Genome-wide linkage and association analysis of primary open-angle glaucoma endophenotypes in the Norfolk Island isolate

Elizabeth Matovinovic, Pik Fang Kho, Rodney A. Lea, Miles C. Benton, David A. Eccles, Larisa M. Haupt, Alex W. Hewitt, Justin C. Sherwin, David A. Mackey, Lyn R. Griffiths

Research output: Contribution to journalArticle

Abstract

Purpose: Primary open-angle glaucoma (POAG) refers to a group of heterogeneous diseases involving optic nerve damage. Two well-established risk factors for POAG are elevated intraocular pressure (IOP) and a thinner central corneal thickness (CCT). These endophenotypes exhibit a high degree of heritability across populations. Large-scale genome-wide association studies (GWASs) of outbred populations have robustly implicated several susceptibility gene variants for both IOP and CCT. Despite this progress, a substantial amount of genetic variance remains unexplained. Population-specific variants that might be rare in outbred populations may also influence POAG endophenotypes. The Norfolk Island population is a founder-effect genetic isolate that has been well characterized for POAG endophenotypes. This population is therefore a suitable candidate for mapping new variants that influence these complex traits. Methods: Three hundred and thirty participants from the Norfolk Island Eye Study (NIES) core pedigree provided DNA. Ocular measurements of CCT and IOP were also taken for analysis. Heritability analyses and genome-wide linkage analyses of short tandem repeats (STRs) were conducted using SOLAR. Pedigree-based GWASs of single-nucleotide polymorphisms (SNPs) were performed using the GenABEL software. Results: CCT was the most heritable endophenotype in this cohort (h2 = 0.77, p = 6×10−6), while IOP showed a heritabil­ity of 0.39 (p = 0.008). A genome-wide linkage analysis of these POAG phenotypes identified a maximum logarithm of the odds (LOD) score of 1.9 for CCT on chromosome 20 (p = 0.0016) and 1.3 for IOP on chromosome 15 (p = 0.0072). The GWAS results revealed a study-wise significant association for IOP at rs790357, which is located within DLG2 on chr11q14.1 (p = 1.02×10−7). DLG2 is involved in neuronal signaling and development, and while it has not previously been associated with IOP, it has been associated with myopia. An analysis of 12 known SNPs for IOP showed that rs12419342 in RAPSN on chromosome 11 was nominally associated in Norfolk Island (NI; p = 0.0021). For CCT, an analysis of 26 known SNPs showed rs9938149 in BANP-ZNF469 on chromosome 16 was nominally associated in NI (p = 0.002). Conclusions: These study results indicate that CCT and IOP exhibit a substantial degree of heritability in the NI pedi­gree, indicating a genetic component. A genome-wide linkage analysis of POAG endophenotypes did not reveal any major effect loci, but the GWASs did implicate several known loci, as well as a potential new locus in DLG2, suggesting a role for neuronal signaling in development in IOP and perhaps POAG. These results also highlight the need to target rarer variants via whole genome sequencing in this genetic isolate.

Original languageEnglish
Pages (from-to)660-665
Number of pages6
JournalMolecular Vision
Volume23
Publication statusPublished - 28 Sep 2017

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Melanesia
Endophenotypes
Genome-Wide Association Study
Intraocular Pressure
Pedigree
Genome
Population
Single Nucleotide Polymorphism
Corneal Pachymetry
Primary Open Angle Glaucoma
Chromosomes, Human, Pair 20
Founder Effect
Chromosomes, Human, Pair 16
Chromosomes, Human, Pair 15
Optic Nerve Diseases
Chromosomes, Human, Pair 11
Myopia
Microsatellite Repeats
Software

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Matovinovic, E., Kho, P. F., Lea, R. A., Benton, M. C., Eccles, D. A., Haupt, L. M., ... Griffiths, L. R. (2017). Genome-wide linkage and association analysis of primary open-angle glaucoma endophenotypes in the Norfolk Island isolate. Molecular Vision, 23, 660-665.
Matovinovic, Elizabeth ; Kho, Pik Fang ; Lea, Rodney A. ; Benton, Miles C. ; Eccles, David A. ; Haupt, Larisa M. ; Hewitt, Alex W. ; Sherwin, Justin C. ; Mackey, David A. ; Griffiths, Lyn R. / Genome-wide linkage and association analysis of primary open-angle glaucoma endophenotypes in the Norfolk Island isolate. In: Molecular Vision. 2017 ; Vol. 23. pp. 660-665.
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title = "Genome-wide linkage and association analysis of primary open-angle glaucoma endophenotypes in the Norfolk Island isolate",
abstract = "Purpose: Primary open-angle glaucoma (POAG) refers to a group of heterogeneous diseases involving optic nerve damage. Two well-established risk factors for POAG are elevated intraocular pressure (IOP) and a thinner central corneal thickness (CCT). These endophenotypes exhibit a high degree of heritability across populations. Large-scale genome-wide association studies (GWASs) of outbred populations have robustly implicated several susceptibility gene variants for both IOP and CCT. Despite this progress, a substantial amount of genetic variance remains unexplained. Population-specific variants that might be rare in outbred populations may also influence POAG endophenotypes. The Norfolk Island population is a founder-effect genetic isolate that has been well characterized for POAG endophenotypes. This population is therefore a suitable candidate for mapping new variants that influence these complex traits. Methods: Three hundred and thirty participants from the Norfolk Island Eye Study (NIES) core pedigree provided DNA. Ocular measurements of CCT and IOP were also taken for analysis. Heritability analyses and genome-wide linkage analyses of short tandem repeats (STRs) were conducted using SOLAR. Pedigree-based GWASs of single-nucleotide polymorphisms (SNPs) were performed using the GenABEL software. Results: CCT was the most heritable endophenotype in this cohort (h2 = 0.77, p = 6×10−6), while IOP showed a heritabil­ity of 0.39 (p = 0.008). A genome-wide linkage analysis of these POAG phenotypes identified a maximum logarithm of the odds (LOD) score of 1.9 for CCT on chromosome 20 (p = 0.0016) and 1.3 for IOP on chromosome 15 (p = 0.0072). The GWAS results revealed a study-wise significant association for IOP at rs790357, which is located within DLG2 on chr11q14.1 (p = 1.02×10−7). DLG2 is involved in neuronal signaling and development, and while it has not previously been associated with IOP, it has been associated with myopia. An analysis of 12 known SNPs for IOP showed that rs12419342 in RAPSN on chromosome 11 was nominally associated in Norfolk Island (NI; p = 0.0021). For CCT, an analysis of 26 known SNPs showed rs9938149 in BANP-ZNF469 on chromosome 16 was nominally associated in NI (p = 0.002). Conclusions: These study results indicate that CCT and IOP exhibit a substantial degree of heritability in the NI pedi­gree, indicating a genetic component. A genome-wide linkage analysis of POAG endophenotypes did not reveal any major effect loci, but the GWASs did implicate several known loci, as well as a potential new locus in DLG2, suggesting a role for neuronal signaling in development in IOP and perhaps POAG. These results also highlight the need to target rarer variants via whole genome sequencing in this genetic isolate.",
author = "Elizabeth Matovinovic and Kho, {Pik Fang} and Lea, {Rodney A.} and Benton, {Miles C.} and Eccles, {David A.} and Haupt, {Larisa M.} and Hewitt, {Alex W.} and Sherwin, {Justin C.} and Mackey, {David A.} and Griffiths, {Lyn R.}",
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Matovinovic, E, Kho, PF, Lea, RA, Benton, MC, Eccles, DA, Haupt, LM, Hewitt, AW, Sherwin, JC, Mackey, DA & Griffiths, LR 2017, 'Genome-wide linkage and association analysis of primary open-angle glaucoma endophenotypes in the Norfolk Island isolate' Molecular Vision, vol. 23, pp. 660-665.

Genome-wide linkage and association analysis of primary open-angle glaucoma endophenotypes in the Norfolk Island isolate. / Matovinovic, Elizabeth; Kho, Pik Fang; Lea, Rodney A.; Benton, Miles C.; Eccles, David A.; Haupt, Larisa M.; Hewitt, Alex W.; Sherwin, Justin C.; Mackey, David A.; Griffiths, Lyn R.

In: Molecular Vision, Vol. 23, 28.09.2017, p. 660-665.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide linkage and association analysis of primary open-angle glaucoma endophenotypes in the Norfolk Island isolate

AU - Matovinovic, Elizabeth

AU - Kho, Pik Fang

AU - Lea, Rodney A.

AU - Benton, Miles C.

AU - Eccles, David A.

AU - Haupt, Larisa M.

AU - Hewitt, Alex W.

AU - Sherwin, Justin C.

AU - Mackey, David A.

AU - Griffiths, Lyn R.

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Y1 - 2017/9/28

N2 - Purpose: Primary open-angle glaucoma (POAG) refers to a group of heterogeneous diseases involving optic nerve damage. Two well-established risk factors for POAG are elevated intraocular pressure (IOP) and a thinner central corneal thickness (CCT). These endophenotypes exhibit a high degree of heritability across populations. Large-scale genome-wide association studies (GWASs) of outbred populations have robustly implicated several susceptibility gene variants for both IOP and CCT. Despite this progress, a substantial amount of genetic variance remains unexplained. Population-specific variants that might be rare in outbred populations may also influence POAG endophenotypes. The Norfolk Island population is a founder-effect genetic isolate that has been well characterized for POAG endophenotypes. This population is therefore a suitable candidate for mapping new variants that influence these complex traits. Methods: Three hundred and thirty participants from the Norfolk Island Eye Study (NIES) core pedigree provided DNA. Ocular measurements of CCT and IOP were also taken for analysis. Heritability analyses and genome-wide linkage analyses of short tandem repeats (STRs) were conducted using SOLAR. Pedigree-based GWASs of single-nucleotide polymorphisms (SNPs) were performed using the GenABEL software. Results: CCT was the most heritable endophenotype in this cohort (h2 = 0.77, p = 6×10−6), while IOP showed a heritabil­ity of 0.39 (p = 0.008). A genome-wide linkage analysis of these POAG phenotypes identified a maximum logarithm of the odds (LOD) score of 1.9 for CCT on chromosome 20 (p = 0.0016) and 1.3 for IOP on chromosome 15 (p = 0.0072). The GWAS results revealed a study-wise significant association for IOP at rs790357, which is located within DLG2 on chr11q14.1 (p = 1.02×10−7). DLG2 is involved in neuronal signaling and development, and while it has not previously been associated with IOP, it has been associated with myopia. An analysis of 12 known SNPs for IOP showed that rs12419342 in RAPSN on chromosome 11 was nominally associated in Norfolk Island (NI; p = 0.0021). For CCT, an analysis of 26 known SNPs showed rs9938149 in BANP-ZNF469 on chromosome 16 was nominally associated in NI (p = 0.002). Conclusions: These study results indicate that CCT and IOP exhibit a substantial degree of heritability in the NI pedi­gree, indicating a genetic component. A genome-wide linkage analysis of POAG endophenotypes did not reveal any major effect loci, but the GWASs did implicate several known loci, as well as a potential new locus in DLG2, suggesting a role for neuronal signaling in development in IOP and perhaps POAG. These results also highlight the need to target rarer variants via whole genome sequencing in this genetic isolate.

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Matovinovic E, Kho PF, Lea RA, Benton MC, Eccles DA, Haupt LM et al. Genome-wide linkage and association analysis of primary open-angle glaucoma endophenotypes in the Norfolk Island isolate. Molecular Vision. 2017 Sep 28;23:660-665.