, Marju %A Pendergrass, Sarah A %A Penninx, Brenda W J H %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Raitakari, Olli T %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Rosenkranz, Alexander R %A Rossing, Peter %A Rotter, Jerome I %A Sabanayagam, Charumathi %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Sedaghat, Sanaz %A Shaffer, Christian M %A Strauch, Konstantin %A Szymczak, Silke %A Taylor, Kent D %A Tremblay, Johanne %A Chaker, Layal %A van der Harst, Pim %A van der Most, Peter J %A Verweij, Niek %A Völker, Uwe %A Waldenberger, Melanie %A Wallentin, Lars %A Waterworth, Dawn M %A White, Harvey D %A Wilson, James G %A Wong, Tien-Yin %A Woodward, Mark %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Yan %A Snieder, Harold %A Wanner, Christoph %A Böger, Carsten A %A Köttgen, Anna %A Kronenberg, Florian %A Pattaro, Cristian %A Heid, Iris M %X

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

%B Kidney Int %8 2020 Oct 30 %G eng %R 10.1016/j.kint.2020.09.030 %0 Journal Article %J Commun Biol %D 2022 %T Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. %A Winkler, Thomas W %A Rasheed, Humaira %A Teumer, Alexander %A Gorski, Mathias %A Rowan, Bryce X %A Stanzick, Kira J %A Thomas, Laurent F %A Tin, Adrienne %A Hoppmann, Anselm %A Chu, Audrey Y %A Tayo, Bamidele %A Thio, Chris H L %A Cusi, Daniele %A Chai, Jin-Fang %A Sieber, Karsten B %A Horn, Katrin %A Li, Man %A Scholz, Markus %A Cocca, Massimiliano %A Wuttke, Matthias %A van der Most, Peter J %A Yang, Qiong %A Ghasemi, Sahar %A Nutile, Teresa %A Li, Yong %A Pontali, Giulia %A Günther, Felix %A Dehghan, Abbas %A Correa, Adolfo %A Parsa, Afshin %A Feresin, Agnese %A de Vries, Aiko P J %A Zonderman, Alan B %A Smith, Albert V %A Oldehinkel, Albertine J %A De Grandi, Alessandro %A Rosenkranz, Alexander R %A Franke, Andre %A Teren, Andrej %A Metspalu, Andres %A Hicks, Andrew A %A Morris, Andrew P %A Tönjes, Anke %A Morgan, Anna %A Podgornaia, Anna I %A Peters, Annette %A Körner, Antje %A Mahajan, Anubha %A Campbell, Archie %A Freedman, Barry I %A Spedicati, Beatrice %A Ponte, Belen %A Schöttker, Ben %A Brumpton, Ben %A Banas, Bernhard %A Krämer, Bernhard K %A Jung, Bettina %A Åsvold, Bjørn Olav %A Smith, Blair H %A Ning, Boting %A Penninx, Brenda W J H %A Vanderwerff, Brett R %A Psaty, Bruce M %A Kammerer, Candace M %A Langefeld, Carl D %A Hayward, Caroline %A Spracklen, Cassandra N %A Robinson-Cohen, Cassianne %A Hartman, Catharina A %A Lindgren, Cecilia M %A Wang, Chaolong %A Sabanayagam, Charumathi %A Heng, Chew-Kiat %A Lanzani, Chiara %A Khor, Chiea-Chuen %A Cheng, Ching-Yu %A Fuchsberger, Christian %A Gieger, Christian %A Shaffer, Christian M %A Schulz, Christina-Alexandra %A Willer, Cristen J %A Chasman, Daniel I %A Gudbjartsson, Daniel F %A Ruggiero, Daniela %A Toniolo, Daniela %A Czamara, Darina %A Porteous, David J %A Waterworth, Dawn M %A Mascalzoni, Deborah %A Mook-Kanamori, Dennis O %A Reilly, Dermot F %A Daw, E Warwick %A Hofer, Edith %A Boerwinkle, Eric %A Salvi, Erika %A Bottinger, Erwin P %A Tai, E-Shyong %A Catamo, Eulalia %A Rizzi, Federica %A Guo, Feng %A Rivadeneira, Fernando %A Guilianini, Franco %A Sveinbjornsson, Gardar %A Ehret, Georg %A Waeber, Gérard %A Biino, Ginevra %A Girotto, Giorgia %A Pistis, Giorgio %A Nadkarni, Girish N %A Delgado, Graciela E %A Montgomery, Grant W %A Snieder, Harold %A Campbell, Harry %A White, Harvey D %A Gao, He %A Stringham, Heather M %A Schmidt, Helena %A Li, Hengtong %A Brenner, Hermann %A Holm, Hilma %A Kirsten, Holgen %A Kramer, Holly %A Rudan, Igor %A Nolte, Ilja M %A Tzoulaki, Ioanna %A Olafsson, Isleifur %A Martins, Jade %A Cook, James P %A Wilson, James F %A Halbritter, Jan %A Felix, Janine F %A Divers, Jasmin %A Kooner, Jaspal S %A Lee, Jeannette Jen-Mai %A O'Connell, Jeffrey %A Rotter, Jerome I %A Liu, Jianjun %A Xu, Jie %A Thiery, Joachim %A Arnlöv, Johan %A Kuusisto, Johanna %A Jakobsdottir, Johanna %A Tremblay, Johanne %A Chambers, John C %A Whitfield, John B %A Gaziano, John M %A Marten, Jonathan %A Coresh, Josef %A Jonas, Jost B %A Mychaleckyj, Josyf C %A Christensen, Kaare %A Eckardt, Kai-Uwe %A Mohlke, Karen L %A Endlich, Karlhans %A Dittrich, Katalin %A Ryan, Kathleen A %A Rice, Kenneth M %A Taylor, Kent D %A Ho, Kevin %A Nikus, Kjell %A Matsuda, Koichi %A Strauch, Konstantin %A Miliku, Kozeta %A Hveem, Kristian %A Lind, Lars %A Wallentin, Lars %A Yerges-Armstrong, Laura M %A Raffield, Laura M %A Phillips, Lawrence S %A Launer, Lenore J %A Lyytikäinen, Leo-Pekka %A Lange, Leslie A %A Citterio, Lorena %A Klaric, Lucija %A Ikram, M Arfan %A Ising, Marcus %A Kleber, Marcus E %A Francescatto, Margherita %A Concas, Maria Pina %A Ciullo, Marina %A Piratsu, Mario %A Orho-Melander, Marju %A Laakso, Markku %A Loeffler, Markus %A Perola, Markus %A de Borst, Martin H %A Gögele, Martin %A Bianca, Martina La %A Lukas, Mary Ann %A Feitosa, Mary F %A Biggs, Mary L %A Wojczynski, Mary K %A Kavousi, Maryam %A Kanai, Masahiro %A Akiyama, Masato %A Yasuda, Masayuki %A Nauck, Matthias %A Waldenberger, Melanie %A Chee, Miao-Li %A Chee, Miao-Ling %A Boehnke, Michael %A Preuss, Michael H %A Stumvoll, Michael %A Province, Michael A %A Evans, Michele K %A O'Donoghue, Michelle L %A Kubo, Michiaki %A Kähönen, Mika %A Kastarinen, Mika %A Nalls, Mike A %A Kuokkanen, Mikko %A Ghanbari, Mohsen %A Bochud, Murielle %A Josyula, Navya Shilpa %A Martin, Nicholas G %A Tan, Nicholas Y Q %A Palmer, Nicholette D %A Pirastu, Nicola %A Schupf, Nicole %A Verweij, Niek %A Hutri-Kähönen, Nina %A Mononen, Nina %A Bansal, Nisha %A Devuyst, Olivier %A Melander, Olle %A Raitakari, Olli T %A Polasek, Ozren %A Manunta, Paolo %A Gasparini, Paolo %A Mishra, Pashupati P %A Sulem, Patrick %A Magnusson, Patrik K E %A Elliott, Paul %A Ridker, Paul M %A Hamet, Pavel %A Svensson, Per O %A Joshi, Peter K %A Kovacs, Peter %A Pramstaller, Peter P %A Rossing, Peter %A Vollenweider, Peter %A van der Harst, Pim %A Dorajoo, Rajkumar %A Sim, Ralene Z H %A Burkhardt, Ralph %A Tao, Ran %A Noordam, Raymond %A Mägi, Reedik %A Schmidt, Reinhold %A de Mutsert, Renée %A Rueedi, Rico %A van Dam, Rob M %A Carroll, Robert J %A Gansevoort, Ron T %A Loos, Ruth J F %A Felicita, Sala Cinzia %A Sedaghat, Sanaz %A Padmanabhan, Sandosh %A Freitag-Wolf, Sandra %A Pendergrass, Sarah A %A Graham, Sarah E %A Gordon, Scott D %A Hwang, Shih-Jen %A Kerr, Shona M %A Vaccargiu, Simona %A Patil, Snehal B %A Hallan, Stein %A Bakker, Stephan J L %A Lim, Su-Chi %A Lucae, Susanne %A Vogelezang, Suzanne %A Bergmann, Sven %A Corre, Tanguy %A Ahluwalia, Tarunveer S %A Lehtimäki, Terho %A Boutin, Thibaud S %A Meitinger, Thomas %A Wong, Tien-Yin %A Bergler, Tobias %A Rabelink, Ton J %A Esko, Tõnu %A Haller, Toomas %A Thorsteinsdottir, Unnur %A Völker, Uwe %A Foo, Valencia Hui Xian %A Salomaa, Veikko %A Vitart, Veronique %A Giedraitis, Vilmantas %A Gudnason, Vilmundur %A Jaddoe, Vincent W V %A Huang, Wei %A Zhang, Weihua %A Wei, Wen Bin %A Kiess, Wieland %A März, Winfried %A Koenig, Wolfgang %A Lieb, Wolfgang %A Gào, Xīn %A Sim, Xueling %A Wang, Ya Xing %A Friedlander, Yechiel %A Tham, Yih-Chung %A Kamatani, Yoichiro %A Okada, Yukinori %A Milaneschi, Yuri %A Yu, Zhi %A Stark, Klaus J %A Stefansson, Kari %A Böger, Carsten A %A Hung, Adriana M %A Kronenberg, Florian %A Köttgen, Anna %A Pattaro, Cristian %A Heid, Iris M %K Creatinine %K Diabetes Mellitus %K Diabetic Nephropathies %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %X

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

%B Commun Biol %V 5 %P 580 %8 2022 Jun 13 %G eng %N 1 %R 10.1038/s42003-022-03448-z %0 Journal Article %J Kidney Int %D 2022 %T Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies. %A Gorski, Mathias %A Rasheed, Humaira %A Teumer, Alexander %A Thomas, Laurent F %A Graham, Sarah E %A Sveinbjornsson, Gardar %A Winkler, Thomas W %A Günther, Felix %A Stark, Klaus J %A Chai, Jin-Fang %A Tayo, Bamidele O %A Wuttke, Matthias %A Li, Yong %A Tin, Adrienne %A Ahluwalia, Tarunveer S %A Arnlöv, Johan %A Åsvold, Bjørn Olav %A Bakker, Stephan J L %A Banas, Bernhard %A Bansal, Nisha %A Biggs, Mary L %A Biino, Ginevra %A Böhnke, Michael %A Boerwinkle, Eric %A Bottinger, Erwin P %A Brenner, Hermann %A Brumpton, Ben %A Carroll, Robert J %A Chaker, Layal %A Chalmers, John %A Chee, Miao-Li %A Chee, Miao-Ling %A Cheng, Ching-Yu %A Chu, Audrey Y %A Ciullo, Marina %A Cocca, Massimiliano %A Cook, James P %A Coresh, Josef %A Cusi, Daniele %A de Borst, Martin H %A Degenhardt, Frauke %A Eckardt, Kai-Uwe %A Endlich, Karlhans %A Evans, Michele K %A Feitosa, Mary F %A Franke, Andre %A Freitag-Wolf, Sandra %A Fuchsberger, Christian %A Gampawar, Piyush %A Gansevoort, Ron T %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Giedraitis, Vilmantas %A Gieger, Christian %A Gudbjartsson, Daniel F %A Hallan, Stein %A Hamet, Pavel %A Hishida, Asahi %A Ho, Kevin %A Hofer, Edith %A Holleczek, Bernd %A Holm, Hilma %A Hoppmann, Anselm %A Horn, Katrin %A Hutri-Kähönen, Nina %A Hveem, Kristian %A Hwang, Shih-Jen %A Ikram, M Arfan %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Karabegović, Irma %A Khor, Chiea-Chuen %A Koenig, Wolfgang %A Kramer, Holly %A Krämer, Bernhard K %A Kuhnel, Brigitte %A Kuusisto, Johanna %A Laakso, Markku %A Lange, Leslie A %A Lehtimäki, Terho %A Li, Man %A Lieb, Wolfgang %A Lind, Lars %A Lindgren, Cecilia M %A Loos, Ruth J F %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Matias-Garcia, Pamela R %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Morris, Andrew P %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Naito, Mariko %A Nakatochi, Masahiro %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Nutile, Teresa %A O'Donoghue, Michelle L %A O'Connell, Jeffrey %A Olafsson, Isleifur %A Orho-Melander, Marju %A Parsa, Afshin %A Pendergrass, Sarah A %A Penninx, Brenda W J H %A Pirastu, Mario %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Raitakari, Olli T %A Rheinberger, Myriam %A Rice, Kenneth M %A Rizzi, Federica %A Rosenkranz, Alexander R %A Rossing, Peter %A Rotter, Jerome I %A Ruggiero, Daniela %A Ryan, Kathleen A %A Sabanayagam, Charumathi %A Salvi, Erika %A Schmidt, Helena %A Schmidt, Reinhold %A Scholz, Markus %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Sedaghat, Sanaz %A Shaffer, Christian M %A Sieber, Karsten B %A Sim, Xueling %A Sims, Mario %A Snieder, Harold %A Stanzick, Kira J %A Thorsteinsdottir, Unnur %A Stocker, Hannah %A Strauch, Konstantin %A Stringham, Heather M %A Sulem, Patrick %A Szymczak, Silke %A Taylor, Kent D %A Thio, Chris H L %A Tremblay, Johanne %A Vaccargiu, Simona %A van der Harst, Pim %A van der Most, Peter J %A Verweij, Niek %A Völker, Uwe %A Wakai, Kenji %A Waldenberger, Melanie %A Wallentin, Lars %A Wallner, Stefan %A Wang, Judy %A Waterworth, Dawn M %A White, Harvey D %A Willer, Cristen J %A Wong, Tien-Yin %A Woodward, Mark %A Yang, Qiong %A Yerges-Armstrong, Laura M %A Zimmermann, Martina %A Zonderman, Alan B %A Bergler, Tobias %A Stefansson, Kari %A Böger, Carsten A %A Pattaro, Cristian %A Köttgen, Anna %A Kronenberg, Florian %A Heid, Iris M %X

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

%B Kidney Int %8 2022 Jun 16 %G eng %R 10.1016/j.kint.2022.05.021 %0 Journal Article %J medRxiv %D 2023 %T Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications. %A Suzuki, Ken %A Hatzikotoulas, Konstantinos %A Southam, Lorraine %A Taylor, Henry J %A Yin, Xianyong %A Lorenz, Kim M %A Mandla, Ravi %A Huerta-Chagoya, Alicia %A Rayner, Nigel W %A Bocher, Ozvan %A Ana Luiza de, S V Arruda %A Sonehara, Kyuto %A Namba, Shinichi %A Lee, Simon S K %A Preuss, Michael H %A Petty, Lauren E %A Schroeder, Philip %A Vanderwerff, Brett %A Kals, Mart %A Bragg, Fiona %A Lin, Kuang %A Guo, Xiuqing %A Zhang, Weihua %A Yao, Jie %A Kim, Young Jin %A Graff, Mariaelisa %A Takeuchi, Fumihiko %A Nano, Jana %A Lamri, Amel %A Nakatochi, Masahiro %A Moon, Sanghoon %A Scott, Robert A %A Cook, James P %A Lee, Jung-Jin %A Pan, Ian %A Taliun, Daniel %A Parra, Esteban J %A Chai, Jin-Fang %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Thorleifsson, Gudmar %A Grarup, Niels %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Kwak, Soo-Heon %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Nongmaithem, Suraj S %A Noordam, Raymond %A Lim, Victor J Y %A Tam, Claudia H T %A Joo, Yoonjung Yoonie %A Chen, Chien-Hsiun %A Raffield, Laura M %A Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Brody, Jennifer A %A Kabagambe, Edmond %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Alaine Broadaway, K %A Williamson, Alice %A Kamali, Zoha %A Cui, Jinrui %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Ahluwalia, Tarunveer S %A Anand, Sonia S %A Bertoni, Alain %A Bork-Jensen, Jette %A Brandslund, Ivan %A Buchanan, Thomas A %A Burant, Charles F %A Butterworth, Adam S %A Canouil, Mickaël %A Chan, Juliana C N %A Chang, Li-Ching %A Chee, Miao-Li %A Chen, Ji %A Chen, Shyh-Huei %A Chen, Yuan-Tsong %A Chen, Zhengming %A Chuang, Lee-Ming %A Cushman, Mary %A Danesh, John %A Das, Swapan K %A Janaka de Silva, H %A Dedoussis, George %A Dimitrov, Latchezar %A Doumatey, Ayo P %A Du, Shufa %A Duan, Qing %A Eckardt, Kai-Uwe %A Emery, Leslie S %A Evans, Daniel S %A Evans, Michele K %A Fischer, Krista %A Floyd, James S %A Ford, Ian %A Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Gordon-Larsen, Penny %A Gross, Myron %A Guare, Lindsay A %A Hackinger, Sophie %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Horikoshi, Momoko %A Howard, Annie-Green %A Hsueh, Willa %A Huang, Mengna %A Huang, Wei %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Hwu, Chii-Min %A Ichihara, Sahoko %A Ikram, Mohammad Arfan %A Ingelsson, Martin %A Islam, Md Tariqul %A Isono, Masato %A Jang, Hye-Mi %A Jasmine, Farzana %A Jiang, Guozhi %A Jonas, Jost B %A Jørgensen, Torben %A Kandeel, Fouad R %A Kasturiratne, Anuradhani %A Katsuya, Tomohiro %A Kaur, Varinderpal %A Kawaguchi, Takahisa %A Keaton, Jacob M %A Kho, Abel N %A Khor, Chiea-Chuen %A Kibriya, Muhammad G %A Kim, Duk-Hwan %A Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Kyung Min %A Lee, Myung-Shik %A Lee, Nanette R %A Leong, Aaron %A Li, Liming %A Li, Yun %A Li-Gao, Ruifang %A Lithgart, Symen %A Lindgren, Cecilia M %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jianjun %A Locke, Adam E %A Louie, Tin %A Luan, Jian'an %A Luk, Andrea O %A Luo, Xi %A Lv, Jun %A Lynch, Julie A %A Lyssenko, Valeriya %A Maeda, Shiro %A Mamakou, Vasiliki %A Mansuri, Sohail Rafik %A Matsuda, Koichi %A Meitinger, Thomas %A Metspalu, Andres %A Mo, Huan %A Morris, Andrew D %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Patil, Snehal %A Pei, Pei %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Polikowsky, Hannah G %A Porneala, Bianca %A Prasad, Gauri %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Katheryn %A Sabanayagam, Charumathi %A Sandow, Kevin %A Sankareswaran, Alagu %A Sattar, Naveed %A Schönherr, Sebastian %A Shahriar, Mohammad %A Shen, Botong %A Shi, Jinxiu %A Shin, Dong Mun %A Shojima, Nobuhiro %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Steinthorsdottir, Valgerdur %A Stilp, Adrienne M %A Strauch, Konstantin %A Taylor, Kent D %A Thorand, Barbara %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Tran, Tam C %A Tsai, Fuu-Jen %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A Valladares-Salgado, Adan %A van Dam, Rob M %A van Klinken, Jan B %A Varma, Rohit %A Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamamoto, Kenichi %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zawistowski, Matthew %A Zhang, Liang %A Zheng, Wei %A Project, Biobank Japan %A BioBank, Penn Medicine %A Center, Regeneron Genetics %A Consortium, eMERGE %A Raffel, Leslie J %A Igase, Michiya %A Ipp, Eli %A Redline, Susan %A Cho, Yoon Shin %A Lind, Lars %A Province, Michael A %A Fornage, Myriam %A Hanis, Craig L %A Ingelsson, Erik %A Zonderman, Alan B %A Psaty, Bruce M %A Wang, Ya-Xing %A Rotimi, Charles N %A Becker, Diane M %A Matsuda, Fumihiko %A Liu, Yongmei %A Yokota, Mitsuhiro %A Kardia, Sharon L R %A Peyser, Patricia A %A Pankow, James S %A Engert, James C %A Bonnefond, Amélie %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Wu, Jer-Yuarn %A Geoffrey Hayes, M %A Ma, Ronald C W %A Wong, Tien-Yin %A Mook-Kanamori, Dennis O %A Tuomi, Tiinamaija %A Chandak, Giriraj R %A Collins, Francis S %A Bharadwaj, Dwaipayan %A Paré, Guillaume %A Sale, Michèle M %A Ahsan, Habibul %A Motala, Ayesha A %A Shu, Xiao-Ou %A Park, Kyong-Soo %A Jukema, J Wouter %A Cruz, Miguel %A Chen, Yii-Der Ida %A Rich, Stephen S %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Ghanbari, Mohsen %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Bowden, Donald W %A Palmer, Colin N A %A Kooner, Jaspal S %A Kooperberg, Charles %A Liu, Simin %A North, Kari E %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Wareham, Nicholas J %A Lee, Juyoung %A Kim, Bong-Jo %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Goodarzi, Mark O %A Mohlke, Karen L %A Langenberg, Claudia %A Haiman, Christopher A %A Loos, Ruth J F %A Florez, Jose C %A Rader, Daniel J %A Ritchie, Marylyn D %A Zöllner, Sebastian %A Mägi, Reedik %A Denny, Joshua C %A Yamauchi, Toshimasa %A Kadowaki, Takashi %A Chambers, John C %A Ng, Maggie C Y %A Sim, Xueling %A Below, Jennifer E %A Tsao, Philip S %A Chang, Kyong-Mi %A McCarthy, Mark I %A Meigs, James B %A Mahajan, Anubha %A Spracklen, Cassandra N %A Mercader, Josep M %A Boehnke, Michael %A Rotter, Jerome I %A Vujkovic, Marijana %A Voight, Benjamin F %A Morris, Andrew P %A Zeggini, Eleftheria %X

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

%B medRxiv %8 2023 Mar 31 %G eng %R 10.1101/2023.03.31.23287839 %0 Journal Article %J Nature %D 2024 %T Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. %A Suzuki, Ken %A Hatzikotoulas, Konstantinos %A Southam, Lorraine %A Taylor, Henry J %A Yin, Xianyong %A Lorenz, Kim M %A Mandla, Ravi %A Huerta-Chagoya, Alicia %A Melloni, Giorgio E M %A Kanoni, Stavroula %A Rayner, Nigel W %A Bocher, Ozvan %A Arruda, Ana Luiza %A Sonehara, Kyuto %A Namba, Shinichi %A Lee, Simon S K %A Preuss, Michael H %A Petty, Lauren E %A Schroeder, Philip %A Vanderwerff, Brett %A Kals, Mart %A Bragg, Fiona %A Lin, Kuang %A Guo, Xiuqing %A Zhang, Weihua %A Yao, Jie %A Kim, Young Jin %A Graff, Mariaelisa %A Takeuchi, Fumihiko %A Nano, Jana %A Lamri, Amel %A Nakatochi, Masahiro %A Moon, Sanghoon %A Scott, Robert A %A Cook, James P %A Lee, Jung-Jin %A Pan, Ian %A Taliun, Daniel %A Parra, Esteban J %A Chai, Jin-Fang %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Thorleifsson, Gudmar %A Grarup, Niels %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Kwak, Soo-Heon %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Nongmaithem, Suraj S %A Noordam, Raymond %A Lim, Victor J Y %A Tam, Claudia H T %A Joo, Yoonjung Yoonie %A Chen, Chien-Hsiun %A Raffield, Laura M %A Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Brody, Jennifer A %A Kabagambe, Edmond %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Broadaway, K Alaine %A Williamson, Alice %A Kamali, Zoha %A Cui, Jinrui %A Thangam, Manonanthini %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Ahluwalia, Tarunveer S %A Anand, Sonia S %A Bertoni, Alain %A Bork-Jensen, Jette %A Brandslund, Ivan %A Buchanan, Thomas A %A Burant, Charles F %A Butterworth, Adam S %A Canouil, Mickaël %A Chan, Juliana C N %A Chang, Li-Ching %A Chee, Miao-Li %A Chen, Ji %A Chen, Shyh-Huei %A Chen, Yuan-Tsong %A Chen, Zhengming %A Chuang, Lee-Ming %A Cushman, Mary %A Danesh, John %A Das, Swapan K %A de Silva, H Janaka %A Dedoussis, George %A Dimitrov, Latchezar %A Doumatey, Ayo P %A Du, Shufa %A Duan, Qing %A Eckardt, Kai-Uwe %A Emery, Leslie S %A Evans, Daniel S %A Evans, Michele K %A Fischer, Krista %A Floyd, James S %A Ford, Ian %A Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Gordon-Larsen, Penny %A Gross, Myron %A Guare, Lindsay A %A Hackinger, Sophie %A Hakaste, Liisa %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Horikoshi, Momoko %A Howard, Annie-Green %A Hsueh, Willa %A Huang, Mengna %A Huang, Wei %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Hwu, Chii-Min %A Ichihara, Sahoko %A Ikram, Mohammad Arfan %A Ingelsson, Martin %A Islam, Md Tariqul %A Isono, Masato %A Jang, Hye-Mi %A Jasmine, Farzana %A Jiang, 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Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

%B Nature %8 2024 Feb 19 %G eng %R 10.1038/s41586-024-07019-6