Association of Genetic Variation with Keratoconus

Bennet J. McComish, Srujana Sahebjada, Yelena Bykhovskaya, Colin E. Willoughby, Andrea J. Richardson, Abi Tenen, Jac C. Charlesworth, Stuart MacGregor, Paul Mitchell, Sionne E.M. Lucas, Richard A. Mills, David A. MacKey, Xiaohui Li, Jie Jin Wang, Richard A. Jensen, Jerome I. Rotter, Kent D. Taylor, Alex W. Hewitt, Yaron S. Rabinowitz, Paul N. BairdJamie E. Craig, Kathryn P. Burdon

    Research output: Contribution to journalArticle

    Abstract

    Importance: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus. Objective: To identify genetic susceptibility regions for keratoconus in the human genome. Design, Setting, and Participants: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019. Main Outcomes and Measures: Associations between keratoconus and 6252612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components. Results: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8). Conclusions and Relevance: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11..

    Original languageEnglish
    JournalJAMA Ophthalmology
    Early online date19 Dec 2019
    DOIs
    Publication statusE-pub ahead of print - 19 Dec 2019

    Fingerprint

    Keratoconus
    Northern Ireland
    Chromosomes, Human, Pair 11
    Phospholipases
    Victoria
    Genome-Wide Association Study
    Genome
    Genes
    Single Nucleotide Polymorphism
    Casein Kinase I
    Chromosomes, Human, Pair 22
    Genetic Loci
    Human Genome
    Genetic Predisposition to Disease
    Quality Control
    Glaucoma
    Cornea
    Protein Isoforms
    Logistic Models
    Genotype

    Cite this

    McComish, B. J., Sahebjada, S., Bykhovskaya, Y., Willoughby, C. E., Richardson, A. J., Tenen, A., ... Burdon, K. P. (2019). Association of Genetic Variation with Keratoconus. JAMA Ophthalmology. https://doi.org/10.1001/jamaophthalmol.2019.5293
    McComish, Bennet J. ; Sahebjada, Srujana ; Bykhovskaya, Yelena ; Willoughby, Colin E. ; Richardson, Andrea J. ; Tenen, Abi ; Charlesworth, Jac C. ; MacGregor, Stuart ; Mitchell, Paul ; Lucas, Sionne E.M. ; Mills, Richard A. ; MacKey, David A. ; Li, Xiaohui ; Wang, Jie Jin ; Jensen, Richard A. ; Rotter, Jerome I. ; Taylor, Kent D. ; Hewitt, Alex W. ; Rabinowitz, Yaron S. ; Baird, Paul N. ; Craig, Jamie E. ; Burdon, Kathryn P. / Association of Genetic Variation with Keratoconus. In: JAMA Ophthalmology. 2019.
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    title = "Association of Genetic Variation with Keratoconus",
    abstract = "Importance: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus. Objective: To identify genetic susceptibility regions for keratoconus in the human genome. Design, Setting, and Participants: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019. Main Outcomes and Measures: Associations between keratoconus and 6252612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components. Results: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8). Conclusions and Relevance: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11..",
    author = "McComish, {Bennet J.} and Srujana Sahebjada and Yelena Bykhovskaya and Willoughby, {Colin E.} and Richardson, {Andrea J.} and Abi Tenen and Charlesworth, {Jac C.} and Stuart MacGregor and Paul Mitchell and Lucas, {Sionne E.M.} and Mills, {Richard A.} and MacKey, {David A.} and Xiaohui Li and Wang, {Jie Jin} and Jensen, {Richard A.} and Rotter, {Jerome I.} and Taylor, {Kent D.} and Hewitt, {Alex W.} and Rabinowitz, {Yaron S.} and Baird, {Paul N.} and Craig, {Jamie E.} and Burdon, {Kathryn P.}",
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    McComish, BJ, Sahebjada, S, Bykhovskaya, Y, Willoughby, CE, Richardson, AJ, Tenen, A, Charlesworth, JC, MacGregor, S, Mitchell, P, Lucas, SEM, Mills, RA, MacKey, DA, Li, X, Wang, JJ, Jensen, RA, Rotter, JI, Taylor, KD, Hewitt, AW, Rabinowitz, YS, Baird, PN, Craig, JE & Burdon, KP 2019, 'Association of Genetic Variation with Keratoconus', JAMA Ophthalmology. https://doi.org/10.1001/jamaophthalmol.2019.5293

    Association of Genetic Variation with Keratoconus. / McComish, Bennet J.; Sahebjada, Srujana; Bykhovskaya, Yelena; Willoughby, Colin E.; Richardson, Andrea J.; Tenen, Abi; Charlesworth, Jac C.; MacGregor, Stuart; Mitchell, Paul; Lucas, Sionne E.M.; Mills, Richard A.; MacKey, David A.; Li, Xiaohui; Wang, Jie Jin; Jensen, Richard A.; Rotter, Jerome I.; Taylor, Kent D.; Hewitt, Alex W.; Rabinowitz, Yaron S.; Baird, Paul N.; Craig, Jamie E.; Burdon, Kathryn P.

    In: JAMA Ophthalmology, 19.12.2019.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Association of Genetic Variation with Keratoconus

    AU - McComish, Bennet J.

    AU - Sahebjada, Srujana

    AU - Bykhovskaya, Yelena

    AU - Willoughby, Colin E.

    AU - Richardson, Andrea J.

    AU - Tenen, Abi

    AU - Charlesworth, Jac C.

    AU - MacGregor, Stuart

    AU - Mitchell, Paul

    AU - Lucas, Sionne E.M.

    AU - Mills, Richard A.

    AU - MacKey, David A.

    AU - Li, Xiaohui

    AU - Wang, Jie Jin

    AU - Jensen, Richard A.

    AU - Rotter, Jerome I.

    AU - Taylor, Kent D.

    AU - Hewitt, Alex W.

    AU - Rabinowitz, Yaron S.

    AU - Baird, Paul N.

    AU - Craig, Jamie E.

    AU - Burdon, Kathryn P.

    PY - 2019/12/19

    Y1 - 2019/12/19

    N2 - Importance: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus. Objective: To identify genetic susceptibility regions for keratoconus in the human genome. Design, Setting, and Participants: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019. Main Outcomes and Measures: Associations between keratoconus and 6252612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components. Results: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8). Conclusions and Relevance: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11..

    AB - Importance: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus. Objective: To identify genetic susceptibility regions for keratoconus in the human genome. Design, Setting, and Participants: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019. Main Outcomes and Measures: Associations between keratoconus and 6252612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components. Results: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8). Conclusions and Relevance: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11..

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    McComish BJ, Sahebjada S, Bykhovskaya Y, Willoughby CE, Richardson AJ, Tenen A et al. Association of Genetic Variation with Keratoconus. JAMA Ophthalmology. 2019 Dec 19. https://doi.org/10.1001/jamaophthalmol.2019.5293