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Genome-wide association study and meta-analysis of intraocular pressure

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Abstract

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma and is influenced by genetic and environmental factors. Recent genome-wide association studies (GWAS) reported associations with IOP at TMCO1 and GAS7, and with primary open-angle glaucoma (POAG) at CDKN2B-AS1, CAV1/CAV2, and SIX1/SIX6. To identify novel genetic variants and replicate the published findings, we performed GWAS and meta-analysis of IOP in >6,000 subjects of European ancestry collected in three datasets: the NEI Glaucoma Human genetics collaBORation, GLAUcoma Genes and ENvironment study, and a subset of the Age-related Macular Degeneration-Michigan, Mayo, AREDS and Pennsylvania study. While no signal achieved genome-wide significance in individual datasets, a meta-analysis identified significant associations with IOP at TMCO1 (rs7518099-G, p = 8.0 × 10−8). Focused analyses of five loci previously reported for IOP and/or POAG, i.e., TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2, and SIX1/SIX6, revealed associations with IOP that were largely consistent across our three datasets, and replicated the previously reported associations in both effect size and direction. These results confirm the involvement of common variants in multiple genomic regions in regulating IOP and/or glaucoma risk.

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Acknowledgments

We acknowledge EY022124 (S.E.M.); 2RO1HL039693 and R01HL112642 (J.Z.L., A.B.O); EY011671, EY09580 (J.E.R.); EY007003 (Michigan Core Center for Vision Research); HG005259-01, 3R01EY015872-05S1, EY015872, EY010886, EY009847 (J.W.); HG004728, EY015473 (L.P.); EY016862, EY007758 (J.R.H.); HG002651 (G.A.); EY009149 (P.R.L.); EY006827 (D.G.); EY016862, EY016862, HL084729, HG002651 (G.R.A.); CA87969, CA49449, CA55075, EY09611 (J.H.K.); T32EY021453 (B.Y.); 3R01EY019126-02S1, EY13315 (M.A.H.); EY015543 (R.R.A.); U01-HG004424 (Broad Institute); HHSN268200782096C; RC1HG005334, U54HG004570 (ENCODE); HG004608 (C.M.M.); HG006389 (C.M.M., M.H.B); EY008208 (F.A.M.); EY015682 (A.R.); EY144428, EY144448, EY18660 (K.Z.); HL073389 (E.H.); U01 HG004446 (C.L.); HG004608 (C.M.); EY008208 (F.A.M.); EY012118, EY012118 (M.A.P–V.); EY015682 (A.R.); EY013178 (J.S.S.); RR015574; EY011008 (L.M.Z.);

Other supports included funding from University of Michigan Glaucoma Research Center (S.E.M., J.E.R., J.Z.L.); Ellison Medical Foundation (J.Z.L.); Harvard Glaucoma Center for Excellence, and the Margolis Fund (J.W. and L.P.); Research to Prevent Blindness (A.S., D.C.M., J.W., L.P., J.R.H., and J.E.R.); the Glaucoma Research Foundation (S.E.M., Y.L.); the Glaucoma Foundation (Y.L.); American Health Assistance Foundation (Y.L., J.E.R., J.R.H., A.S.); Elmer and Silvia Sramek Foundation (J.R.H., A.S.); Foundation Fighting Blindness (J.R.H., A.S.); the Macula Vision Research Foundation (J.R.H., A.S.); the Pew Charitable Trusts (J.R.H., A.S.); the Casey Macular Degeneration Center Fund (J.R.H., A.S.); the Marion W. and Edward F. Knight AMD Fund (J.R.H., A.S.); the Harold and Pauline Price Foundation, National Genotyping Centre of Spain (J.R.H., A.S.).

A list of the GLAUGEN collaborators is found at The Primary Open-Angle Glaucoma Genes and Environment (GLAUGEN) Study listing on dbGAP, study Accession: phs000308.v1.p1. www.ncbi.nlm.nih.gov/projects/gap, December 21, 2010. A list of the NEIGHBOR investigators is found at the NEIGHBORHOOD Consortium http://glaucomagenetics.org/members (accessed March 18, 2013).

Author information

Authors and Affiliations

  1. Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA

    A. Bilge Ozel & Jun Z. Li

  2. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA

    Sayoko E. Moroi, David M. Reed, Melisa Nika, Caroline M. Schmidt, Sara Akbari, Kathleen Scott, Frank Rozsa, Hemant Pawar, David C. Musch, Paul R. Lichter, Kari Branham, Jesse Gilbert, Sarah J. Garnai, Mohammad Othman, John Heckenlively & Julia E. Richards

  3. Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA

    David C. Musch & Julia E. Richards

  4. Eye Doctors of Washington DC, Washington, DC, USA

    Doug Gaasterland

  5. Division of Pulmonary Medicine, Allergy and Immunology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical School, Pittsburgh, PA, USA

    Wei Chen

  6. Departments of Biostatistics and Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    Wei Chen

  7. National Eye Institute, National Institutes of Health, Bethesda, MD, USA

    Anand Swaroop

  8. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

    Gonçalo Abecasis

  9. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    David S. Friedman & Don Zack

  10. Center for Human Genetics, Duke University School of Medicine, Durham, NC, USA

    Allison Ashley-Koch, Megan Ulmer, Yutao Liu, R. Rand Allingham & Michael A. Hauser

  11. Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Jae H. Kang & Louis Pasquale

  12. Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN, USA

    Brian L. Yaspan & Jonathan Haines

  13. Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA

    Louis Pasquale & Janey Wiggs

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  1. A. Bilge Ozel
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  2. Sayoko E. Moroi
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  3. David M. Reed
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  4. Melisa Nika
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  5. Caroline M. Schmidt
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  7. Kathleen Scott
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  8. Frank Rozsa
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  9. Hemant Pawar
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  10. David C. Musch
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  11. Paul R. Lichter
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  13. Kari Branham
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  14. Jesse Gilbert
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  15. Sarah J. Garnai
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  16. Wei Chen
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  17. Mohammad Othman
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  18. John Heckenlively
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  19. Anand Swaroop
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  20. Gonçalo Abecasis
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  21. David S. Friedman
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  22. Don Zack
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  23. Allison Ashley-Koch
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  24. Megan Ulmer
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  25. Jae H. Kang
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  26. Yutao Liu
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  27. Brian L. Yaspan
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  28. Jonathan Haines
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  29. R. Rand Allingham
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  30. Michael A. Hauser
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  31. Louis Pasquale
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  32. Janey Wiggs
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  33. Julia E. Richards
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  34. Jun Z. Li
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Consortia

NEIGHBOR Consortium

Corresponding authors

Correspondence to Sayoko E. Moroi or Jun Z. Li.

Additional information

NEIGHBOR Consortium: http://glaucomagenetics.org/.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1179 kb)

Supplementary Fig. 1 Left panels: IOP distributions for controls (red), untreated IOP (blue), and extrapolated IOP (green) in (a) NEIGHBOR (n = 4,088), (b) GLAUGEN (n = 1,153), (c) AMD-MMAP MI (n = 995). Right panels: IOP histogram for the entire study, combining the three groups in the left panels, its density plot (red), and the theoretical normal distribution (black).

Supplementary Fig. 2 GWAS results for the three datasets (a) -log10 (p value) plot of ~ 507 K SNPs in NEIGHBOR. The horizontal line marks the 9.9 × 10−8 threshold of genome-wide significance. (b) Quantile–Quantile plot of observed vs. expected -log10 (p value) for IOP in NEIGHBOR. (c) -log10 (p value) plot of ~484 K SNPs in GLAUGEN. The horizontal line marks the 1.1 × 10−7 threshold of genome-wide significance (d) −log10 (p value) plot of ~2.4 million SNPs in AMD-MMAP MI. The horizontal line marks the 2.08 × 10−8 threshold of genome-wide significance

Supplementary Fig. 3 NEIGHBOR seven-site meta-analysis (~507 k SNPs) (a) −log10 (p value) plot. The horizontal line marks the 1.1 × 10−7 threshold of genome-wide significance (b) Quantile–Quantile plot of the seven-site meta-analysis versus the original NEIGHBOR GWAS

Supplementary Fig. 4 Comparison of effect size and direction of the top SNPs in TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2 and SIX1/SIX6 in the overall meta-analysis across Sites 1–6 and 8 in NEIGHBOR. Shown are forest plots for the seven sites, seven-site meta-analysis, and original NEIGHBOR GWAS for (a) TMCO1 SNP, rs7518099(G) (b) CDKN2B-AS1 SNP, rs1412829(G) (c) GAS7 SNP, rs121502849(A) (d) CAV1/CAV2 SNP, rs4236601(A) (e) SIX1/SIX6 SNP, rs10483727(A)

Supplementary Fig. 5 Gender-specific analyses in NEIGHBOR (a) −log10 (p value) plot using only males (n = 1,905). The horizontal line marks the 9.9 × 10−8 threshold (b) −log10 (p value) plot using only females (N = 2,183)

Supplementary Fig. 6 Comparison of effect size and direction of the top SNPs in TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2 and SIX1/SIX6 by gender. Shown are forest plots for male-only, female-only, and overall for (a) TMCO1 SNP, rs7518099(G), (b) CDKN2B-AS1 SNP, rs1412829(G), (c) GAS7 SNP, rs12150284(A), (d) CAV1/CAV2 SNP, rs4236601(A), (e) SIX1/SIX6 SNP, rs10483727(A)

Supplementary Fig. 7 Age-specific analyses in NEIGHBOR. (a) The distributions of IOP are similar across the four age groups. (b) −log10 (p value) plot in the youngest group (n = 1,022). The horizontal line marks the 9.9 × 10−8 threshold of genome-wide significance. (c) Comparison of effect size and direction of the top SNP at 18q22 (rs1876486) across four age groups

Supplementary Fig. 8 Comparison of effect size and direction of the top SNPs in TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2 and SIX1/SIX6 across four age groups, and the original overall results. (a) TMCO1 SNP, rs7518099(G). (b) CDKN2B-AS1 SNP, rs1412829(G). (c) GAS7 SNP, rs12150284(A). (d) CAV1/CAV2 SNP, rs4236601(A). (e) SIX1/SIX6 SNP, rs10483727(A)

Supplementary Fig. 9 Effect of adjusting for central corneal thickness (CCT) in NEIGHBOR. Analysis of ~507 k SNPs with 4,088 individuals, with IOP adjusted by CCT (for cases with CCT available). (a) −log10 (p value) plot. The horizontal line marks the 9.9 × 10−8 threshold of genome-wide significance. (b) Log-scatter plot comparison of the observed −log10 (p value) with and without adjusting by CCT

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Ozel, A.B., Moroi, S.E., Reed, D.M. et al. Genome-wide association study and meta-analysis of intraocular pressure. Hum Genet 133, 41–57 (2014). https://doi.org/10.1007/s00439-013-1349-5

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  • DOI: https://doi.org/10.1007/s00439-013-1349-5

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