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. Boeger, 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, Asa Johansson, Anke Toenjes, Abbas Dehghan, Jean-Charles Lambert, Elizabeth G. Holliday, Rossella Sorice, Zoltan Kutalik, Terho Lehtimaeki, Tonu Esko, Harshal Deshmukh, Sheila Ulivi, Audrey Y. Chu, Federico Murgia, Stella Trompet, Medea Imboden, Helen Colhoun, Alexander Doney, Colin Palmer, CARDIoGRAM Consortium, ICBP Consortium, CARe Consortium, WTCCC2

    Research output: Contribution to journalArticle

    39 Citations (Scopus)

    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 5.6 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 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 languageEnglish
    Pages (from-to)5329-5343
    Number of pages15
    JournalHuman Molecular Genetics
    Volume21
    Issue number24
    DOIs
    Publication statusPublished - 15 Dec 2012

    Keywords

    • TRAITS
    • SERUM CREATININE
    • R PACKAGE
    • RENAL-FUNCTION
    • SNPS
    • EXPRESSION
    • DISEASE
    • GLOMERULAR-FILTRATION-RATE
    • COMMUNITY-BASED POPULATION
    • LOCI

    Cite this

    Chasman, D. I., Fuchsberger, C., Pattaro, C., Teumer, A., Boeger, C. A., Endlich, K., ... WTCCC2 (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, Daniel I. ; Fuchsberger, Christian ; Pattaro, Cristian ; Teumer, Alexander ; Boeger, Carsten A. ; Endlich, Karlhans ; Olden, Matthias ; Chen, Ming-Huei ; Tin, Adrienne ; Taliun, Daniel ; Li, Man ; Gao, Xiaoyi ; Gorski, Mathias ; Yang, Qiong ; Hundertmark, Claudia ; Foster, Meredith C. ; O'Seaghdha, Conall M. ; Glazer, Nicole ; Isaacs, Aaron ; Liu, Ching-Ti ; Smith, Albert V. ; O'Connell, Jeffrey R. ; Struchalin, Maksim ; Tanaka, Toshiko ; Li, Guo ; Johnson, Andrew D. ; Gierman, Hinco J. ; Feitosa, Mary F. ; Hwang, Shih-Jen ; Atkinson, Elizabeth J. ; Lohman, Kurt ; Cornelis, Marilyn C. ; Johansson, Asa ; Toenjes, Anke ; Dehghan, Abbas ; Lambert, Jean-Charles ; Holliday, Elizabeth G. ; Sorice, Rossella ; Kutalik, Zoltan ; Lehtimaeki, Terho ; Esko, Tonu ; Deshmukh, Harshal ; Ulivi, Sheila ; Chu, Audrey Y. ; Murgia, Federico ; Trompet, Stella ; Imboden, Medea ; Colhoun, Helen ; Doney, Alexander ; Palmer, Colin ; CARDIoGRAM Consortium ; ICBP Consortium ; CARe Consortium ; WTCCC2. / Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 24. pp. 5329-5343.
    @article{bf9b045b2b7c45eb8bdb2b7a06176d81,
    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 5.6 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 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.",
    keywords = "TRAITS, SERUM CREATININE, R PACKAGE, RENAL-FUNCTION, SNPS, EXPRESSION, DISEASE, GLOMERULAR-FILTRATION-RATE, COMMUNITY-BASED POPULATION, LOCI",
    author = "Chasman, {Daniel I.} and Christian Fuchsberger and Cristian Pattaro and Alexander Teumer and Boeger, {Carsten A.} and Karlhans Endlich and Matthias Olden and Ming-Huei Chen 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 Ching-Ti Liu 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 Shih-Jen Hwang and Atkinson, {Elizabeth J.} and Kurt Lohman and Cornelis, {Marilyn C.} and Asa Johansson and Anke Toenjes and Abbas Dehghan and Jean-Charles Lambert and Holliday, {Elizabeth G.} and Rossella Sorice and Zoltan Kutalik and Terho Lehtimaeki and Tonu Esko and Harshal Deshmukh and Sheila Ulivi and Chu, {Audrey Y.} and Federico Murgia and Stella Trompet and Medea Imboden and Helen Colhoun and Alexander Doney and Colin Palmer and {CARDIoGRAM Consortium} and {ICBP Consortium} and {CARe Consortium} and WTCCC2",
    year = "2012",
    month = "12",
    day = "15",
    doi = "10.1093/hmg/dds369",
    language = "English",
    volume = "21",
    pages = "5329--5343",
    journal = "Human Molecular Genetics",
    issn = "0964-6906",
    publisher = "Oxford University Press",
    number = "24",

    }

    Chasman, DI, Fuchsberger, C, Pattaro, C, Teumer, A, Boeger, CA, Endlich, K, Olden, M, Chen, M-H, Tin, A, Taliun, D, Li, M, Gao, X, Gorski, M, Yang, Q, Hundertmark, C, Foster, MC, O'Seaghdha, CM, Glazer, N, Isaacs, A, Liu, C-T, Smith, AV, O'Connell, JR, Struchalin, M, Tanaka, T, Li, G, Johnson, AD, Gierman, HJ, Feitosa, MF, Hwang, S-J, Atkinson, EJ, Lohman, K, Cornelis, MC, Johansson, A, Toenjes, A, Dehghan, A, Lambert, J-C, Holliday, EG, Sorice, R, Kutalik, Z, Lehtimaeki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, AY, Murgia, F, Trompet, S, Imboden, M, Colhoun, H, Doney, A, Palmer, C, CARDIoGRAM Consortium, ICBP Consortium, CARe Consortium & WTCCC2 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

    Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. / Chasman, Daniel I.; Fuchsberger, Christian; Pattaro, Cristian; Teumer, Alexander; Boeger, Carsten A.; Endlich, Karlhans; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C.; O'Seaghdha, Conall M.; Glazer, Nicole; Isaacs, Aaron; Liu, Ching-Ti; Smith, Albert V.; O'Connell, Jeffrey R.; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Johnson, Andrew D.; Gierman, Hinco J.; Feitosa, Mary F.; Hwang, Shih-Jen; Atkinson, Elizabeth J.; Lohman, Kurt; Cornelis, Marilyn C.; Johansson, Asa; Toenjes, Anke; Dehghan, Abbas; Lambert, Jean-Charles; Holliday, Elizabeth G.; Sorice, Rossella; Kutalik, Zoltan; Lehtimaeki, Terho; Esko, Tonu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y.; Murgia, Federico; Trompet, Stella; Imboden, Medea; Colhoun, Helen; Doney, Alexander; Palmer, Colin; CARDIoGRAM Consortium; ICBP Consortium; CARe Consortium; WTCCC2.

    In: Human Molecular Genetics, Vol. 21, No. 24, 15.12.2012, p. 5329-5343.

    Research output: Contribution to journalArticle

    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 - Boeger, 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, Asa

    AU - Toenjes, Anke

    AU - Dehghan, Abbas

    AU - Lambert, Jean-Charles

    AU - Holliday, Elizabeth G.

    AU - Sorice, Rossella

    AU - Kutalik, Zoltan

    AU - Lehtimaeki, Terho

    AU - Esko, Tonu

    AU - Deshmukh, Harshal

    AU - Ulivi, Sheila

    AU - Chu, Audrey Y.

    AU - Murgia, Federico

    AU - Trompet, Stella

    AU - Imboden, Medea

    AU - Colhoun, Helen

    AU - Doney, Alexander

    AU - Palmer, Colin

    AU - CARDIoGRAM Consortium

    AU - ICBP Consortium

    AU - CARe Consortium

    AU - WTCCC2

    PY - 2012/12/15

    Y1 - 2012/12/15

    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 5.6 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 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 5.6 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 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.

    KW - TRAITS

    KW - SERUM CREATININE

    KW - R PACKAGE

    KW - RENAL-FUNCTION

    KW - SNPS

    KW - EXPRESSION

    KW - DISEASE

    KW - GLOMERULAR-FILTRATION-RATE

    KW - COMMUNITY-BASED POPULATION

    KW - LOCI

    U2 - 10.1093/hmg/dds369

    DO - 10.1093/hmg/dds369

    M3 - Article

    C2 - 22962313

    VL - 21

    SP - 5329

    EP - 5343

    JO - Human Molecular Genetics

    JF - Human Molecular Genetics

    SN - 0964-6906

    IS - 24

    ER -