Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

Daniel I. Chasman; Christian Fuchsberger; Cristian Pattaro; Alexander Teumer; Carsten A. Böger; Karlhans Endlich; Matthias Olden; Ming Huei Chen; Adrienne Tin; Daniel Taliun; Man Li; Xiaoyi Gao; Mathias Gorski; Qiong Yang; Claudia Hundertmark; Meredith C. Foster; Conall M. O'Seaghdha; Nicole Glazer; Aaron Isaacs; Ching Ti Liu; Albert V. Smith; Jeffrey R. O'Connell; Maksim Struchalin; Toshiko Tanaka; Guo Li; Andrew D. Johnson; Hinco J. Gierman; Mary F. Feitosa; Shih Jen Hwang; Elizabeth J. Atkinson; Kurt Lohman; Marilyn C. Cornelis; Åsa Johansson; Anke Tönjes; Abbas Dehghan; Jean Charles Lambert; Elizabeth G. Holliday; Rossella Sorice; Zoltan Kutalik; Terho Lehtimäki; Tõnu Esko; Harshal Deshmukh; Sheila Ulivi; Audrey Y. Chu; Federico Murgia; Stella Trompet; Medea Imboden; Stefan Coassin; Giorgio Pistis; Tamara B. Harris; Lenore J. Launer; Thor Aspelund; Gudny Eiriksdottir; Braxton D. Mitchell; Eric Boerwinkle; Helena Schmidt; Margherita Cavalieri; Madhumathi Rao; Frank Hu; Ayse Demirkan; Ben A. Oostra; Mariza de Andrade; Stephen T. Turner; Jingzhong Ding; Jeanette S. Andrews; Barry I. Freedman; Franco Giulianini; Wolfgang Koenig; Thomas Illig; Christa Meisinger; Christian Gieger; Lina Zgaga; Tatijana Zemunik; Mladen Boban; Cosetta Minelli; Heather E. Wheeler; Wilmar Igl; Ghazal Zaboli; Sarah H. Wild; Alan F. Wright; Harry Campbell; David Ellinghaus; Ute Nöthlings; Gunnar Jacobs; Reiner Biffar; Florian Ernst; Georg Homuth; Heyo K. Kroemer; Matthias Nauck; Sylvia Stracke; Uwe Völker; Henry Völzke; Peter Kovacs; Michael Stumvoll; Reedik Mägi; Albert Hofman; Andre G. Uitterlinden; Fernando Rivadeneira; Yurii S. Aulchenko; Ozren Polasek; Nick Hastie; Veronique Vitart; Catherine Helmer; Jie Jin Wang; Bénédicte Stengel; Daniela Ruggiero; Sven Bergmann; Mika Kähönen; Jorma Viikari; Tiit Nikopensius; Michael Province; Shamika Ketkar; Helen Colhoun; Alex Doney; Antonietta Robino; Bernhard K. Krämer; Laura Portas; Ian Ford; Brendan M. Buckley; Martin Adam; Gian Andri Thun; Bernhard Paulweber; Margot Haun; Cinzia Sala; Paul Mitchell; Marina Ciullo; Stuart K. Kim; Peter Vollenweider; Olli Raitakari; Andres Metspalu; Colin Palmer; Paolo Gasparini; Mario Pirastu; J. Wouter Jukema; Nicole M. Probst-Hensch; Florian Kronenberg; Daniela Toniolo; Vilmundur Gudnason; Alan R. Shuldiner; Josef Coresh; Reinhold Schmidt; Luigi Ferrucci; David S. Siscovick; Cornelia M. van Duijn; Ingrid B. Borecki; Sharon L.R. Kardia; Yongmei Liu; Gary C. Curhan; Igor Rudan; Ulf Gyllensten; James F. Wilson; Andre Franke; Peter P. Pramstaller; Rainer Rettig; Inga Prokopenko; Jacqueline Witteman; Caroline Hayward; Paul M. Ridker; Afshin Parsa; Murielle Bochud; Iris M. Heid; W. H.Linda Kao; Caroline S. Fox; Anna Köttgen

doi:10.1093/hmg/dds369

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

Daniel I. Chasman, Christian Fuchsberger, Cristian Pattaro, Alexander Teumer, Carsten A. Böger, Karlhans Endlich, Matthias Olden, Ming Huei Chen, Adrienne Tin, Daniel Taliun, Man Li, Xiaoyi Gao, Mathias Gorski, Qiong Yang, Claudia Hundertmark, Meredith C. Foster, Conall M. O'Seaghdha, Nicole Glazer, Aaron Isaacs, Ching Ti LiuAlbert V. Smith, Jeffrey R. O'Connell, Maksim Struchalin, Toshiko Tanaka, Guo Li, Andrew D. Johnson, Hinco J. Gierman, Mary F. Feitosa, Shih Jen Hwang, Elizabeth J. Atkinson, Kurt Lohman, Marilyn C. Cornelis, Åsa Johansson, Anke Tönjes, Abbas Dehghan, Jean Charles Lambert, Elizabeth G. Holliday, Rossella Sorice, Zoltan Kutalik, Terho Lehtimäki, Tõnu Esko, Harshal Deshmukh, Sheila Ulivi, Audrey Y. Chu, Federico Murgia, Stella Trompet, Medea Imboden, Stefan Coassin, Giorgio Pistis, Tamara B. Harris, Lenore J. Launer, Thor Aspelund, Gudny Eiriksdottir, Braxton D. Mitchell, Eric Boerwinkle, Helena Schmidt, Margherita Cavalieri, Madhumathi Rao, Frank Hu, Ayse Demirkan, Ben A. Oostra, Mariza de Andrade, Stephen T. Turner, Jingzhong Ding, Jeanette S. Andrews, Barry I. Freedman, Franco Giulianini, Wolfgang Koenig, Thomas Illig, Christa Meisinger, Christian Gieger, Lina Zgaga, Tatijana Zemunik, Mladen Boban, Cosetta Minelli, Heather E. Wheeler, Wilmar Igl, Ghazal Zaboli, Sarah H. Wild, Alan F. Wright, Harry Campbell, David Ellinghaus, Ute Nöthlings, Gunnar Jacobs, Reiner Biffar, Florian Ernst, Georg Homuth, Heyo K. Kroemer, Matthias Nauck, Sylvia Stracke, Uwe Völker, Henry Völzke, Peter Kovacs, Michael Stumvoll, Reedik Mägi, Albert Hofman, Andre G. Uitterlinden, Fernando Rivadeneira, Yurii S. Aulchenko, Ozren Polasek, Nick Hastie, Veronique Vitart, Catherine Helmer, Jie Jin Wang, Bénédicte Stengel, Daniela Ruggiero, Sven Bergmann, Mika Kähönen, Jorma Viikari, Tiit Nikopensius, Michael Province, Shamika Ketkar, Helen Colhoun, Alex Doney, Antonietta Robino, Bernhard K. Krämer, Laura Portas, Ian Ford, Brendan M. Buckley, Martin Adam, Gian Andri Thun, Bernhard Paulweber, Margot Haun, Cinzia Sala, Paul Mitchell, Marina Ciullo, Stuart K. Kim, Peter Vollenweider, Olli Raitakari, Andres Metspalu, Colin Palmer, Paolo Gasparini, Mario Pirastu, J. Wouter Jukema, Nicole M. Probst-Hensch, Florian Kronenberg, Daniela Toniolo, Vilmundur Gudnason, Alan R. Shuldiner, Josef Coresh, Reinhold Schmidt, Luigi Ferrucci, David S. Siscovick, Cornelia M. van Duijn, Ingrid B. Borecki, Sharon L.R. Kardia, Yongmei Liu, Gary C. Curhan, Igor Rudan, Ulf Gyllensten, James F. Wilson, Andre Franke, Peter P. Pramstaller, Rainer Rettig, Inga Prokopenko, Jacqueline Witteman, Caroline Hayward, Paul M. Ridker, Afshin Parsa, Murielle Bochud, Iris M. Heid, W. H.Linda Kao, Caroline S. Fox, Anna Köttgen

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5 5.6 3 10 ^-9 ) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 3 10 ^-4 -2.2× 10 ^-7 . Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Original language	English (US)
Pages (from-to)	5329-5343
Number of pages	15
Journal	Human molecular genetics
Volume	21
Issue number	24
DOIs	https://doi.org/10.1093/hmg/dds369
State	Published - Dec 2012

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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10.1093/hmg/dds369

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Chasman, D. I., Fuchsberger, C., Pattaro, C., Teumer, A., Böger, C. A., Endlich, K., Olden, M., Chen, M. H., Tin, A., Taliun, D., Li, M., Gao, X., Gorski, M., Yang, Q., Hundertmark, C., Foster, M. C., O'Seaghdha, C. M., Glazer, N., Isaacs, A., ... Köttgen, A. (2012). Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. Human molecular genetics, 21(24), 5329-5343. https://doi.org/10.1093/hmg/dds369

Chasman, DI, Fuchsberger, C, Pattaro, C, Teumer, A, Böger, CA, Endlich, K, Olden, M, Chen, MH, Tin, A, Taliun, D, Li, M, Gao, X, Gorski, M, Yang, Q, Hundertmark, C, Foster, MC, O'Seaghdha, CM, Glazer, N, Isaacs, A, Liu, CT, Smith, AV, O'Connell, JR, Struchalin, M, Tanaka, T, Li, G, Johnson, AD, Gierman, HJ, Feitosa, MF, Hwang, SJ, Atkinson, EJ, Lohman, K, Cornelis, MC, Johansson, Å, Tönjes, A, Dehghan, A, Lambert, JC, Holliday, EG, Sorice, R, Kutalik, Z, Lehtimäki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, AY, Murgia, F, Trompet, S, Imboden, M, Coassin, S, Pistis, G, Harris, TB, Launer, LJ, Aspelund, T, Eiriksdottir, G, Mitchell, BD, Boerwinkle, E, Schmidt, H, Cavalieri, M, Rao, M, Hu, F, Demirkan, A, Oostra, BA, de Andrade, M, Turner, ST, Ding, J, Andrews, JS, Freedman, BI, Giulianini, F, Koenig, W, Illig, T, Meisinger, C, Gieger, C, Zgaga, L, Zemunik, T, Boban, M, Minelli, C, Wheeler, HE, Igl, W, Zaboli, G, Wild, SH, Wright, AF, Campbell, H, Ellinghaus, D, Nöthlings, U, Jacobs, G, Biffar, R, Ernst, F, Homuth, G, Kroemer, HK, Nauck, M, Stracke, S, Völker, U, Völzke, H, Kovacs, P, Stumvoll, M, Mägi, R, Hofman, A, Uitterlinden, AG, Rivadeneira, F, Aulchenko, YS, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, JJ, Stengel, B, Ruggiero, D, Bergmann, S, Kähönen, M, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Doney, A, Robino, A, Krämer, BK, Portas, L, Ford, I, Buckley, BM, Adam, M, Thun, GA, Paulweber, B, Haun, M, Sala, C, Mitchell, P, Ciullo, M, Kim, SK, Vollenweider, P, Raitakari, O, Metspalu, A, Palmer, C, Gasparini, P, Pirastu, M, Jukema, JW, Probst-Hensch, NM, Kronenberg, F, Toniolo, D, Gudnason, V, Shuldiner, AR, Coresh, J, Schmidt, R, Ferrucci, L, Siscovick, DS, van Duijn, CM, Borecki, IB, Kardia, SLR, Liu, Y, Curhan, GC, Rudan, I, Gyllensten, U, Wilson, JF, Franke, A, Pramstaller, PP, Rettig, R, Prokopenko, I, Witteman, J, Hayward, C, Ridker, PM, Parsa, A, Bochud, M, Heid, IM, Kao, WHL, Fox, CS & Köttgen, A 2012, 'Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function', Human molecular genetics, vol. 21, no. 24, pp. 5329-5343. https://doi.org/10.1093/hmg/dds369

@article{54f14729b45147a592561f5e5d4b4405,

title = "Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function",

abstract = " In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5 5.6 3 10 -9 ) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 3 10 -4 -2.2× 10 -7 . Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.",

author = "Chasman, {Daniel I.} and Christian Fuchsberger and Cristian Pattaro and Alexander Teumer and B{\"o}ger, {Carsten A.} and Karlhans Endlich and Matthias Olden and Chen, {Ming Huei} and Adrienne Tin and Daniel Taliun and Man Li and Xiaoyi Gao and Mathias Gorski and Qiong Yang and Claudia Hundertmark and Foster, {Meredith C.} and O'Seaghdha, {Conall M.} and Nicole Glazer and Aaron Isaacs and Liu, {Ching Ti} and Smith, {Albert V.} and O'Connell, {Jeffrey R.} and Maksim Struchalin and Toshiko Tanaka and Guo Li and Johnson, {Andrew D.} and Gierman, {Hinco J.} and Feitosa, {Mary F.} and Hwang, {Shih Jen} and Atkinson, {Elizabeth J.} and Kurt Lohman and Cornelis, {Marilyn C.} and {\AA}sa Johansson and Anke T{\"o}njes and Abbas Dehghan and Lambert, {Jean Charles} and Holliday, {Elizabeth G.} and Rossella Sorice and Zoltan Kutalik and Terho Lehtim{\"a}ki and T{\~o}nu Esko and Harshal Deshmukh and Sheila Ulivi and Chu, {Audrey Y.} and Federico Murgia and Stella Trompet and Medea Imboden and Stefan Coassin and Giorgio Pistis and Harris, {Tamara B.} and Launer, {Lenore J.} and Thor Aspelund and Gudny Eiriksdottir and Mitchell, {Braxton D.} and Eric Boerwinkle and Helena Schmidt and Margherita Cavalieri and Madhumathi Rao and Frank Hu and Ayse Demirkan and Oostra, {Ben A.} and {de Andrade}, Mariza and Turner, {Stephen T.} and Jingzhong Ding and Andrews, {Jeanette S.} and Freedman, {Barry I.} and Franco Giulianini and Wolfgang Koenig and Thomas Illig and Christa Meisinger and Christian Gieger and Lina Zgaga and Tatijana Zemunik and Mladen Boban and Cosetta Minelli and Wheeler, {Heather E.} and Wilmar Igl and Ghazal Zaboli and Wild, {Sarah H.} and Wright, {Alan F.} and Harry Campbell and David Ellinghaus and Ute N{\"o}thlings and Gunnar Jacobs and Reiner Biffar and Florian Ernst and Georg Homuth and Kroemer, {Heyo K.} and Matthias Nauck and Sylvia Stracke and Uwe V{\"o}lker and Henry V{\"o}lzke and Peter Kovacs and Michael Stumvoll and Reedik M{\"a}gi and Albert Hofman and Uitterlinden, {Andre G.} and Fernando Rivadeneira and Aulchenko, {Yurii S.} and Ozren Polasek and Nick Hastie and Veronique Vitart and Catherine Helmer and Wang, {Jie Jin} and B{\'e}n{\'e}dicte Stengel and Daniela Ruggiero and Sven Bergmann and Mika K{\"a}h{\"o}nen and Jorma Viikari and Tiit Nikopensius and Michael Province and Shamika Ketkar and Helen Colhoun and Alex Doney and Antonietta Robino and Kr{\"a}mer, {Bernhard K.} and Laura Portas and Ian Ford and Buckley, {Brendan M.} and Martin Adam and Thun, {Gian Andri} and Bernhard Paulweber and Margot Haun and Cinzia Sala and Paul Mitchell and Marina Ciullo and Kim, {Stuart K.} and Peter Vollenweider and Olli Raitakari and Andres Metspalu and Colin Palmer and Paolo Gasparini and Mario Pirastu and Jukema, {J. Wouter} and Probst-Hensch, {Nicole M.} and Florian Kronenberg and Daniela Toniolo and Vilmundur Gudnason and Shuldiner, {Alan R.} and Josef Coresh and Reinhold Schmidt and Luigi Ferrucci and Siscovick, {David S.} and {van Duijn}, {Cornelia M.} and Borecki, {Ingrid B.} and Kardia, {Sharon L.R.} and Yongmei Liu and Curhan, {Gary C.} and Igor Rudan and Ulf Gyllensten and Wilson, {James F.} and Andre Franke and Pramstaller, {Peter P.} and Rainer Rettig and Inga Prokopenko and Jacqueline Witteman and Caroline Hayward and Ridker, {Paul M.} and Afshin Parsa and Murielle Bochud and Heid, {Iris M.} and Kao, {W. H.Linda} and Fox, {Caroline S.} and Anna K{\"o}ttgen",

year = "2012",

month = dec,

doi = "10.1093/hmg/dds369",

language = "English (US)",

volume = "21",

pages = "5329--5343",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "24",

}

TY - JOUR

T1 - Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

AU - Chasman, Daniel I.

AU - Fuchsberger, Christian

AU - Pattaro, Cristian

AU - Teumer, Alexander

AU - Böger, Carsten A.

AU - Endlich, Karlhans

AU - Olden, Matthias

AU - Chen, Ming Huei

AU - Tin, Adrienne

AU - Taliun, Daniel

AU - Li, Man

AU - Gao, Xiaoyi

AU - Gorski, Mathias

AU - Yang, Qiong

AU - Hundertmark, Claudia

AU - Foster, Meredith C.

AU - O'Seaghdha, Conall M.

AU - Glazer, Nicole

AU - Isaacs, Aaron

AU - Liu, Ching Ti

AU - Smith, Albert V.

AU - O'Connell, Jeffrey R.

AU - Struchalin, Maksim

AU - Tanaka, Toshiko

AU - Li, Guo

AU - Johnson, Andrew D.

AU - Gierman, Hinco J.

AU - Feitosa, Mary F.

AU - Hwang, Shih Jen

AU - Atkinson, Elizabeth J.

AU - Lohman, Kurt

AU - Cornelis, Marilyn C.

AU - Johansson, Åsa

AU - Tönjes, Anke

AU - Dehghan, Abbas

AU - Lambert, Jean Charles

AU - Holliday, Elizabeth G.

AU - Sorice, Rossella

AU - Kutalik, Zoltan

AU - Lehtimäki, Terho

AU - Esko, Tõnu

AU - Deshmukh, Harshal

AU - Ulivi, Sheila

AU - Chu, Audrey Y.

AU - Murgia, Federico

AU - Trompet, Stella

AU - Imboden, Medea

AU - Coassin, Stefan

AU - Pistis, Giorgio

AU - Harris, Tamara B.

AU - Launer, Lenore J.

AU - Aspelund, Thor

AU - Eiriksdottir, Gudny

AU - Mitchell, Braxton D.

AU - Boerwinkle, Eric

AU - Schmidt, Helena

AU - Cavalieri, Margherita

AU - Rao, Madhumathi

AU - Hu, Frank

AU - Demirkan, Ayse

AU - Oostra, Ben A.

AU - de Andrade, Mariza

AU - Turner, Stephen T.

AU - Ding, Jingzhong

AU - Andrews, Jeanette S.

AU - Freedman, Barry I.

AU - Giulianini, Franco

AU - Koenig, Wolfgang

AU - Illig, Thomas

AU - Meisinger, Christa

AU - Gieger, Christian

AU - Zgaga, Lina

AU - Zemunik, Tatijana

AU - Boban, Mladen

AU - Minelli, Cosetta

AU - Wheeler, Heather E.

AU - Igl, Wilmar

AU - Zaboli, Ghazal

AU - Wild, Sarah H.

AU - Wright, Alan F.

AU - Campbell, Harry

AU - Ellinghaus, David

AU - Nöthlings, Ute

AU - Jacobs, Gunnar

AU - Biffar, Reiner

AU - Ernst, Florian

AU - Homuth, Georg

AU - Kroemer, Heyo K.

AU - Nauck, Matthias

AU - Stracke, Sylvia

AU - Völker, Uwe

AU - Völzke, Henry

AU - Kovacs, Peter

AU - Stumvoll, Michael

AU - Mägi, Reedik

AU - Hofman, Albert

AU - Uitterlinden, Andre G.

AU - Rivadeneira, Fernando

AU - Aulchenko, Yurii S.

AU - Polasek, Ozren

AU - Hastie, Nick

AU - Vitart, Veronique

AU - Helmer, Catherine

AU - Wang, Jie Jin

AU - Stengel, Bénédicte

AU - Ruggiero, Daniela

AU - Bergmann, Sven

AU - Kähönen, Mika

AU - Viikari, Jorma

AU - Nikopensius, Tiit

AU - Province, Michael

AU - Ketkar, Shamika

AU - Colhoun, Helen

AU - Doney, Alex

AU - Robino, Antonietta

AU - Krämer, Bernhard K.

AU - Portas, Laura

AU - Ford, Ian

AU - Buckley, Brendan M.

AU - Adam, Martin

AU - Thun, Gian Andri

AU - Paulweber, Bernhard

AU - Haun, Margot

AU - Sala, Cinzia

AU - Mitchell, Paul

AU - Ciullo, Marina

AU - Kim, Stuart K.

AU - Vollenweider, Peter

AU - Raitakari, Olli

AU - Metspalu, Andres

AU - Palmer, Colin

AU - Gasparini, Paolo

AU - Pirastu, Mario

AU - Jukema, J. Wouter

AU - Probst-Hensch, Nicole M.

AU - Kronenberg, Florian

AU - Toniolo, Daniela

AU - Gudnason, Vilmundur

AU - Shuldiner, Alan R.

AU - Coresh, Josef

AU - Schmidt, Reinhold

AU - Ferrucci, Luigi

AU - Siscovick, David S.

AU - van Duijn, Cornelia M.

AU - Borecki, Ingrid B.

AU - Kardia, Sharon L.R.

AU - Liu, Yongmei

AU - Curhan, Gary C.

AU - Rudan, Igor

AU - Gyllensten, Ulf

AU - Wilson, James F.

AU - Franke, Andre

AU - Pramstaller, Peter P.

AU - Rettig, Rainer

AU - Prokopenko, Inga

AU - Witteman, Jacqueline

AU - Hayward, Caroline

AU - Ridker, Paul M.

AU - Parsa, Afshin

AU - Bochud, Murielle

AU - Heid, Iris M.

AU - Kao, W. H.Linda

AU - Fox, Caroline S.

AU - Köttgen, Anna

PY - 2012/12

Y1 - 2012/12

N2 - In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5 5.6 3 10 -9 ) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 3 10 -4 -2.2× 10 -7 . Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

AB - In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5 5.6 3 10 -9 ) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 3 10 -4 -2.2× 10 -7 . Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

UR - http://www.scopus.com/inward/record.url?scp=84870691564&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870691564&partnerID=8YFLogxK

U2 - 10.1093/hmg/dds369

DO - 10.1093/hmg/dds369

M3 - Article

C2 - 22962313

AN - SCOPUS:84870691564

VL - 21

SP - 5329

EP - 5343

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 24

ER -

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

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