ORCID Profile
0000-0003-0104-5406
Current Organisation
University of Tasmania
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Publisher: Springer Science and Business Media LLC
Date: 14-05-2018
DOI: 10.1038/S41467-018-03646-6
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, % of the CCT-loci are near or within Mendelian disorder genes. These included FBN1 , ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus ( r = −0.62, P = 5.30 × 10 −5 ) but not between CCT and primary open-angle glaucoma ( r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Publisher: American Medical Association (AMA)
Date: 02-2020
Publisher: Elsevier BV
Date: 05-2023
Publisher: Cold Spring Harbor Laboratory
Date: 13-04-2022
DOI: 10.1101/2022.04.11.22273677
Abstract: Knowledge of rare, inherited variants in DNA damage repair (DDR) genes is informing clinical management in common cancers. However, defining the rare disease- associated variants in prostate cancer (PrCa) is challenging due to their low frequency. Here, whole-genome and -exome sequencing data from two independent, high- risk Australian and North American familial PrCa datasets were interrogated for novel, rare DDR variants. Segregating, high-risk, likely pathogenic DDR gene variants were identified and subsequently genotyped in 1,963 in iduals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls) and association analyses performed accounting for relatedness (M QLS ). Rare variants significantly associated with PrCa risk were identified in ERCC3 (rs145201970, p=2.57×10 −4 ) and BRIP1 (rs4988345, p=0.025) in the combined datasets. A PARP2 (rs200603922, p=0.028) variant in the Australian dataset and a MUTYH (rs36053993, p=0.031) variant in the North American dataset were also associated with PrCa risk. No evidence for a younger age or higher-grade disease at diagnosis was evident in variant carriers. Here, we provide new evidence for four novel germline DDR PrCa risk variants. Defining the full spectrum of PrCa associated DDR genes is important for effective clinical screening and disease management.
Publisher: Public Library of Science (PLoS)
Date: 20-06-2018
Publisher: Wiley
Date: 16-05-2018
DOI: 10.1002/MGG3.406
Publisher: Springer Science and Business Media LLC
Date: 03-2021
DOI: 10.1038/S42003-021-01784-0
Abstract: Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.
Publisher: Annual Reviews
Date: 15-09-2020
DOI: 10.1146/ANNUREV-VISION-121219-081723
Abstract: Keratoconus, a progressive corneal ectasia, is a complex disease with both genetic and environmental risk factors. The exact etiology is not known and is likely variable between in iduals. Conditions such as hay fever and allergy are associated with increased risk, while diabetes may be protective. Behaviors such as eye rubbing are also implicated, but direct causality has not been proven. Genetics plays a major role in risk for some in iduals, with many large pedigrees showing autosomal inheritance patterns. Several genes have been implicated using linkage and follow-up sequencing in these families. Genome-wide association studies for keratoconus and for quantitative traits such as central corneal thickness have identified several genetic loci that contribute to a cumulative risk for keratoconus, even in people without a family history of the disease. Identification of risk genes for keratoconus is improving our understanding of the biology of this complex disease.
Publisher: Cold Spring Harbor Laboratory
Date: 28-04-2022
DOI: 10.1101/2022.04.27.22274348
Abstract: Family history is amongst the strongest risk factors for interstitial lung disease (ILD), with emerging evidence for a shared genetic aetiology across ILD subtypes. Recruited families comprised at least two first-degree relatives who had been previously diagnosed with an ILD. All living cases and available unaffected first-degree relatives underwent a clinical examination for evidence of ILD. Preclinical ILD was diagnosed in 47.7% of first-degree relatives who had previously self-reported as unaffected. This study highlights the strong genetic predisposition in family members of ILD cases, and supports the call for routine screening of in iduals with a family history of ILD.
No related grants have been discovered for Sionne Lucas.