Targeting 160 Candidate Genes for Blood Pressure Regulation with a Genome-Wide Genotyping Array

Siim Sober, Elin Org, Katrin Kepp, Peeter Juhanson, Susana Eyheramendy, Christian Gieger, Peter Lichtner, Norman Klopp, Gudrun Veldre, Margus Viigimaa, Angela Doering, Margus Putku, Piret Kelgo, Sue Shaw-Hawkins, Philip Howard, Abiodun Onipinla, Richard J. Dobson, Stephen J. Newhouse, Morris Brown, Anna Dominiczak & 10 others John Connell, Nilesh Samani, Martin Farrall, Mark J. Caulfield, Patricia B. Munroe, Thomas Illig, H. Erich Wichmann, Thomas Meitinger, Maris Laan, HYPertens ESTonia Study, MRC British Genet Hypertens Study, Kooperative Gesundheitsforsch

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    Abstract

    The outcome of Genome-Wide Association Studies (GWAS) has challenged the field of blood pressure (BP) genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany) to address (i) SNP coverage in 160 BP candidate genes; (ii) the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region +/- 10 kb) covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11) to 0.6 SNPs/kb. On average 52.5% of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P < 10(-3)) were detected for the genes, where > 50% of HAPMAP SNPs were tagged. In general, genes with higher marker density (> 0.2 SNPs/ kb) revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P < 0.05/2319, P < 2.15 x 10(-5)), the strength of some detected associations was close to this level: rs10889553 (LEPR) and systolic BP (SBP) (P = 4.5 x 10(-5)) as well as rs10954174 (LEP) and diastolic BP (DBP) (P = 5.20 x 10(-5)). In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1) revealed considerable association (P < 10(-3)) either with SBP, DBP, and/or hypertension (HYP). None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT). However, supportive evidence for the association of rs10889553 (LEPR) and rs11195419 (ADRA2A) with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.

    Original languageEnglish
    Article numbere6034
    Pages (from-to)-
    Number of pages13
    JournalPLoS ONE
    Volume4
    Issue number6
    DOIs
    Publication statusPublished - 29 Jun 2009

    Cite this

    Sober, S., Org, E., Kepp, K., Juhanson, P., Eyheramendy, S., Gieger, C., ... HYPertens ESTonia Study, MRC British Genet Hypertens Study, Kooperative Gesundheitsforsch (2009). Targeting 160 Candidate Genes for Blood Pressure Regulation with a Genome-Wide Genotyping Array. PLoS ONE, 4(6), -. [e6034]. https://doi.org/10.1371/journal.pone.0006034
    Sober, Siim ; Org, Elin ; Kepp, Katrin ; Juhanson, Peeter ; Eyheramendy, Susana ; Gieger, Christian ; Lichtner, Peter ; Klopp, Norman ; Veldre, Gudrun ; Viigimaa, Margus ; Doering, Angela ; Putku, Margus ; Kelgo, Piret ; Shaw-Hawkins, Sue ; Howard, Philip ; Onipinla, Abiodun ; Dobson, Richard J. ; Newhouse, Stephen J. ; Brown, Morris ; Dominiczak, Anna ; Connell, John ; Samani, Nilesh ; Farrall, Martin ; Caulfield, Mark J. ; Munroe, Patricia B. ; Illig, Thomas ; Wichmann, H. Erich ; Meitinger, Thomas ; Laan, Maris ; HYPertens ESTonia Study, MRC British Genet Hypertens Study, Kooperative Gesundheitsforsch. / Targeting 160 Candidate Genes for Blood Pressure Regulation with a Genome-Wide Genotyping Array. In: PLoS ONE. 2009 ; Vol. 4, No. 6. pp. -.
    @article{190838c7e6b342588c4a78700962a3ac,
    title = "Targeting 160 Candidate Genes for Blood Pressure Regulation with a Genome-Wide Genotyping Array",
    abstract = "The outcome of Genome-Wide Association Studies (GWAS) has challenged the field of blood pressure (BP) genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany) to address (i) SNP coverage in 160 BP candidate genes; (ii) the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region +/- 10 kb) covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11) to 0.6 SNPs/kb. On average 52.5{\%} of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P < 10(-3)) were detected for the genes, where > 50{\%} of HAPMAP SNPs were tagged. In general, genes with higher marker density (> 0.2 SNPs/ kb) revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P < 0.05/2319, P < 2.15 x 10(-5)), the strength of some detected associations was close to this level: rs10889553 (LEPR) and systolic BP (SBP) (P = 4.5 x 10(-5)) as well as rs10954174 (LEP) and diastolic BP (DBP) (P = 5.20 x 10(-5)). In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1) revealed considerable association (P < 10(-3)) either with SBP, DBP, and/or hypertension (HYP). None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT). However, supportive evidence for the association of rs10889553 (LEPR) and rs11195419 (ADRA2A) with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.",
    author = "Siim Sober and Elin Org and Katrin Kepp and Peeter Juhanson and Susana Eyheramendy and Christian Gieger and Peter Lichtner and Norman Klopp and Gudrun Veldre and Margus Viigimaa and Angela Doering and Margus Putku and Piret Kelgo and Sue Shaw-Hawkins and Philip Howard and Abiodun Onipinla and Dobson, {Richard J.} and Newhouse, {Stephen J.} and Morris Brown and Anna Dominiczak and John Connell and Nilesh Samani and Martin Farrall and Caulfield, {Mark J.} and Munroe, {Patricia B.} and Thomas Illig and Wichmann, {H. Erich} and Thomas Meitinger and Maris Laan and {HYPertens ESTonia Study, MRC British Genet Hypertens Study, Kooperative Gesundheitsforsch}",
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    Sober, S, Org, E, Kepp, K, Juhanson, P, Eyheramendy, S, Gieger, C, Lichtner, P, Klopp, N, Veldre, G, Viigimaa, M, Doering, A, Putku, M, Kelgo, P, Shaw-Hawkins, S, Howard, P, Onipinla, A, Dobson, RJ, Newhouse, SJ, Brown, M, Dominiczak, A, Connell, J, Samani, N, Farrall, M, Caulfield, MJ, Munroe, PB, Illig, T, Wichmann, HE, Meitinger, T, Laan, M & HYPertens ESTonia Study, MRC British Genet Hypertens Study, Kooperative Gesundheitsforsch 2009, 'Targeting 160 Candidate Genes for Blood Pressure Regulation with a Genome-Wide Genotyping Array', PLoS ONE, vol. 4, no. 6, e6034, pp. -. https://doi.org/10.1371/journal.pone.0006034

    Targeting 160 Candidate Genes for Blood Pressure Regulation with a Genome-Wide Genotyping Array. / Sober, Siim; Org, Elin; Kepp, Katrin; Juhanson, Peeter; Eyheramendy, Susana; Gieger, Christian; Lichtner, Peter; Klopp, Norman; Veldre, Gudrun; Viigimaa, Margus; Doering, Angela; Putku, Margus; Kelgo, Piret; Shaw-Hawkins, Sue; Howard, Philip; Onipinla, Abiodun; Dobson, Richard J.; Newhouse, Stephen J.; Brown, Morris; Dominiczak, Anna; Connell, John; Samani, Nilesh; Farrall, Martin; Caulfield, Mark J.; Munroe, Patricia B.; Illig, Thomas; Wichmann, H. Erich; Meitinger, Thomas; Laan, Maris; HYPertens ESTonia Study, MRC British Genet Hypertens Study, Kooperative Gesundheitsforsch.

    In: PLoS ONE, Vol. 4, No. 6, e6034, 29.06.2009, p. -.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Targeting 160 Candidate Genes for Blood Pressure Regulation with a Genome-Wide Genotyping Array

    AU - Sober, Siim

    AU - Org, Elin

    AU - Kepp, Katrin

    AU - Juhanson, Peeter

    AU - Eyheramendy, Susana

    AU - Gieger, Christian

    AU - Lichtner, Peter

    AU - Klopp, Norman

    AU - Veldre, Gudrun

    AU - Viigimaa, Margus

    AU - Doering, Angela

    AU - Putku, Margus

    AU - Kelgo, Piret

    AU - Shaw-Hawkins, Sue

    AU - Howard, Philip

    AU - Onipinla, Abiodun

    AU - Dobson, Richard J.

    AU - Newhouse, Stephen J.

    AU - Brown, Morris

    AU - Dominiczak, Anna

    AU - Connell, John

    AU - Samani, Nilesh

    AU - Farrall, Martin

    AU - Caulfield, Mark J.

    AU - Munroe, Patricia B.

    AU - Illig, Thomas

    AU - Wichmann, H. Erich

    AU - Meitinger, Thomas

    AU - Laan, Maris

    AU - HYPertens ESTonia Study, MRC British Genet Hypertens Study, Kooperative Gesundheitsforsch

    PY - 2009/6/29

    Y1 - 2009/6/29

    N2 - The outcome of Genome-Wide Association Studies (GWAS) has challenged the field of blood pressure (BP) genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany) to address (i) SNP coverage in 160 BP candidate genes; (ii) the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region +/- 10 kb) covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11) to 0.6 SNPs/kb. On average 52.5% of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P < 10(-3)) were detected for the genes, where > 50% of HAPMAP SNPs were tagged. In general, genes with higher marker density (> 0.2 SNPs/ kb) revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P < 0.05/2319, P < 2.15 x 10(-5)), the strength of some detected associations was close to this level: rs10889553 (LEPR) and systolic BP (SBP) (P = 4.5 x 10(-5)) as well as rs10954174 (LEP) and diastolic BP (DBP) (P = 5.20 x 10(-5)). In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1) revealed considerable association (P < 10(-3)) either with SBP, DBP, and/or hypertension (HYP). None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT). However, supportive evidence for the association of rs10889553 (LEPR) and rs11195419 (ADRA2A) with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.

    AB - The outcome of Genome-Wide Association Studies (GWAS) has challenged the field of blood pressure (BP) genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany) to address (i) SNP coverage in 160 BP candidate genes; (ii) the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region +/- 10 kb) covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11) to 0.6 SNPs/kb. On average 52.5% of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P < 10(-3)) were detected for the genes, where > 50% of HAPMAP SNPs were tagged. In general, genes with higher marker density (> 0.2 SNPs/ kb) revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P < 0.05/2319, P < 2.15 x 10(-5)), the strength of some detected associations was close to this level: rs10889553 (LEPR) and systolic BP (SBP) (P = 4.5 x 10(-5)) as well as rs10954174 (LEP) and diastolic BP (DBP) (P = 5.20 x 10(-5)). In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1) revealed considerable association (P < 10(-3)) either with SBP, DBP, and/or hypertension (HYP). None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT). However, supportive evidence for the association of rs10889553 (LEPR) and rs11195419 (ADRA2A) with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.

    U2 - 10.1371/journal.pone.0006034

    DO - 10.1371/journal.pone.0006034

    M3 - Article

    VL - 4

    SP - -

    JO - PLoS ONE

    JF - PLoS ONE

    SN - 1932-6203

    IS - 6

    M1 - e6034

    ER -

    Sober S, Org E, Kepp K, Juhanson P, Eyheramendy S, Gieger C et al. Targeting 160 Candidate Genes for Blood Pressure Regulation with a Genome-Wide Genotyping Array. PLoS ONE. 2009 Jun 29;4(6):-. e6034. https://doi.org/10.1371/journal.pone.0006034