1000 Genomes-based metaanalysis identifies 10 novel loci for kidney function

Mathias Gorski, Peter J. Van Der Most, Alexander Teumer, Audrey Y. Chu, Man Li, Vladan Mijatovic, Ilja M. Nolte, Massimiliano Cocca, Daniel Taliun, Felicia Gomez, Yong Li, Bamidele Tayo, Adrienne Tin, Mary F. Feitosa, Thor Aspelund, John Attia, Reiner Biffar, Murielle Bochud, Eric Boerwinkle, Ingrid Borecki & 106 others Erwin P. Bottinger, Ming Huei Chen, Vincent Chouraki, Marina Ciullo, Josef Coresh, Marilyn C. Cornelis, Gary C. Curhan, Adamo Pio D'Adamo, Abbas Dehghan, Laura Dengler, Jingzhong Ding, Gudny Eiriksdottir, Karlhans Endlich, Stefan Enroth, Tõnu Esko, Oscar H. Franco, Paolo Gasparini, Christian Gieger, Giorgia Girotto, Omri Gottesman, Vilmundur Gudnason, Ulf Gyllensten, Stephen J. Hancock, Tamara B. Harris, Catherine Helmer, Simon Höllerer, Edith Hofer, Albert Hofman, Elizabeth G. Holliday, Georg Homuth, Frank B. Hu, Cornelia Huth, Nina Hutri-Kähönen, Shih Jen Hwang, Medea Imboden, Asa Johansson, Mika Kähönen, Wolfgang König, Holly Kramer, Bernhard K. Krämer, Ashish Kumar, Zoltan Kutalik, Jean Charles Lambert, Lenore J. Launer, Terho Lehtimäki, Martin H. De Borst, Gerjan Navis, Morris Swertz, Yongmei Liu, Kurt Lohman, Ruth J.F. Loos, Yingchang Lu, Leo Pekka Lyytikäinen, Mark A. McEvoy, Christa Meisinger, Thomas Meitinger, Andres Metspalu, Marie Metzger, Evelin Mihailov, Paul Mitchell, Matthias Nauck, Albertine J. Oldehinkel, Matthias Olden, Brenda W.J.H. Penninx, Giorgio Pistis, Peter P. Pramstaller, Nicole Probst-Hensch, Olli T. Raitakari, Rainer Rettig, Paul M. Ridker, Fernando Rivadeneira, Antonietta Robino, Sylvia E. Rosas, Douglas Ruderfer, Daniela Ruggiero, Yasaman Saba, Cinzia Sala, Helena Schmidt, Reinhold Schmidt, Rodney J. Scott, Sanaz Sedaghat, Albert V. Smith, Rossella Sorice, Benedicte Stengel, Sylvia Stracke, Konstantin Strauch, Daniela Toniolo, Andre G. Uitterlinden, Sheila Ulivi, Jorma S. Viikari, Uwe Völker, Peter Vollenweider, Henry Völzke, Dragana Vuckovic, Melanie Waldenberger, Jie Jin Wang, Qiong Yang, Daniel I. Chasman, Gerard Tromp, Harold Snieder, Iris M. Heid, Caroline S. Fox, Anna Köttgen, Cristian Pattaro, Carsten A. Böger, Christian Fuchsberger

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-Analysis of kidney function based on the estimated glomerular filtration rate (EGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10-8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until wholegenome sequencing becomes feasible in large samples.

Original languageEnglish
Article number45040
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - Jan 1 2017

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Genome-Wide Association Study
Genome
HapMap Project
Kidney
Heart Septum
Genes
Carbohydrate Metabolism
Glomerular Filtration Rate
Gene Frequency
Single Nucleotide Polymorphism
Meta-Analysis
Glucose

ASJC Scopus subject areas

  • General

Cite this

Gorski, M., Van Der Most, P. J., Teumer, A., Chu, A. Y., Li, M., Mijatovic, V., ... Fuchsberger, C. (2017). 1000 Genomes-based metaanalysis identifies 10 novel loci for kidney function. Scientific Reports, 7, [45040]. https://doi.org/10.1038/srep45040

1000 Genomes-based metaanalysis identifies 10 novel loci for kidney function. / Gorski, Mathias; Van Der Most, Peter J.; Teumer, Alexander; Chu, Audrey Y.; Li, Man; Mijatovic, Vladan; Nolte, Ilja M.; Cocca, Massimiliano; Taliun, Daniel; Gomez, Felicia; Li, Yong; Tayo, Bamidele; Tin, Adrienne; Feitosa, Mary F.; Aspelund, Thor; Attia, John; Biffar, Reiner; Bochud, Murielle; Boerwinkle, Eric; Borecki, Ingrid; Bottinger, Erwin P.; Chen, Ming Huei; Chouraki, Vincent; Ciullo, Marina; Coresh, Josef; Cornelis, Marilyn C.; Curhan, Gary C.; D'Adamo, Adamo Pio; Dehghan, Abbas; Dengler, Laura; Ding, Jingzhong; Eiriksdottir, Gudny; Endlich, Karlhans; Enroth, Stefan; Esko, Tõnu; Franco, Oscar H.; Gasparini, Paolo; Gieger, Christian; Girotto, Giorgia; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Hancock, Stephen J.; Harris, Tamara B.; Helmer, Catherine; Höllerer, Simon; Hofer, Edith; Hofman, Albert; Holliday, Elizabeth G.; Homuth, Georg; Hu, Frank B.; Huth, Cornelia; Hutri-Kähönen, Nina; Hwang, Shih Jen; Imboden, Medea; Johansson, Asa; Kähönen, Mika; König, Wolfgang; Kramer, Holly; Krämer, Bernhard K.; Kumar, Ashish; Kutalik, Zoltan; Lambert, Jean Charles; Launer, Lenore J.; Lehtimäki, Terho; De Borst, Martin H.; Navis, Gerjan; Swertz, Morris; Liu, Yongmei; Lohman, Kurt; Loos, Ruth J.F.; Lu, Yingchang; Lyytikäinen, Leo Pekka; McEvoy, Mark A.; Meisinger, Christa; Meitinger, Thomas; Metspalu, Andres; Metzger, Marie; Mihailov, Evelin; Mitchell, Paul; Nauck, Matthias; Oldehinkel, Albertine J.; Olden, Matthias; Penninx, Brenda W.J.H.; Pistis, Giorgio; Pramstaller, Peter P.; Probst-Hensch, Nicole; Raitakari, Olli T.; Rettig, Rainer; Ridker, Paul M.; Rivadeneira, Fernando; Robino, Antonietta; Rosas, Sylvia E.; Ruderfer, Douglas; Ruggiero, Daniela; Saba, Yasaman; Sala, Cinzia; Schmidt, Helena; Schmidt, Reinhold; Scott, Rodney J.; Sedaghat, Sanaz; Smith, Albert V.; Sorice, Rossella; Stengel, Benedicte; Stracke, Sylvia; Strauch, Konstantin; Toniolo, Daniela; Uitterlinden, Andre G.; Ulivi, Sheila; Viikari, Jorma S.; Völker, Uwe; Vollenweider, Peter; Völzke, Henry; Vuckovic, Dragana; Waldenberger, Melanie; Wang, Jie Jin; Yang, Qiong; Chasman, Daniel I.; Tromp, Gerard; Snieder, Harold; Heid, Iris M.; Fox, Caroline S.; Köttgen, Anna; Pattaro, Cristian; Böger, Carsten A.; Fuchsberger, Christian.

In: Scientific Reports, Vol. 7, 45040, 01.01.2017.

Research output: Contribution to journalArticle

Gorski, M, Van Der Most, PJ, Teumer, A, Chu, AY, Li, M, Mijatovic, V, Nolte, IM, Cocca, M, Taliun, D, Gomez, F, Li, Y, Tayo, B, Tin, A, Feitosa, MF, Aspelund, T, Attia, J, Biffar, R, Bochud, M, Boerwinkle, E, Borecki, I, Bottinger, EP, Chen, MH, Chouraki, V, Ciullo, M, Coresh, J, Cornelis, MC, Curhan, GC, D'Adamo, AP, Dehghan, A, Dengler, L, Ding, J, Eiriksdottir, G, Endlich, K, Enroth, S, Esko, T, Franco, OH, Gasparini, P, Gieger, C, Girotto, G, Gottesman, O, Gudnason, V, Gyllensten, U, Hancock, SJ, Harris, TB, Helmer, C, Höllerer, S, Hofer, E, Hofman, A, Holliday, EG, Homuth, G, Hu, FB, Huth, C, Hutri-Kähönen, N, Hwang, SJ, Imboden, M, Johansson, A, Kähönen, M, König, W, Kramer, H, Krämer, BK, Kumar, A, Kutalik, Z, Lambert, JC, Launer, LJ, Lehtimäki, T, De Borst, MH, Navis, G, Swertz, M, Liu, Y, Lohman, K, Loos, RJF, Lu, Y, Lyytikäinen, LP, McEvoy, MA, Meisinger, C, Meitinger, T, Metspalu, A, Metzger, M, Mihailov, E, Mitchell, P, Nauck, M, Oldehinkel, AJ, Olden, M, Penninx, BWJH, Pistis, G, Pramstaller, PP, Probst-Hensch, N, Raitakari, OT, Rettig, R, Ridker, PM, Rivadeneira, F, Robino, A, Rosas, SE, Ruderfer, D, Ruggiero, D, Saba, Y, Sala, C, Schmidt, H, Schmidt, R, Scott, RJ, Sedaghat, S, Smith, AV, Sorice, R, Stengel, B, Stracke, S, Strauch, K, Toniolo, D, Uitterlinden, AG, Ulivi, S, Viikari, JS, Völker, U, Vollenweider, P, Völzke, H, Vuckovic, D, Waldenberger, M, Wang, JJ, Yang, Q, Chasman, DI, Tromp, G, Snieder, H, Heid, IM, Fox, CS, Köttgen, A, Pattaro, C, Böger, CA & Fuchsberger, C 2017, '1000 Genomes-based metaanalysis identifies 10 novel loci for kidney function', Scientific Reports, vol. 7, 45040. https://doi.org/10.1038/srep45040
Gorski M, Van Der Most PJ, Teumer A, Chu AY, Li M, Mijatovic V et al. 1000 Genomes-based metaanalysis identifies 10 novel loci for kidney function. Scientific Reports. 2017 Jan 1;7. 45040. https://doi.org/10.1038/srep45040
Gorski, Mathias ; Van Der Most, Peter J. ; Teumer, Alexander ; Chu, Audrey Y. ; Li, Man ; Mijatovic, Vladan ; Nolte, Ilja M. ; Cocca, Massimiliano ; Taliun, Daniel ; Gomez, Felicia ; Li, Yong ; Tayo, Bamidele ; Tin, Adrienne ; Feitosa, Mary F. ; Aspelund, Thor ; Attia, John ; Biffar, Reiner ; Bochud, Murielle ; Boerwinkle, Eric ; Borecki, Ingrid ; Bottinger, Erwin P. ; Chen, Ming Huei ; Chouraki, Vincent ; Ciullo, Marina ; Coresh, Josef ; Cornelis, Marilyn C. ; Curhan, Gary C. ; D'Adamo, Adamo Pio ; Dehghan, Abbas ; Dengler, Laura ; Ding, Jingzhong ; Eiriksdottir, Gudny ; Endlich, Karlhans ; Enroth, Stefan ; Esko, Tõnu ; Franco, Oscar H. ; Gasparini, Paolo ; Gieger, Christian ; Girotto, Giorgia ; Gottesman, Omri ; Gudnason, Vilmundur ; Gyllensten, Ulf ; Hancock, Stephen J. ; Harris, Tamara B. ; Helmer, Catherine ; Höllerer, Simon ; Hofer, Edith ; Hofman, Albert ; Holliday, Elizabeth G. ; Homuth, Georg ; Hu, Frank B. ; Huth, Cornelia ; Hutri-Kähönen, Nina ; Hwang, Shih Jen ; Imboden, Medea ; Johansson, Asa ; Kähönen, Mika ; König, Wolfgang ; Kramer, Holly ; Krämer, Bernhard K. ; Kumar, Ashish ; Kutalik, Zoltan ; Lambert, Jean Charles ; Launer, Lenore J. ; Lehtimäki, Terho ; De Borst, Martin H. ; Navis, Gerjan ; Swertz, Morris ; Liu, Yongmei ; Lohman, Kurt ; Loos, Ruth J.F. ; Lu, Yingchang ; Lyytikäinen, Leo Pekka ; McEvoy, Mark A. ; Meisinger, Christa ; Meitinger, Thomas ; Metspalu, Andres ; Metzger, Marie ; Mihailov, Evelin ; Mitchell, Paul ; Nauck, Matthias ; Oldehinkel, Albertine J. ; Olden, Matthias ; Penninx, Brenda W.J.H. ; Pistis, Giorgio ; Pramstaller, Peter P. ; Probst-Hensch, Nicole ; Raitakari, Olli T. ; Rettig, Rainer ; Ridker, Paul M. ; Rivadeneira, Fernando ; Robino, Antonietta ; Rosas, Sylvia E. ; Ruderfer, Douglas ; Ruggiero, Daniela ; Saba, Yasaman ; Sala, Cinzia ; Schmidt, Helena ; Schmidt, Reinhold ; Scott, Rodney J. ; Sedaghat, Sanaz ; Smith, Albert V. ; Sorice, Rossella ; Stengel, Benedicte ; Stracke, Sylvia ; Strauch, Konstantin ; Toniolo, Daniela ; Uitterlinden, Andre G. ; Ulivi, Sheila ; Viikari, Jorma S. ; Völker, Uwe ; Vollenweider, Peter ; Völzke, Henry ; Vuckovic, Dragana ; Waldenberger, Melanie ; Wang, Jie Jin ; Yang, Qiong ; Chasman, Daniel I. ; Tromp, Gerard ; Snieder, Harold ; Heid, Iris M. ; Fox, Caroline S. ; Köttgen, Anna ; Pattaro, Cristian ; Böger, Carsten A. ; Fuchsberger, Christian. / 1000 Genomes-based metaanalysis identifies 10 novel loci for kidney function. In: Scientific Reports. 2017 ; Vol. 7.
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title = "1000 Genomes-based metaanalysis identifies 10 novel loci for kidney function",
abstract = "HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5{\%} are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-Analysis of kidney function based on the estimated glomerular filtration rate (EGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10-8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until wholegenome sequencing becomes feasible in large samples.",
author = "Mathias Gorski and {Van Der Most}, {Peter J.} and Alexander Teumer and Chu, {Audrey Y.} and Man Li and Vladan Mijatovic and Nolte, {Ilja M.} and Massimiliano Cocca and Daniel Taliun and Felicia Gomez and Yong Li and Bamidele Tayo and Adrienne Tin and Feitosa, {Mary F.} and Thor Aspelund and John Attia and Reiner Biffar and Murielle Bochud and Eric Boerwinkle and Ingrid Borecki and Bottinger, {Erwin P.} and Chen, {Ming Huei} and Vincent Chouraki and Marina Ciullo and Josef Coresh and Cornelis, {Marilyn C.} and Curhan, {Gary C.} and D'Adamo, {Adamo Pio} and Abbas Dehghan and Laura Dengler and Jingzhong Ding and Gudny Eiriksdottir and Karlhans Endlich and Stefan Enroth and T{\~o}nu Esko and Franco, {Oscar H.} and Paolo Gasparini and Christian Gieger and Giorgia Girotto and Omri Gottesman and Vilmundur Gudnason and Ulf Gyllensten and Hancock, {Stephen J.} and Harris, {Tamara B.} and Catherine Helmer and Simon H{\"o}llerer and Edith Hofer and Albert Hofman and Holliday, {Elizabeth G.} and Georg Homuth and Hu, {Frank B.} and Cornelia Huth and Nina Hutri-K{\"a}h{\"o}nen and Hwang, {Shih Jen} and Medea Imboden and Asa Johansson and Mika K{\"a}h{\"o}nen and Wolfgang K{\"o}nig and Holly Kramer and Kr{\"a}mer, {Bernhard K.} and Ashish Kumar and Zoltan Kutalik and Lambert, {Jean Charles} and Launer, {Lenore J.} and Terho Lehtim{\"a}ki and {De Borst}, {Martin H.} and Gerjan Navis and Morris Swertz and Yongmei Liu and Kurt Lohman and Loos, {Ruth J.F.} and Yingchang Lu and Lyytik{\"a}inen, {Leo Pekka} and McEvoy, {Mark A.} and Christa Meisinger and Thomas Meitinger and Andres Metspalu and Marie Metzger and Evelin Mihailov and Paul Mitchell and Matthias Nauck and Oldehinkel, {Albertine J.} and Matthias Olden and Penninx, {Brenda W.J.H.} and Giorgio Pistis and Pramstaller, {Peter P.} and Nicole Probst-Hensch and Raitakari, {Olli T.} and Rainer Rettig and Ridker, {Paul M.} and Fernando Rivadeneira and Antonietta Robino and Rosas, {Sylvia E.} and Douglas Ruderfer and Daniela Ruggiero and Yasaman Saba and Cinzia Sala and Helena Schmidt and Reinhold Schmidt and Scott, {Rodney J.} and Sanaz Sedaghat and Smith, {Albert V.} and Rossella Sorice and Benedicte Stengel and Sylvia Stracke and Konstantin Strauch and Daniela Toniolo and Uitterlinden, {Andre G.} and Sheila Ulivi and Viikari, {Jorma S.} and Uwe V{\"o}lker and Peter Vollenweider and Henry V{\"o}lzke and Dragana Vuckovic and Melanie Waldenberger and Wang, {Jie Jin} and Qiong Yang and Chasman, {Daniel I.} and Gerard Tromp and Harold Snieder and Heid, {Iris M.} and Fox, {Caroline S.} and Anna K{\"o}ttgen and Cristian Pattaro and B{\"o}ger, {Carsten A.} and Christian Fuchsberger",
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T1 - 1000 Genomes-based metaanalysis identifies 10 novel loci for kidney function

AU - Gorski, Mathias

AU - Van Der Most, Peter J.

AU - Teumer, Alexander

AU - Chu, Audrey Y.

AU - Li, Man

AU - Mijatovic, Vladan

AU - Nolte, Ilja M.

AU - Cocca, Massimiliano

AU - Taliun, Daniel

AU - Gomez, Felicia

AU - Li, Yong

AU - Tayo, Bamidele

AU - Tin, Adrienne

AU - Feitosa, Mary F.

AU - Aspelund, Thor

AU - Attia, John

AU - Biffar, Reiner

AU - Bochud, Murielle

AU - Boerwinkle, Eric

AU - Borecki, Ingrid

AU - Bottinger, Erwin P.

AU - Chen, Ming Huei

AU - Chouraki, Vincent

AU - Ciullo, Marina

AU - Coresh, Josef

AU - Cornelis, Marilyn C.

AU - Curhan, Gary C.

AU - D'Adamo, Adamo Pio

AU - Dehghan, Abbas

AU - Dengler, Laura

AU - Ding, Jingzhong

AU - Eiriksdottir, Gudny

AU - Endlich, Karlhans

AU - Enroth, Stefan

AU - Esko, Tõnu

AU - Franco, Oscar H.

AU - Gasparini, Paolo

AU - Gieger, Christian

AU - Girotto, Giorgia

AU - Gottesman, Omri

AU - Gudnason, Vilmundur

AU - Gyllensten, Ulf

AU - Hancock, Stephen J.

AU - Harris, Tamara B.

AU - Helmer, Catherine

AU - Höllerer, Simon

AU - Hofer, Edith

AU - Hofman, Albert

AU - Holliday, Elizabeth G.

AU - Homuth, Georg

AU - Hu, Frank B.

AU - Huth, Cornelia

AU - Hutri-Kähönen, Nina

AU - Hwang, Shih Jen

AU - Imboden, Medea

AU - Johansson, Asa

AU - Kähönen, Mika

AU - König, Wolfgang

AU - Kramer, Holly

AU - Krämer, Bernhard K.

AU - Kumar, Ashish

AU - Kutalik, Zoltan

AU - Lambert, Jean Charles

AU - Launer, Lenore J.

AU - Lehtimäki, Terho

AU - De Borst, Martin H.

AU - Navis, Gerjan

AU - Swertz, Morris

AU - Liu, Yongmei

AU - Lohman, Kurt

AU - Loos, Ruth J.F.

AU - Lu, Yingchang

AU - Lyytikäinen, Leo Pekka

AU - McEvoy, Mark A.

AU - Meisinger, Christa

AU - Meitinger, Thomas

AU - Metspalu, Andres

AU - Metzger, Marie

AU - Mihailov, Evelin

AU - Mitchell, Paul

AU - Nauck, Matthias

AU - Oldehinkel, Albertine J.

AU - Olden, Matthias

AU - Penninx, Brenda W.J.H.

AU - Pistis, Giorgio

AU - Pramstaller, Peter P.

AU - Probst-Hensch, Nicole

AU - Raitakari, Olli T.

AU - Rettig, Rainer

AU - Ridker, Paul M.

AU - Rivadeneira, Fernando

AU - Robino, Antonietta

AU - Rosas, Sylvia E.

AU - Ruderfer, Douglas

AU - Ruggiero, Daniela

AU - Saba, Yasaman

AU - Sala, Cinzia

AU - Schmidt, Helena

AU - Schmidt, Reinhold

AU - Scott, Rodney J.

AU - Sedaghat, Sanaz

AU - Smith, Albert V.

AU - Sorice, Rossella

AU - Stengel, Benedicte

AU - Stracke, Sylvia

AU - Strauch, Konstantin

AU - Toniolo, Daniela

AU - Uitterlinden, Andre G.

AU - Ulivi, Sheila

AU - Viikari, Jorma S.

AU - Völker, Uwe

AU - Vollenweider, Peter

AU - Völzke, Henry

AU - Vuckovic, Dragana

AU - Waldenberger, Melanie

AU - Wang, Jie Jin

AU - Yang, Qiong

AU - Chasman, Daniel I.

AU - Tromp, Gerard

AU - Snieder, Harold

AU - Heid, Iris M.

AU - Fox, Caroline S.

AU - Köttgen, Anna

AU - Pattaro, Cristian

AU - Böger, Carsten A.

AU - Fuchsberger, Christian

PY - 2017/1/1

Y1 - 2017/1/1

N2 - HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-Analysis of kidney function based on the estimated glomerular filtration rate (EGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10-8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until wholegenome sequencing becomes feasible in large samples.

AB - HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-Analysis of kidney function based on the estimated glomerular filtration rate (EGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10-8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until wholegenome sequencing becomes feasible in large samples.

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