Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma

Gharahkhani, Puya; Burdon, Kathryn P.; Fogarty, Rhys; Sharma, Shilpi; Hewitt, Alex W.; Martin, Sarah; Law, Matthew H.; Cremin, Katie; Bailey, Jessica N. Cooke; Loomis, Stephanie; Pasquale, Louis R.; Haines, Jonathan L.; Hauser, Michael A.; Viswanathan, Ananth C.; McGuffin, Peter; Topouzis, Fotis; Foster, Paul J.; Graham, Stuart; Casson, Robert J.; Chehade, Mark; White, Andrew; Zhou, Tiger; Souzeau, Emmanuelle; Landers, John; Fitzgerald, Jude; Klebe, Sonja; Ruddle, Jonathan B; Goldberg, Ivan; Healey, Paul R.; Mills, Richard A.; Wang, Jie Jin; Montgomery, Grant W.; Martin, Nicholas G.; Radford‐Smith, Graham; Whiteman, David C.; Brown, Matthew A.; Wiggs, Janey L.; Mackey, David A.; Mitchell, Paul; MacGregor, Stuart; Craig, Jamie E

doi:10.1038/ng.3079

Cited by 197 publications

(179 citation statements)

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“…Classic twin studies in POAG are lacking and there is no consensus on heritability for POAG, but work by Cuellar-Partida et al estimated the heritability of POAG based on genome-wide array data at 0.42 6 0.09 (6). Several genome-wide association studies (GWAS) have identified new POAG genes by examining POAG directly or studying endophenotypes like VCDR and IOP (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Several genes associated with VCDR and IOP -CDKN2B-AS1, SIX6 (VCDR); and CAV1/CAV2, TMCO1, ABCA1 and ARHGEF12 (IOP) -are associated with POAG.…”

Section: Introductionmentioning

confidence: 99%

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

et al. 2017

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Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

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Section: Introductionmentioning

confidence: 99%

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

et al. 2017

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“…European ancestry populations (CAV1 [150], CDKN2BAS [151], TMCO1 [151], SIX1 [152], ABCA1 [153,154], GMDS [154], AFAP1 [154]) were removed. For AMD, we removed loci from 35 loci summarized in Fritsche et al [305].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, 7 loci of relatively small effect have been implicated in POAG [150][151][152][153][154]. At genome-wide significant level only the ATPbinding cassette transporter ABCA1 is associated with both diseases [154,305].…”

Section: Conflicts Of Interestsmentioning

confidence: 99%

“…Genetic studies of POAG have also identified multiple variants such as Gln368Ter in the MYOC gene which accounts for ~4% of all the POAG cases [149]. In the last years, SNPs in seven other loci (CAV1 [150], CDKN2BAS, TMCO1 [151], SIX1 [152], ABCA1, GMDS and AFAP1 [153,154]) have been identified through GWAS of POAG and its endophenotypes IOP and optic disc parameters. However, the variance explained by these seven SNPs is relatively small and it is unclear how important other common genetic variants are in explaining trait variation.…”

Section: Primary Open Angle Glaucoma and Age-related Macular Degeneramentioning

confidence: 99%

“…Genome-wide association studies (GWAS) meta-analyses have identified 35 genetic loci associated to AMD [162,302,304,305] that explain a major part of the heritability of AMD [305]. In contrast, 7 loci of relatively small effect have been implicated in POAG [150][151][152][153][154]. At genome-wide significant level only the ATPbinding cassette transporter ABCA1 is associated with both diseases [154,305].…”

Section: Conflicts Of Interestsmentioning

confidence: 99%

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Complex trait genetics: mapping, correlation and causation

Partida¹

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Efforts to understand the genetic aetiology of complex traits have gained a lot of momentum in the last decade. Advancement of next generation sequencing and the ever-decreasing price of genotyping platforms have allowed us to carry out a vast number of genome wide association studies (GWAS). Until relatively recently, GWAS was guided by the common disease -common genetic variation paradigm.However, recent findings and developments have made us look at the bigger picture, including rare genetic variation. In addition, methodological developments are guiding the translation of GWAS findings. For instance, diverse statistical methods can be applied on genetically informative data to estimate the genetic correlation between complex diseases. The latter can have important medical implications, as genetically correlated diseases might be responsive to the same treatments. Also, approaches such as Mendelian randomization (MR) can help investigations of causal factors in disease when is unfeasible to carry out randomized control trials.My focus is on the application of statistical methods in complex trait genetics -I cover a range of phenotypes, ranging from eye disease to cancer.

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Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

Hauser

Allingham

Aung

et al. 2019

JAMA

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Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. OBJECTIVES To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. DESIGN, SETTINGS, AND PARTICIPANTS A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic-and population-based participant recruitment approaches. Study participants were recruited from

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Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma

Cited by 197 publications

References 45 publications

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Complex trait genetics: mapping, correlation and causation

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

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