Genomewide association study of acute anterior uveitis identifies new susceptibility loci

Xiu Feng Huang; Zhixiu Li; Erika de Guzman; Philip Robinson; Lianne Gensler; Michael M. Ward; Mohammad Hossein Rahbar; Min Jae Lee; Michael H. Weisman; Gary J. Macfarlane; Gareth T. Jones; Eva Klingberg; Helena Forsblad-D’Elia; Peter McCluskey; Denis Wakefield; Jeff S. Coombes; Maria A. Fiatarone Singh; Yorgi Mavros; Nicole Vlahovich; David C. Hughes; Helena Marzo-Ortega; Irene van der Horste-Bruinsma; Finbar O’Shea; Tammy M. Martin; James Rosenbaum; Maxime Breban; Zi Bing Jin; Paul Leo; John D. Reveille; B. Paul Wordsworth; Matthew A. Brown

doi:10.1167/IOVS.61.6.3

Genomewide association study of acute anterior uveitis identifies new susceptibility loci

Xiu Feng Huang, Zhixiu Li, Erika de Guzman, Philip Robinson, Lianne Gensler, Michael M. Ward, Mohammad Hossein Rahbar, Min Jae Lee, Michael H. Weisman, Gary J. Macfarlane, Gareth T. Jones, Eva Klingberg, Helena Forsblad-D’Elia, Peter McCluskey, Denis Wakefield, Jeff S. Coombes, Maria A. Fiatarone Singh, Yorgi Mavros, Nicole Vlahovich, David C. HughesHelena Marzo-Ortega, Irene van der Horste-Bruinsma, Finbar O’Shea, Tammy M. Martin, James Rosenbaum, Maxime Breban, Zi Bing Jin, Paul Leo, John D. Reveille, B. Paul Wordsworth, Matthew A. Brown

Ophthalmology

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

35 Scopus citations

Abstract

PURPOSE. Acute anterior uveitis (AAU) is a common intraocular inflammatory disease. AAU occurs in 30% to 50% of patients with ankylosing spondylitis (AS), and both conditions are strongly associated with human leukocyte antigen (HLA)-B27, implying a shared etiology. This study aims to apply genomewide association study (GWAS) to characterize the genetic associations of AAU and their relationship to the genetics of AS. METHODS. We undertook the GWAS analyses in 2752 patients with AS with AAU (cases) and 3836 patients with AS without AAU (controls). There were 7,436,415 single-nucleotide polymorphisms (SNPs) available after SNP microarray genotyping, imputation, and quality-control filtering. RESULTS. We identified one locus associated with AAU at genomewide significance: rs9378248 (P = 2.69 × 10⁻⁸, odds ratio [OR] = 0.78), lying close to HLA-B. Suggestive association was observed at 11 additional loci, including previously reported AS loci ERAP1 (rs27529, P = 2.19 × 10⁻⁷, OR = 1.22) and NOS2 (rs2274894, P = 8.22 × 10⁻⁷, OR = 0.83). Multiple novel suggestive associations were also identified, including MERTK (rs10171979, P = 2.56 × 10⁻⁶, OR = 1.20), KIFAP3 (rs508063, P = 5.64 × 10⁻⁷, OR = 1.20), CLCN7 (rs67412457, P = 1.33 × 10⁻⁶, OR = 1.25), ACAA2 (rs9947182, P = 9.70 × 10⁻⁷, OR = 1.37), and 5 intergenic loci. The SNP-based heritability is approximately 0.5 for AS alone, and is much higher (approximately 0.7) for AS with AAU. Consistent with the high heritability, a genomewide polygenic risk score shows strong power in identifying individuals at high risk of either AS with AAU or AS alone. CONCLUSIONS. We report here the first GWAS for AAU and identify new susceptibility loci. Our findings confirm the strong overlap in etiopathogenesis of AAU with AS, and also provide new insights into the genetic basis of AAU.

Original language	English (US)
Article number	3
Journal	Investigative Ophthalmology and Visual Science
Volume	61
Issue number	6
DOIs	https://doi.org/10.1167/IOVS.61.6.3
State	Published - Jun 2020

Keywords

Acute anterior uveitis
Ankylosing spondylitis
GWAS
Genetic risk scores
Heritability

ASJC Scopus subject areas

Ophthalmology
Sensory Systems
Cellular and Molecular Neuroscience

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10.1167/IOVS.61.6.3

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Huang, X. F., Li, Z., de Guzman, E., Robinson, P., Gensler, L., Ward, M. M., Rahbar, M. H., Lee, M. J., Weisman, M. H., Macfarlane, G. J., Jones, G. T., Klingberg, E., Forsblad-D’Elia, H., McCluskey, P., Wakefield, D., Coombes, J. S., Fiatarone Singh, M. A., Mavros, Y., Vlahovich, N., ... Brown, M. A. (2020). Genomewide association study of acute anterior uveitis identifies new susceptibility loci. Investigative Ophthalmology and Visual Science, 61(6), Article 3. https://doi.org/10.1167/IOVS.61.6.3

Huang, XF, Li, Z, de Guzman, E, Robinson, P, Gensler, L, Ward, MM, Rahbar, MH, Lee, MJ, Weisman, MH, Macfarlane, GJ, Jones, GT, Klingberg, E, Forsblad-D’Elia, H, McCluskey, P, Wakefield, D, Coombes, JS, Fiatarone Singh, MA, Mavros, Y, Vlahovich, N, Hughes, DC, Marzo-Ortega, H, van der Horste-Bruinsma, I, O’Shea, F, Martin, TM, Rosenbaum, J, Breban, M, Jin, ZB, Leo, P, Reveille, JD, Wordsworth, BP & Brown, MA 2020, 'Genomewide association study of acute anterior uveitis identifies new susceptibility loci', Investigative Ophthalmology and Visual Science, vol. 61, no. 6, 3. https://doi.org/10.1167/IOVS.61.6.3

@article{ea25ac73939a42e287d1c0f6731c2bd1,

title = "Genomewide association study of acute anterior uveitis identifies new susceptibility loci",

abstract = "PURPOSE. Acute anterior uveitis (AAU) is a common intraocular inflammatory disease. AAU occurs in 30% to 50% of patients with ankylosing spondylitis (AS), and both conditions are strongly associated with human leukocyte antigen (HLA)-B27, implying a shared etiology. This study aims to apply genomewide association study (GWAS) to characterize the genetic associations of AAU and their relationship to the genetics of AS. METHODS. We undertook the GWAS analyses in 2752 patients with AS with AAU (cases) and 3836 patients with AS without AAU (controls). There were 7,436,415 single-nucleotide polymorphisms (SNPs) available after SNP microarray genotyping, imputation, and quality-control filtering. RESULTS. We identified one locus associated with AAU at genomewide significance: rs9378248 (P = 2.69 × 10−8, odds ratio [OR] = 0.78), lying close to HLA-B. Suggestive association was observed at 11 additional loci, including previously reported AS loci ERAP1 (rs27529, P = 2.19 × 10−7, OR = 1.22) and NOS2 (rs2274894, P = 8.22 × 10−7, OR = 0.83). Multiple novel suggestive associations were also identified, including MERTK (rs10171979, P = 2.56 × 10−6, OR = 1.20), KIFAP3 (rs508063, P = 5.64 × 10−7, OR = 1.20), CLCN7 (rs67412457, P = 1.33 × 10−6, OR = 1.25), ACAA2 (rs9947182, P = 9.70 × 10−7, OR = 1.37), and 5 intergenic loci. The SNP-based heritability is approximately 0.5 for AS alone, and is much higher (approximately 0.7) for AS with AAU. Consistent with the high heritability, a genomewide polygenic risk score shows strong power in identifying individuals at high risk of either AS with AAU or AS alone. CONCLUSIONS. We report here the first GWAS for AAU and identify new susceptibility loci. Our findings confirm the strong overlap in etiopathogenesis of AAU with AS, and also provide new insights into the genetic basis of AAU.",

keywords = "Acute anterior uveitis, Ankylosing spondylitis, GWAS, Genetic risk scores, Heritability",

author = "Huang, {Xiu Feng} and Zhixiu Li and {de Guzman}, Erika and Philip Robinson and Lianne Gensler and Ward, {Michael M.} and Rahbar, {Mohammad Hossein} and Lee, {Min Jae} and Weisman, {Michael H.} and Macfarlane, {Gary J.} and Jones, {Gareth T.} and Eva Klingberg and Helena Forsblad-D{\textquoteright}Elia and Peter McCluskey and Denis Wakefield and Coombes, {Jeff S.} and {Fiatarone Singh}, {Maria A.} and Yorgi Mavros and Nicole Vlahovich and Hughes, {David C.} and Helena Marzo-Ortega and {van der Horste-Bruinsma}, Irene and Finbar O{\textquoteright}Shea and Martin, {Tammy M.} and James Rosenbaum and Maxime Breban and Jin, {Zi Bing} and Paul Leo and Reveille, {John D.} and Wordsworth, {B. Paul} and Brown, {Matthew A.}",

year = "2020",

month = jun,

doi = "10.1167/IOVS.61.6.3",

language = "English (US)",

volume = "61",

journal = "Investigative Ophthalmology and Visual Science",

issn = "0146-0404",

publisher = "Association for Research in Vision and Ophthalmology Inc.",

number = "6",

}

TY - JOUR

T1 - Genomewide association study of acute anterior uveitis identifies new susceptibility loci

AU - Huang, Xiu Feng

AU - Li, Zhixiu

AU - de Guzman, Erika

AU - Robinson, Philip

AU - Gensler, Lianne

AU - Ward, Michael M.

AU - Rahbar, Mohammad Hossein

AU - Lee, Min Jae

AU - Weisman, Michael H.

AU - Macfarlane, Gary J.

AU - Jones, Gareth T.

AU - Klingberg, Eva

AU - Forsblad-D’Elia, Helena

AU - McCluskey, Peter

AU - Wakefield, Denis

AU - Coombes, Jeff S.

AU - Fiatarone Singh, Maria A.

AU - Mavros, Yorgi

AU - Vlahovich, Nicole

AU - Hughes, David C.

AU - Marzo-Ortega, Helena

AU - van der Horste-Bruinsma, Irene

AU - O’Shea, Finbar

AU - Martin, Tammy M.

AU - Rosenbaum, James

AU - Breban, Maxime

AU - Jin, Zi Bing

AU - Leo, Paul

AU - Reveille, John D.

AU - Wordsworth, B. Paul

AU - Brown, Matthew A.

PY - 2020/6

Y1 - 2020/6

N2 - PURPOSE. Acute anterior uveitis (AAU) is a common intraocular inflammatory disease. AAU occurs in 30% to 50% of patients with ankylosing spondylitis (AS), and both conditions are strongly associated with human leukocyte antigen (HLA)-B27, implying a shared etiology. This study aims to apply genomewide association study (GWAS) to characterize the genetic associations of AAU and their relationship to the genetics of AS. METHODS. We undertook the GWAS analyses in 2752 patients with AS with AAU (cases) and 3836 patients with AS without AAU (controls). There were 7,436,415 single-nucleotide polymorphisms (SNPs) available after SNP microarray genotyping, imputation, and quality-control filtering. RESULTS. We identified one locus associated with AAU at genomewide significance: rs9378248 (P = 2.69 × 10−8, odds ratio [OR] = 0.78), lying close to HLA-B. Suggestive association was observed at 11 additional loci, including previously reported AS loci ERAP1 (rs27529, P = 2.19 × 10−7, OR = 1.22) and NOS2 (rs2274894, P = 8.22 × 10−7, OR = 0.83). Multiple novel suggestive associations were also identified, including MERTK (rs10171979, P = 2.56 × 10−6, OR = 1.20), KIFAP3 (rs508063, P = 5.64 × 10−7, OR = 1.20), CLCN7 (rs67412457, P = 1.33 × 10−6, OR = 1.25), ACAA2 (rs9947182, P = 9.70 × 10−7, OR = 1.37), and 5 intergenic loci. The SNP-based heritability is approximately 0.5 for AS alone, and is much higher (approximately 0.7) for AS with AAU. Consistent with the high heritability, a genomewide polygenic risk score shows strong power in identifying individuals at high risk of either AS with AAU or AS alone. CONCLUSIONS. We report here the first GWAS for AAU and identify new susceptibility loci. Our findings confirm the strong overlap in etiopathogenesis of AAU with AS, and also provide new insights into the genetic basis of AAU.

AB - PURPOSE. Acute anterior uveitis (AAU) is a common intraocular inflammatory disease. AAU occurs in 30% to 50% of patients with ankylosing spondylitis (AS), and both conditions are strongly associated with human leukocyte antigen (HLA)-B27, implying a shared etiology. This study aims to apply genomewide association study (GWAS) to characterize the genetic associations of AAU and their relationship to the genetics of AS. METHODS. We undertook the GWAS analyses in 2752 patients with AS with AAU (cases) and 3836 patients with AS without AAU (controls). There were 7,436,415 single-nucleotide polymorphisms (SNPs) available after SNP microarray genotyping, imputation, and quality-control filtering. RESULTS. We identified one locus associated with AAU at genomewide significance: rs9378248 (P = 2.69 × 10−8, odds ratio [OR] = 0.78), lying close to HLA-B. Suggestive association was observed at 11 additional loci, including previously reported AS loci ERAP1 (rs27529, P = 2.19 × 10−7, OR = 1.22) and NOS2 (rs2274894, P = 8.22 × 10−7, OR = 0.83). Multiple novel suggestive associations were also identified, including MERTK (rs10171979, P = 2.56 × 10−6, OR = 1.20), KIFAP3 (rs508063, P = 5.64 × 10−7, OR = 1.20), CLCN7 (rs67412457, P = 1.33 × 10−6, OR = 1.25), ACAA2 (rs9947182, P = 9.70 × 10−7, OR = 1.37), and 5 intergenic loci. The SNP-based heritability is approximately 0.5 for AS alone, and is much higher (approximately 0.7) for AS with AAU. Consistent with the high heritability, a genomewide polygenic risk score shows strong power in identifying individuals at high risk of either AS with AAU or AS alone. CONCLUSIONS. We report here the first GWAS for AAU and identify new susceptibility loci. Our findings confirm the strong overlap in etiopathogenesis of AAU with AS, and also provide new insights into the genetic basis of AAU.

KW - Acute anterior uveitis

KW - Ankylosing spondylitis

KW - GWAS

KW - Genetic risk scores

KW - Heritability

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Genomewide association study of acute anterior uveitis identifies new susceptibility loci

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