National Health and Medical Research Council (NHMRC)

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This is a collection of NHMRC-funded research publications authored by Flinders academics.

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Finding My Way: results of a multicentre RCT evaluating a web-based self-guided psychosocial intervention for newly diagnosed cancer survivors
(Springer Verlag., 2018-11-09) Beatty, Lisa Jane; Kemp, Emma; Coll, Joseph R; Turner, Jane; Butow, Phyllis N; Milne, Donna; Yates, Patsy; Lambert, Sylvie D; Wootten, Addie; Yip, Desmond; Koczwara, Bogda
Purpose This multicentre randomised controlled trial examined the efficacy of Finding My Way (FMW), a 6-week/6-module online self-guided psychotherapeutic intervention for newly diagnosed curatively treated cancer survivors, in reducing cancer-related distress and improving quality of life compared to an online attention control. Methods Participants were randomised on a 1:1 ratio using a gender-stratified block design to intervention (n = 94) or attention control (n = 97), and were blinded to condition. Assessments were completed at baseline (T0), post-intervention (T1), 3 months (T2), and 6 months (T3) post-intervention. Mixed model repeated measures analyses examined differences between groups for cancer-specific distress (primary outcome) and general distress, quality of life (QoL), coping, and health service utilisation (secondary outcomes). Results While both groups reported reduced cancer-specific and general distress over time, between-group differences were not significant. Intervention participants reported lower total health service utilisation and supportive care utilisation post-intervention than controls (total HS use: between-group mean difference = − 1.07 (− 1.85 to − 0.28); supportive care use: between-group mean difference = − 0.64 (− 1.21 to − 0.06)) and significantly higher emotional functioning at 3 months (between-group mean difference = 7.04 (0.15 to 13.9)). At 6 months, the supportive care utilisation finding reversed (between-group mean difference = 0.78 points (0.19 to 1.37). Across remaining QoL and coping outcomes, no significant group differences emerged. Conclusions While both groups experienced reductions in distress, between-group differences were not significant. This contrasts with the significantly improved emotional functioning observed in FMW participants at 3 months and the short-term reductions in health service utilisation. Long-term increases in supportive care service utilisation suggest FMW only met needs while being actively used.
Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma
(Nature Publishing Group, 2018-02-18) Gharahkhani, Puya; Burdon, Kathryn Penelope; Cooke-Bailey, Jessica N; Hewitt, Alex W; Law, Matthew H; Pasquale, Louis R; Kang, Jae Hee; Haines, Jonathan L; Souzeau, Emmanuelle; Zhou, Tiger; Siggs, Owen M; Landers, John; Awadalla, Mona S; Sharma, Shiwani; Mills, Richard Arthur; Ridge, Bronwyn; Lynn, David J; Casson, Robert J; Graham, Stuart L; Goldberg, Ivan; White, Andrew J; Healey, Paul R; Grigg, John RB; Lawlor, Mitchell; Mitchell, Paul; Ruddle, Jonathan B; Coote, Michael A; Walland, Mark; Best, Stephen; Vincent, Andrea; Gale, Jesse; Radford-Smith, Graham; Whiteman, David C; Montgomery, Grant W; Martin, Nicholas G; Mackey, David A; Wiggs, Janey L; MacGregor, Stuart; Craig, Jamie E; Neighborhood Consortium
Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - “response to fluid shear stress” and “abnormal retina morphology” - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.
DNA methylation at the 9p21 glaucoma susceptibility locus is associated with normal-tension glaucoma
(Taylor & Francis Group, 2017-12-21) Burdon, Kathryn Penelope; Awadalla, Mona S; Mitchell, Paul; Wang, Jie Jin; White, Andrew J; Keane, Miriam Claire; Souzeau, Emmanuelle; Graham, Stuart L; Goldberg, Ivan; Healey, Paul R; Landers, John; Mills, Richard Arthur; Best, Stephen; Hewitt, Alex W; Sharma, Shiwani; Craig, Jamie E
Purpose: Recent genome-wide association studies reported strong association of genetic variation at the CDKN2B/CDKN2B-AS1 locus on 9p21 with normal-tension glaucoma (NTG) in multiple populations. The mechanism by which this locus causes disease remains to be elucidated. We investigated the association of DNA methylation of CpG islands at this locus with NTG. Methods: We conducted a retrospective case–control study of 178 NTG cases and 202 unaffected controls from Australia. CDKN2B and CDKN2B-AS1 promoter methylation was measured quantitatively using the MassCleave assay, and assessed for association with the disease, and the genotype of the associated risk variants using IBM SPSS statistics 22.0 CpG sites at which methylation status was associated with NTG were validated using pyrosequencing. Results: We identified one CpG site (F1:13–14) in the CDKN2B promoter which showed significant association with NTG (p = 0.001). The association was highly significant in female cases (p = 0.006) but not in male cases (p = 0.054). The association was validated using an independent method confirming the likely association of DNA methylation with NTG in females (p = 0.015), but not in males (p = 0.497). In addition, methylation at CpG sites in CDKN2B was also associated with genotype at rs1063192, which is known to confer risk for NTG. Conclusion: This study reveals an association of methylation status in the CDKN2B promoter with NTG, particularly in females. This suggests that the observed genetic association with the disease at this locus could be in part due to epigenetic mechanisms, and is likely to be independent of the association of nonsynonymous coding variation within the gene.
Rare, Potentially Pathogenic Variants in ZNF469 Are Not Enriched in Keratoconus in a Large Australian Cohort of European Descent
(Investigative Ophthalmology and Visual Science, 2017-12) Lucas, Sionne E; Zhou, Tiger; Blackburn, Nicholas B; Mills, Richard Arthur; Ellis, Jonathan; Leo, Paul; Souzeau, Emmanuelle; Ridge, Bronwyn; Charlesworth, Jac C; Brown, Matthew A; Lindsay, Richard; Craig, Jamie E; Burdon, Kathryn Penelope
Purpose: The Zinc Finger Protein 469 (ZNF469) gene has been proposed as a candidate gene for keratoconus due to the association of an upstream polymorphism (rs9938149) with the disease in two independent studies, and the role of the gene in the autosomal recessive disease Brittle Cornea Syndrome. Coding variants in ZNF469 have been assessed for association with keratoconus in several small studies, with conflicting results. We assessed rare, potentially pathogenic variants in ZNF469 for enrichment in keratoconus patients in a cohort larger than all previous studies combined. Methods: ZNF469 was sequenced in 385 Australian keratoconus patients of European descent, 346 population controls, and 230 ethnically matched screened controls by either whole exome sequencing or targeted gene sequencing. The frequency of rare and very rare potentially pathogenic variants was compared between cases and controls using χ2 or Fisher's exact tests and further explored using a gene based test (Sequence Kernel Association Test [SKAT]), weighting on the rarity of variants. Results: A total of 49 rare, including 33 very rare, potentially pathogenic variants were identified across all groups. No enrichment of rare or very rare potentially pathogenic variants in ZNF469 was observed in our cases compared to the control groups following analysis using χ2 or Fisher's exact tests. This finding was further supported by the SKAT results, which found no significant difference in the frequency of variants predicted to be damaging between cases and either control group (P = 0.06).
Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma
(Association for Research in Vision and Ophthalmology, Inc., 2017-03) Zhou, Tiger; Souzeau, Emmanuelle; Siggs, Owen M; Landers, John; Mills, Richard Arthur; Goldberg, Ivan; Healey, Paul R; Graham, Stuart L; Hewitt, Alex W; Mackey, David A; Galanopoulos, Anna; Casson, Robert J; Ruddle, Jonathan B; Ellis, Jonathan; Leo, Jonathan; Brown, Matthew A; MacGregor, Stuart; Sharma, Shiwani; Burdon, Kathryn Penelope; Simmonds, Jamie E
Purpose: Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of individuals with advanced early-onset POAG. Methods: The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninety-three previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case–control mutational burdens were calculated for glaucoma-linked genes. Results: Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] = 16.62, P = 6.31×10−16). Conclusions: Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.
Partial duplication of the CRYBB1-CRYBA4 locus is associated with autosomal dominant congenital cataract
(Nature Publishing Group, 2017-03-08) Siggs, Owen M; Javadiyan, Shahrbanou; Sharma, Shiwani; Souzeau, Emmanuelle; Lower, Karen Marie; Taranath, Deepa A; Black, J A; Pater, John Brian; Willoughby, John G; Burdon, Kathryn Penelope; Craig, Jamie E
Congenital cataract is a rare but severe paediatric visual impediment, often caused by variants in one of several crystallin genes that produce the bulk of structural proteins in the lens. Here we describe a pedigree with autosomal dominant isolated congenital cataract and linkage to the crystallin gene cluster on chromosome 22. No rare single nucleotide variants or short indels were identified by exome sequencing, yet copy number variant analysis revealed a duplication spanning both CRYBB1 and CRYBA4. While the CRYBA4 duplication was complete, the CRYBB1 duplication was not, with the duplicated CRYBB1 product predicted to create a gain of function allele. This association suggests a new genetic mechanism for the development of isolated congenital cataract.
Promotility Action of the Probiotic Bifidobacterium lactis HN019 Extract Compared with Prucalopride in Isolated Rat Large Intestine
(Frontiers Media S.A., 2017-01-26) Dalziel, Julie E; Anderson, Rachel C; Peters, Jason S; Lynch, Amy T; Spencer, Nicholas John; Dekker, James; Roy, Nicole C
Attention is increasingly being focussed on probiotics as potential agents to restore or improve gastrointestinal (GI) transit. Determining mechanism of action would support robust health claims. The probiotic bacterium Bifidobacterium lactis HN019 reduces transit time, but its mechanisms of action and effects on motility patterns are poorly understood. The aim of this study was to investigate changes in GI motility induced by an extract of HN019 on distinct patterns of colonic motility in isolated rat large intestine, compared with a known promotility modulator, prucalopride. The large intestines from male Sprague Dawley rats (3–6 months) were perfused with Kreb's buffer at 37°C in an oxygenated tissue bath. Isometric force transducers recorded changes in circular muscle activity at four independent locations assessing contractile propagation between the proximal colon and the rectum. HN019 extract was perfused through the tissue bath and differences in tension and frequency quantified relative to pre-treatment controls. Prucalopride (1 μM) increased the frequency of propagating contractions (by 75 ± 26%) in the majority of preparations studied (10/12), concurrently decreasing the frequency of non-propagating contractions (by 50 ± 11%). HN019 extract had no effect on contractile activity during exposure (n = 8). However, following wash out, contraction amplitude of propagating contractions increased (by 55 ± 18%) in the distal colon, while the frequency of non-propagating proximal contractions decreased by 57 ± 7%. The prokinetic action of prucalopride increased the frequency of synchronous contractions along the length of colon, likely explaining increased colonic rate of transit in vivo. HN019 extract modified motility patterns in a different manner by promoting propagating contractile amplitude and inhibiting non-propagations, also demonstrating prokinetic activity consistent with the reduction of constipation by B. lactis HN019 in humans.
Active Foot Synovitis in Patients With Rheumatoid Arthritis: Unstable Remission Status, Radiographic Progression, and Worse Functional Outcomes in Patients With Foot Synovitis in Apparent Remission
(John Wiley & Sons Ltd, 2016-10-26) Wechalekar, Mihir; Lester, Susan; Hill, Catherine L; Lee, Anita; Rischmueller, Maureen; Smith, Malcolm Douglas; Walker, Jennifer; Proudman, Susanna
Sensory innervation of the guinea pig colon and rectum compared using retrograde tracing and immunohistochemistry.
(Wiley, 2016-04-02) Chen, B N; Olsson, C; Sharrad, DF; Brookes, Simon Jonathan
Selective expression of α-synuclein-immunoreactivity in vesicular acetylcholine transporter-immunoreactive axons in the guinea pig rectum and human colon.
(Wiley, 2012-12-17) Sharrad, DF; de Vries, E; Brookes, Simon Jonathan
Parkinson's disease is a neurodegenerative disorder characterized by motor and nonmotor impairments, including constipation. The hallmark pathological features of Parkinson's disease are Lewy bodies and neurites, of which aggregated α-synuclein is a major constituent. Frequently, Lewy pathology is identified in the distal gut of constipated Parkinson's disease patients. The neurons that innervate the distal gut that express α-synuclein have not been identified. We used multiple-labeling immunohistochemistry and anterograde tracing to quantify which neurons projecting to the guinea pig rectum and human colon expressed α-synuclein in their axons. α-Synuclein-immunoreactivity was present in 24 ± 0.7% of somatostatin (SOM)-immunoreactive (IR) varicosities; 20 ± 4.3% of substance P (SP)-IR varicosities and 9 ± 1.3% vasoactive intestinal polypeptide (VIP)-IR varicosities in guinea pig rectal myenteric ganglia. However, α-synuclein-immunoreactivity was localized in significantly more vesicular acetylcholine transporter (VAChT)-IR varicosities (88 ± 3%, P < 0.001). Of SOM-IR, SP-IR, and VIP-IR varicosities that lacked VAChT-immunoreactivity, only 1 ± 0.3%, 0 ± 0.3%, and 0% contained α-synuclein-immunoreactivity, respectively. 71 ± 0.8% of VAChT-IR varicosities in myenteric ganglia of human colon were α-synuclein-IR. In guinea pig rectal myenteric ganglia, α-synuclein- and VAChT-immunoreactivity coexisted in 15 ± 1.4% of biotinamide-labeled extrinsic varicosities; only 1 ± 0.3% of biotinamide-labeled extrinsic varicosities contained α-synuclein-immunoreactivity without VAChT-immunoreactivity. α-Synuclein expression in axons to the distal gut correlates closely with expression of the cholinergic marker, VAChT. This is the first report of cell-selective α-synuclein expression in the nervous system. Our results suggest cholinergic neurons in the gut may be vulnerable in Parkinson's disease.
Circuit class or seven-day therapy for increasing intensity of rehabilitation after stroke: protocol of the CIRCIT trial
(John Wiley & Sons Ltd, 2011-11-24) Hillier, Susan; English, Coralie; Crotty, Maria; Segal, Leonie; Bernhardt, Julie; Esterman, Adrian Jeffrey
Meta-analysis comparing the efficacy of anti-EGFR monoclonal antibody therapy between KRAS G13D and other KRAS mutant metastatic colorectal cancer tumours
(Elsevier, 2016-01-23) Rowland, Andrew; Dias, Mafalda; Wiese, Michael D; Kichenadasse, Ganessan; McKinnon, Ross A; Karapetis, Christos Stelios; Sorich, Michael J
Background Metastatic colorectal cancer (mCRC) tumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies (mAbs). However, observational evidence has led to speculation that mCRC patients with KRAS G13D mutant (MT) tumours may derive a benefit from treatment with anti-EGFR mAbs. Methods We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between tumours harbouring a KRAS G13D mutation (KRAS G13D) and KRAS mutations other than G13D (other KRAS MT). Results Eight RCTs (n = 5967) met the inclusion criteria for assessment of both overall survival (OS) and progression-free survival (PFS). For other KRAS MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 (95% confidence interval [CI]; 0.96, 1.17), compared to 1.08 (95% CI; 0.73, 1.60) for KRAS G13D [test for interaction p = 0.99]. In contrast, the hazard ratio for KRAS wild-type (WT) tumours was 0.85 (95% CI; 0.76, 0.95). Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 1.07 (95% CI; 0.92, 1.26) for other KRAS MT, 0.96 (95% CI; 0.73, 1.27) for KRAS G13D, and 0.68 (95% CI; 0.54, 0.85) for KRAS WT. Again, the test for interaction (p = 0.46) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT. Conclusion This meta-analysis demonstrates no significant difference between KRAS G13D and other KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC.
Spinal afferent nerve endings in visceral organs: recent advances.
(The American Physiological Society., 2016-11-17) Spencer, Nicholas John; Zagorodnyuk, Vladimir Petrovich; Brookes, Simon Jonathan; Hibberd, T
Hydrogen peroxide preferentially activates capsaicin-sensitive high threshold afferents via TRPA1 channels in the guinea pig bladder
(Wiley, 2016-12-06) Nicholas, S; Yuan, S Y; Brookes, Simon Jonathan; Spencer, Nicholas John; Zagorodnyuk, Vladimir Petrovich
Interpreting the clinical utility of a pharmacogenomic marker based on observational association studies
(Springer Nature, 2014-02) Sorich, Michael J; Coory, Michael
It is increasingly recognized that the clinical utility of a pharmacogenomic marker is a fundamental characteristic influencing the likelihood of successful clinical translation. Although appropriately designed and executed randomized controlled trials generally provide the most valid evidence for the clinical utility of a pharmacogenomic marker, such evidence may not always be available. Observational pharmacogenomic association studies are a common form of evidence available, but the assessment of clinical utility based on such evidence is often not straightforward. This paper aims to provide insight into this issue using a range of illustrative examples.
Rotenone and elevated extracellular potassium concentration induce cell-specific fibrillation of α-synuclein in axons of cholinergic enteric neurons in the guinea-pig ileum.
(John Wiley & Sons., 2016-11-07) Sharrad, DF; Chen, B N; Gai, WP; Vaikath, N; El-Agnaf, OM; Brookes, Simon Jonathan
Background: Parkinson’s disease is a progressive neurodegenerative disorder that results in the widespread loss of select classes of neurons throughout the nervous system. The pathological hallmarks of Parkinson’s disease are Lewy bodies and neurites, of which α-synuclein fibrils are the major component. α-Synuclein aggregation has been reported in the gut of Parkinson’s disease patients, even up to a decade before motor symptoms, and similar observations have been made in animal models of disease. However, unlike the central nervous system, the nature of α-synuclein species that form these aggregates and the classes of neurons affected in the gut are unclear. We have previously reported selective expression of α-synuclein in cholinergic neurons in the gut (1), suggesting they may be particularly vulnerable to degeneration in Parkinson’s disease. Methods: In this study, we used immunohistochemistry to detect α-synuclein oligomers and fibrils via conformation-specific antibodies after rotenone treatment or prolonged exposure to high [K+] in ex vivo segments of guinea-pig ileum maintained in organotypic culture. Key Results: Rotenone and prolonged raising of [K+] caused accumulation of α-synuclein fibrils in the axons of cholinergic enteric neurons. This took place in a time- and, in the case of rotenone, concentration-dependent manner. Rotenone also caused selective necrosis, indicated by increased cellular autofluorescence, of cholinergic enteric neurons, labeled by ChAT-immunoreactivity, also in a concentration-dependent manner. Conclusions & Inferences: To our knowledge, this is the first report of rotenone causing selective loss of a neurochemical class in the enteric nervous system. Cholinergic enteric neurons may be particularly susceptible to Lewy pathology and degeneration in Parkinson’s disease.
Measurement of strains experienced by viscerofugal nerve cell bodies during mechanosensitive firing using digital image correlation.
(The American Physiological Society., 2016-11-01) Palmer, Gwen; Hibberd, Timothy J; Roose, Tiina; Brookes, Simon Jonathan; Taylor, Mark
Mechanosensory neurons detect physical events in the local environments of the tissues that they innervate. Studies of mechanosensitivity of neurons or nerve endings in the gut have related their firing to strain, wall tension or pressure. Digital Image Correlation (DIC) is a technique from materials engineering that can be adapted to measure the local physical environments of afferent neurons at high resolution. Flat sheet preparations of guinea pig distal colon were set up with arrays of tissue markers, in vitro. Firing of single viscerofugal neurons was identified in extracellular colonic nerve recordings. The locations of viscerofugal nerve cell bodies were inferred by mapping firing responses to focal application of the nicotinic receptor agonist, DMPP. Mechanosensory firing was recorded during load-evoked uni-axial or bi-axial distensions. Distension caused movement of surface markers which was captured using video imaging. DIC tracked the markers, interpolating the mechanical state of the gut at the location of the viscerofugal nerve cell body. This technique revealed heterogeneous load-evoked strain within preparations. Local strains at viscerofugal nerve cell bodies were usually smaller than global strain measurements and correlated more closely with mechanosensitive firing. Both circumferential and longitudinal strain activated viscerofugal neurons. Simultaneous loading in circumferential and longitudinal axes, caused the highest levels of viscerofugal neuron firing. Multiaxial strains, reflecting tissue shearing and changing area, linearly correlated with mechanosensory firing of viscerofugal neurons. Viscerofugal neurons were mechanically sensitive to both local circumferential and local longitudinal gut strain, and appear to lack directionality in their stretch sensitivity.
Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma Leads to Early Identification of At-Risk Individuals.
(American Academy of Ophthalmology, 2016-12-16) Souzeau, Emmanuelle; Tram, Kien Hou; Witney, Martin; Ruddle, Jonathan B; Graham, Stuart L; Healey, Paul R; Goldberg, Ivan; Mackey, David A; Hewitt, Alex W; Burdon, Kathryn Penelope; Craig, Jamie E
Whole exome sequencing implicates eye development, the unfolded protein response and plasma membrane homeostasis in primary open-angle glaucoma.
(PLOS, 2017) Zhou, Tiger; Souzeau, Emmanuelle; Sharma, Shiwani; Landers, John; Mills, Richard Arthur; Goldberg, Ivan; Healey, Paul R; Graham, Stuart L; Hewitt, Alex W; Mackey, David A; Galanopoulos, Anna; Casson, Robert J; Ruddle, Jonathan; Ellis, Jonathan; Leo, Paul; Brown, Matthew A; MacGregor, Stuart; Lynn, David J; Burdon, Kathryn Penelope; Craig, Jamie E
Purpose: To identify biological processes associated with POAG and its subtypes, high-tension (HTG) and normal-tension glaucoma (NTG), by analyzing rare potentially damaging genetic variants. Methods: A total of 122 and 65 unrelated HTG and NTG participants, respectively, with early onset advanced POAG, 103 non-glaucoma controls and 993 unscreened ethnicity-matched controls were included in this study. Study participants without myocilin disease-causing variants and non-glaucoma controls were subjected to whole exome sequencing on an Illumina HiSeq2000. Exomes of participants were sequenced on an Illumina HiSeq2000. Qualifying variants were rare in the general population (MAF < 0.001) and potentially functionally damaging (nonsense, frameshift, splice or predicted pathogenic using SIFT or Polyphen2 software). Genes showing enrichment of qualifying variants in cases were selected for pathway and network analysis using InnateDB. Results: POAG cases showed enrichment of rare variants in camera-type eye development genes (p = 1.40×10-7, corrected p = 3.28×10-4). Implicated eye development genes were related to neuronal or retinal development. HTG cases were significantly enriched for key regulators in the unfolded protein response (UPR) (p = 7.72×10-5, corrected p = 0.013). The UPR is known to be involved in myocilin-related glaucoma; our results suggest the UPR has a role in non-myocilin causes of HTG. NTG cases showed enrichment in ion channel transport processes (p = 1.05×10-4, corrected p = 0.027) including calcium, chloride and phospholipid transporters involved in plasma membrane homeostasis. Network analysis also revealed enrichment of the MHC Class I antigen presentation pathway in HTG, and the EGFR1 and cell-cycle pathways in both HTG and NTG. Conclusion: This study suggests that mutations in eye development genes are enriched in POAG. HTG can result from aberrant responses to protein misfolding which may be amenable to molecular chaperone therapy. NTG is associated with impaired plasma membrane homeostasis increasing susceptibility to apoptosis.
New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.
(Oxford University Press, 2017-01) Springelkamp, Henriët; Iglesias, Adriana; Mishra, Aniket; Hohn, Rene; Wojciechowski, Robert; Khwaja, Anthony P; Nag, Abhishek; Wang, Ya Xing; Wang, Jie Jin; Cuellar-Partida, Gabriel; Gibson, Jane; Cooke-Bailey, Jessica N; Vithana, Eranga; Gharahkhani, Puya; Boutin, Thibaud; Ramdas, Wishal D; Zeller, Tanja; Luben, Robert N; Yonova-Doing, Ekaterina; Yazar, Seyhan; Cree, Angela J; Haines, Jonathan L; Koh, Jia Yu; Souzeau, Emmanuelle; Wilson, James F; Amin, Najaf; Muller, Christian; Venturini, Cristina; Kearns, Lisa S; Kang, Jae Hee; Tham, Yih Chung; Zhou, Tiger; van Leeuwen, Elisabeth M; NIckels, Stefan; Sanfilippo, Paul Gerard; Liao, Jiemin; van der Linde, Herma; Zhao, Wanting; van Koolwijk, Leonieke M E; Zheng, Li; Rivadeneira, Fernando; Baskaran, Mani; van der Lee, Sven J; Perera, Shamira; de Jong, Paulus T V M; Oostra, Ben A; Uitterlinden, Andre G; Fan, Qiao; Hofman, Albert; Tai, E-Shyong; Vingerling, Johannes R; Sim, Xueling; Wolfs, Roger C W; Teo, Yik Ying; Lemij, Hans G; Khor, Chiea Chuen; Willemsen, Rob; Lackner, Karl J; Aung, Tin; Jansonius, Nomdo M; Montgomery, Grant W; Wild, Philipp S; Young, Terri L; Burdon, Kathryn Penelope; Hysi, Pirro G; Pasquale, Louis R; Wong, Tien Yin; Klaver, Caroline C W; Hewitt, Alex W; Jonas, Jost B; Mitchell, Paul; Lotery, Andrew J; Foster, Paul J; Vitart, Veronique; Pfeiffer, Norbert; Craig, Jamie E; Mackey, David A; Hammond, Christopher J; Wiggs, Janey L; Cheng, Ching-Yu; van Duijin, Cornelia M; MacGregor, Stuart; Viswanathan, Ananth C
Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increase 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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