Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Bailey, Jessica N. Cooke; Loomis, Stephanie; Kang, Jae H.; Allingham, R. Rand; Gharahkhani, Puya; Khor, Chiea‐Chuen; Burdon, Kathryn P.; Aschard, Hugues; Chasman, Daniel I.; Igo, Robert P.; Hysi, Pirro G.; Glastonbury, Craig A.; Ashley-Koch, Allison E.; Brilliant, Murray H.; Brown, Andrew Anand; Budenz, Donald L.; Buil, Alfonso; Cheng, Ching‐Yu; Choi, Hyon K.; Christen, William G.; Curhan, Gary C.; Vivo, Immaculata De; Fingert, John H.; Foster, Paul J.; Fuchs, Charles S.; Gaasterland, Douglas E.; Gaasterland, Terry; Hewitt, Alex W.; Hu, Frank B.; Hunter, David J.; Khawaja, Anthony P.; Lee, Richard K.; Li, Zheng; Lichter, Paul R.; Mackey, David A.; McGuffin, Peter; Mitchell, Paul; Moroi, Sayoko E.; Perera, Shamira A.; Pepper, Keating W.; Qi, Qibin; Realini, Tony; Richards, Julia E.; Ridker, Paul M.; Rimm, Eric B.; Ritch, Robert; Ritchie, Marylyn D.; Schuman, Joel S.; Scott, William K.; Singh, Kuldev; Sit, Arthur J.; Song, Yeunjoo E.; Tamimi, Rulla M.; Topouzis, Fotis; Viswanathan, Ananth C.; Verma, Shefali S.; Vollrath, Douglas; Wang, Jie Jin; Weisschuh, Nicole; Wissinger, Bernd; Wollstein, Gadi; Wong, Tien Yin; Yaspan, Brian L.; Zack, Donald J.; Zhang, Kang; Weinreb, Robert N.; Pericak‐Vance, Margaret A.; Small, Kerrin S.; Hammond, Christopher J.; Aung, Tin; Liu, Yutao; Vithana, Eranga N.; MacGregor, Stuart; Craig, Jamie E; Kraft, Peter; Howell, Gareth R.; Hauser, Michael A.; Pasquale, Louis R.; Haines, Jonathan L.; Wiggs, Janey L.

doi:10.1038/ng.3482

Cited by 241 publications

(269 citation statements)

References 52 publications

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“…In fact, glaucoma resistant individuals who have not developed glaucomatous neuropathy despite years of high IOP are reported to have systemic mitochondrial efficiency 49 , including increased rates of ADP phosphorylation by mitochondrial complexes I, II and IV as compared to both unaffected controls and glaucoma patients. Other lines of inquiry have demonstrated that OPA1 expression (which promotes mitochondrial stability) was decreased in open-angle glaucoma patients 50 and genome wide expression studies (GWAS) have linked a key mitochondrial gene ( TXNRD2 ) to glaucoma susceptibility 51 . A recent study has identified certain African (and African-American) mtDNA haplogroups as risk factors for primary open-angle glaucoma.…”

Section: Mitochondria and Human Glaucomamentioning

confidence: 99%

Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma

Williams

Harder

John

2017

Journal of Glaucoma

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Mitochondrial dysfunction may be an important, if not essential, component of human glaucoma. Using transcriptomics followed by molecular and neurobiological techniques, we have recently demonstrated that mitochondrial dysfunction within retinal ganglion cells is an early feature in the DBA/2J mouse model of inherited glaucoma. Guided by these findings, we discovered that the retinal level of nicotinamide adenine dinucleotide (NAD, a key molecule for mitochondrial health) declines in an age-dependent manner. We hypothesized that this decline in NAD renders retinal ganglion cells susceptible to damage during periods of elevated intraocular pressure. To replete NAD levels in this glaucoma, we administered nicotinamide (the amide of vitamin B3). At the lowest dose tested, nicotinamide robustly protected from glaucoma (~70% of eyes had no detectable glaucomatous neurodegeneration). At this dose, nicotinamide had no influence on intraocular pressure and so its affect was neuroprotective. At the highest dose tested, 93% of eyes had no detectable glaucoma. This represents a ~10-fold decrease in the risk of developing glaucoma. At this dose, intraocular pressure still became elevated but there was a reduction in the degree of elevation showing an additional benefit. Thus, nicotinamide is unexpectedly potent at preventing this glaucoma and is an attractive option for glaucoma therapeutics. Our findings demonstrate the promise for both preventing and treating glaucoma via interventions that bolster metabolism during increasing age and during periods of elevated intraocular pressure. Nicotinamide prevents age-related declines in NAD (a decline that occurs in different genetic contexts and species). NAD precursors are reported to protect from a variety of neurodegenerative conditions. Thus, nicotinamide may provide a much needed neuroprotective treatment against human glaucoma. This manuscript summarizes human data implicating mitochondria in glaucoma, and argues for studies to further assess the safety and efficacy of nicotinamide in human glaucoma care.

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Section: Mitochondria and Human Glaucomamentioning

confidence: 99%

Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma

Williams

Harder

John

2017

Journal of Glaucoma

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“…Variants in PITX2 are more often associated with dental and/or umbilical anomalies, whereas individuals with FOXC1 variants often have the ARM phenotype alone, or display a range of other systemic anomalies including heart anomalies, hearing defects, developmental delay and/or growth delay. 11,15,18 In addition, FOXC1 has recently been identified as a primary open-angle glaucoma (POAG) susceptibility locus 19 and an essential regulator of lymphangiogenesis. 20 FOXC1 encodes a forkhead transcription factor encoded by a single exon, whereas PITX2 is a member of a paired class of homeodomain transcription factors and encodes four alternative transcripts (PITX2A, B, C and D).…”

Section: Introductionmentioning

confidence: 99%

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Souzeau¹,

Siggs²,

Zhou³

et al. 2017

Eur J Hum Genet

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Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P = 0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0 ± 13.0 years) compared with PITX2 carriers (18.0 ± 10.6 years, P = 0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P = 0.03) but became comparable at 25 years old (71.4% vs 57.7%, P = 0.38). These findings have important implications for the genetic counselling of families affected by AxenfeldRieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes.

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“…Liftover of mouse genomic coordinates resulted in one whole syntenic region located on human chromosome 5. This region was queried for associations with POAG in the NEIGHBORHOOD (Bailey et al, 2016) dataset.…”

Section: Methodsmentioning

confidence: 99%

Genomic loci modulating retinal ganglion cell death following elevated IOP in the mouse

Struebing

King

Liu

et al. 2018

Experimental Eye Research

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The present study was designed to identify genomic loci modulating the susceptibility of retinal ganglion cells (RGC) to elevated intraocular pressure (IOP) in the BXD recombinant inbred mouse strain set. IOP was elevated by injecting magnetic microspheres into the anterior chamber and blocking the trabecular meshwork using a handheld magnet to impede drainage. The IOP was then measured over the next 21 days. Only animals with IOP greater than 25 mmHg for two consecutive days or an IOP above 30 mmHg on a single day after microsphere-injection were used in this study. On day 21, mice were sacrificed and the optic nerve was processed for histology. Axons were counted for both the injected and the control eye in 49 BXD strains, totaling 181 normal counts and 191 counts associated with elevated IOP. The axon loss for each strain was calculated and the data were entered into genenetwork.org. The average number of normal axons in the optic nerve across all strains was 54,788 ± 16% (SD), which dropped to 49,545 ± 20% in animals with artificially elevated IOP. Interval mapping demonstrated a relatively similar genome-wide map for both conditions with a suggestive Quantitative Trait Locus (QTL) on proximal Chromosome 3. When the relative axon loss was used to generate a genome-wide interval map, we identified one significant QTL (p < 0.05) on Chromosome 18 between 53.6 and 57 Mb. Within this region, the best candidate gene for modulating axon loss was Aldh7a1. Immunohistochemistry demonstrated ALDH7A1 expression in mouse RGCs. ALDH7A1 variants were not significantly associated with glaucoma in the NEIGHBORHOOD GWAS dataset, but this enzyme was identified as part of the butanoate pathway previously associated with glaucoma risk. Our results suggest that genomic background influences susceptibility to RGC degeneration and death in an inducible glaucoma model.

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Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Cited by 241 publications

References 52 publications

Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma

Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Genomic loci modulating retinal ganglion cell death following elevated IOP in the mouse

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