Publications by authors named "Puya Gharahkhani"

76 Publications

Assessing the genetic relationship between gastro-esophageal reflux disease and risk of COVID-19 infection.

Hum Mol Genet 2021 Sep 6. Epub 2021 Sep 6.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Brisbane, Australia.

Background: Symptoms related with Gastro-esophageal reflux disease (GERD) were previously shown to be linked with increased risk for the 2019 coronavirus disease (COVID-19). We aim to interrogate the possibility of a shared genetic basis between GERD and COVID-19 outcomes.

Methods: Using published GWAS data for GERD (78 707 cases; 288 734 controls) and COVID-19 susceptibility (up to 32 494 cases; 1.5 million controls), we examined the genetic relationship between GERD and three COVID-19 outcomes: risk of developing severe COVID-19, COVID-19 hospitalization and overall COVID-19 risk. We estimated the genetic correlation between GERD and COVID-19 outcomes followed by Mendelian randomization (MR) analyses to assess genetic causality. Conditional analyses were conducted to examine whether known COVID-19 risk factors (obesity, smoking, type-II diabetes, coronary artery disease) can explain the relationship between GERD and COVID-19.

Results: We found small to moderate genetic correlations between GERD and COVID-19 outcomes (rg between 0.06-0.24). MR analyses revealed a OR of 1.15 (95% CI: 0.96-1.39) for severe COVID-19; 1.16 (1.01-1.34) for risk of COVID-19 hospitalization; 1.05 (0.97-1.13) for overall risk of COVID-19 per doubling of odds in developing GERD. The genetic correlation/associations between GERD and COVID-19 showed mild attenuation towards the null when obesity and smoking was adjusted for.

Conclusions: Susceptibility for GERD and risk of COVID-19 hospitalization were genetically correlated, with MR findings supporting a potential causal role between the two. The genetic association between GERD and COVID-19 was partially attenuated when obesity is accounted for, consistent with obesity being a major risk factor for both diseases.
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http://dx.doi.org/10.1093/hmg/ddab253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522419PMC
September 2021

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.

HGG Adv 2021 Jul 12;2(3). Epub 2021 Jun 12.

Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the and genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
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http://dx.doi.org/10.1016/j.xhgg.2021.100041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336922PMC
July 2021

Association of Monogenic and Polygenic Risk With the Prevalence of Open-Angle Glaucoma.

JAMA Ophthalmol 2021 Sep;139(9):1023-1028

Department of Ophthalmology, Flinders University, Bedford Park, Australia.

Importance: Early diagnosis of open-angle glaucoma can lead to vision-saving treatment, and genetic variation is an increasingly powerful indicator in disease risk stratification.

Objective: To compare polygenic and monogenic variants in risk of glaucoma.

Design, Setting, And Participants: Clinical and genetic data were obtained for 2507 individuals from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) and 411 337 individuals in cross-sectional cohort studies including individuals of European ancestry in the UK Biobank. Recruitment to the UK Biobank occurred between 2006 and 2010, and data analysis occurred between September 2019 and August 2020.

Main Outcomes And Measures: Association of monogenic and polygenic variants with glaucoma risk.

Results: Individuals at high polygenic risk, defined as those in the top 5% of an unselected population, had a glaucoma risk (odds ratio [OR], 2.77; 95% CI, 2.58-2.98) comparable with the risk among individuals heterozygous for the MYOC p.Gln368Ter variant (OR 4.19; 95% CI, 3.25-5.31), which is the most common single-gene variant known to cause primary open-angle glaucoma. High polygenic risk was more than 6 times more common than MYOC p.Gln368Ter heterozygosity in ANZRAG (15.7% vs 2.6%) and more than 15 times more common in the general population (5.0% vs 0.32%). Within ANZRAG, high polygenic risk was associated with a mean (SD) age at glaucoma diagnosis that did not differ from the age at glaucoma diagnosis among individuals heterozygous for MYOC p.Gln368Ter (57.2 [14.2] vs 54.8 [13.6] years; P > .99).

Conclusions And Relevance: Monogenic and high polygenic risk were each associated with a more than 2.5-fold increased odds of developing glaucoma and an equivalent mean age at glaucoma diagnosis, with high polygenic risk more than 15 times more common in the general population.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.2440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283675PMC
September 2021

Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett's oesophagus and provides insights into clinical heterogeneity in reflux diagnosis.

Gut 2021 Jun 29. Epub 2021 Jun 29.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

Objective: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.

Design: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).

Results: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.

Conclusion: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.
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http://dx.doi.org/10.1136/gutjnl-2020-323906DOI Listing
June 2021

Identification of a Locus Near Associated With Progression-Free Survival in Ovarian Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Sep 23;30(9):1669-1680. Epub 2021 Jun 23.

Gynecologic Oncology Center, Kiel, Germany.

Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.

Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.

Results: We found seven SNPs at 12q24.33 associated with PFS ( < 5 × 10), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; = 1.47 × 10). High expression of a nearby gene, , is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin .

Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. is a plausible candidate for the target of this association.

Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options..
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419101PMC
September 2021

Polygenic Risk Scores Stratify Keratinocyte Cancer Risk among Solid Organ Transplant Recipients with Chronic Immunosuppression in a High Ultraviolet Radiation Environment.

J Invest Dermatol 2021 Jun 2. Epub 2021 Jun 2.

Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia.

Solid organ transplant recipients (SOTRs) have elevated risks for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), especially in high UVR environments. We assessed whether polygenic risk scores can improve the prediction of BCC and SCC risks and multiplicity over and above the traditional risk factors in SOTRs in a high UV setting. We built polygenic risk scores for BCC (n = 594,881) and SCC (n = 581,431) using UK Biobank and 23andMe datasets, validated them in the Australian QSkin Sun and Health Study cohort (n > 6,300), and applied them in SOTRs in the skin tumor in allograft recipients cohort from Queensland, Australia, a high UV environment. About half of the SOTRs with a high genetic risk developed BCC (absolute risk = 45.45%, 95% confidence interval = 33.14-58.19%) and SCC (absolute risk = 44.12%, 95% confidence interval = 32.08-56.68%). For both cancers, SOTRs in the top quintile were at >3-fold increased risk relative to those in the bottom quintile. The respective polygenic risk scores improved risk predictions by 2% for BCC (area under the curve = 0.77 vs. 0.75, P = 0.0691) and SCC (area under the curve = 0.84 vs. 0.82, P = 0.0260), over and above the established risk factors, and 19.03% (for BCC) and 18.10% (for SCC) of the SOTRs were reclassified in a high/medium/low risk scenario. The polygenic risk scores also added predictive accuracy for tumor multiplicity (BCC R = 0.21 vs. 0.19, P = 3.2 × 10; SCC R = 0.30 vs. 0.27, P = 4.6 × 10).
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http://dx.doi.org/10.1016/j.jid.2021.03.034DOI Listing
June 2021

Polyunsaturated Fatty Acid Levels and the Risk of Keratinocyte Cancer: A Mendelian Randomization Analysis.

Cancer Epidemiol Biomarkers Prev 2021 Aug 4;30(8):1591-1598. Epub 2021 Jun 4.

Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Background: Keratinocyte cancer is the commonest cancer, imposing a high economic burden on the health care system. Observational studies have shown mixed associations between polyunsaturated fatty acids (PUFA) and keratinocyte cancer, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). We explored whether genetically predicted PUFA levels are associated with BCC and SCC risks.

Methods: We conducted a two-sample Mendelian randomization study using PUFA level genome-wide association studies (GWAS) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium ( > 8,000), and the meta-analysis GWASs from UKB, 23andMe, and Qskin for BCC ( = 651,138) and SCC ( = 635,331) risk.

Results: One SD increase in genetically predicted levels of linoleic acid [OR = 0.94, 95% confidence interval (CI) = 0.91-0.97, = 1.4 × 10] and alpha-linolenic acid (OR = 0.91, 95% CI = 0.86-0.96, = 5.1 × 10) was associated with a reduced BCC risk, while arachidonic acid (OR = 1.04, 95% CI = 1.02-1.06, = 3.2 × 10) and eicosapentaenoic acid (OR = 1.10, 95% CI = 1.04-1.16, = 1.5 × 10) were associated with an increased BCC risk.

Conclusions: Higher genetically predicted levels of linoleic acid and alpha-linolenic acid were associated with a reduced BCC risk, but arachidonic acid and eicosapentaenoic acid were associated with a higher BCC risk.

Impact: PUFA-related diet and supplementation could influence BCC etiology.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1765DOI Listing
August 2021

Automated AI labeling of optic nerve head enables insights into cross-ancestry glaucoma risk and genetic discovery in >280,000 images from UKB and CLSA.

Am J Hum Genet 2021 07 1;108(7):1204-1216. Epub 2021 Jun 1.

Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, Brisbane, Herston, QLD 4006, Australia.

Cupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach, we perform a systematic comparison of the distribution of VCDR and VDD and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI-based gradings increased estimates of heritability by ∼50% for VCDR and VDD. Our GWAS identified more than 200 loci associated with both VCDR and VDD (double the number of loci from previous studies) and uncovered dozens of biological pathways; many of the loci we discovered also confer risk for glaucoma.
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http://dx.doi.org/10.1016/j.ajhg.2021.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322932PMC
July 2021

Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images.

PLoS Genet 2021 05 12;17(5):e1009497. Epub 2021 May 12.

School of Life Course Sciences, Section of Ophthalmology, King's College London, London, United Kingdom.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.
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http://dx.doi.org/10.1371/journal.pgen.1009497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143408PMC
May 2021

Normal-tension glaucoma is associated with cognitive impairment.

Br J Ophthalmol 2021 Mar 29. Epub 2021 Mar 29.

Ophthalmology, Flinders University, Adelaide, South Australia, Australia.

Background/aims: Recent research suggests an association between normal-tension glaucoma (NTG) and dementia. This study investigated whether cognitive impairment is more strongly associated with NTG than high tension glaucoma (HTG) using cognitive screening within an Australiasian Glaucoma Disease Registry.

Methods: The authors completed a case-control cross-sectional cognitive screening involving 290 age-matched and sex-matched NTG participants and HTG controls aged ≥65 randomly sampled from the Australian and New Zealand Registry of Advanced Glaucoma. Cognitive screening was performed using the Telephone Version of the Montreal Cognitive Assessment (T-MoCA). The T-MoCA omits points requiring visual interpretation, accounting for confounding factors related to vision loss in visually impaired participants. Cognitive impairment was defined by a T-MoCA score of <11/22. Cognition was compared between NTG and HTG participants using predetermined thresholds and absolute screening scores.

Results: A total of 290 participants completed cognitive assessment. There were no differences in NTG (n=144) and HTG (n=146) cohort demographics or ocular parameters at baseline. Cognitive impairment was more prevalent in the NTG cohort than the HTG cohort (OR=2.2; 95% CI 1.1 to 6.7, p=0.030). Though a linear trend was also observed between lower absolute T-MoCA scores in the NTG cohort when compared with the HTG cohort, this association was not statistically significant (p=0.108).

Conclusion: This study demonstrated an association between NTG status and poor cognition, supporting the hypothesis that there exists a disease association and shared pathoaetiological features between NTG and dementia.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317461DOI Listing
March 2021

Characteristics of p.Gln368Ter Myocilin Variant and Influence of Polygenic Risk on Glaucoma Penetrance in the UK Biobank.

Ophthalmology 2021 Sep 10;128(9):1300-1311. Epub 2021 Mar 10.

Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; Ocular Genomics Institute, Harvard Medical School, Boston, Massachusetts.

Purpose: MYOC (myocilin) mutations account for 3% to 5% of primary open-angle glaucoma (POAG) cases. We aimed to understand the true population-wide penetrance and characteristics of glaucoma among individuals with the most common MYOC variant (p.Gln368Ter) and the impact of a POAG polygenic risk score (PRS) in this population.

Design: Cross-sectional population-based study.

Participants: Individuals with the p.Gln368Ter variant among 77 959 UK Biobank participants with fundus photographs (FPs).

Methods: A genome-wide POAG PRS was computed, and 2 masked graders reviewed FPs for disc-defined glaucoma (DDG).

Main Outcome Measures: Penetrance of glaucoma.

Results: Two hundred individuals carried the p.Gln368Ter heterozygous genotype, and 177 had gradable FPs. One hundred thirty-two showed no evidence of glaucoma, 45 (25.4%) had probable/definite glaucoma in at least 1 eye, and 19 (10.7%) had bilateral glaucoma. No differences were found in age, race/ethnicity, or gender among groups (P > 0.05). Of those with DDG, 31% self-reported or had International Classification of Diseases codes for glaucoma, whereas 69% were undiagnosed. Those with DDG had higher medication-adjusted cornea-corrected intraocular pressure (IOPcc) (P < 0.001) vs. those without glaucoma. This difference in IOPcc was larger in those with DDG with a prior glaucoma diagnosis versus those not diagnosed (P < 0.001). Most p.Gln368Ter carriers showed IOP in the normal range (≤21 mmHg), although this proportion was lower in those with DDG (P < 0.02) and those with prior glaucoma diagnosis (P < 0.03). Prevalence of DDG increased with each decile of POAG PRS. Individuals with DDG demonstrated significantly higher PRS compared with those without glaucoma (0.37 ± 0.97 vs. 0.01 ± 0.90; P = 0.03). Of those with DDG, individuals with a prior diagnosis of glaucoma had higher PRS compared with undiagnosed individuals (1.31 ± 0.64 vs. 0.00 ± 0.81; P < 0.001) and 27.5 times (95% confidence interval, 2.5-306.6) adjusted odds of being in the top decile of PRS for POAG.

Conclusions: One in 4 individuals with the MYOC p.Gln368Ter mutation demonstrated evidence of glaucoma, a substantially higher penetrance than previously estimated, with 69% of cases undetected. A large portion of p.Gln368Ter carriers, including those with DDG, have IOP in the normal range, despite similar age. Polygenic risk score increases disease penetrance and severity, supporting the usefulness of PRS in risk stratification among MYOC p.Gln368Ter carriers.
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http://dx.doi.org/10.1016/j.ophtha.2021.03.007DOI Listing
September 2021

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Nat Commun 2021 02 24;12(1):1258. Epub 2021 Feb 24.

Faculty of Medicine, University of Southampton, Southampton, UK.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
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http://dx.doi.org/10.1038/s41467-020-20851-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904932PMC
February 2021

A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization.

Nat Commun 2021 01 11;12(1):246. Epub 2021 Jan 11.

Statistical Genetics Group, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD, 4006, Australia.

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.
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http://dx.doi.org/10.1038/s41467-020-20368-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801600PMC
January 2021

A Polygenic Risk Score Predicts Intraocular Pressure Readings Outside Office Hours and Early Morning Spikes as Measured by Home Tonometry.

Ophthalmol Glaucoma 2021 Jul-Aug;4(4):411-420. Epub 2020 Dec 11.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, Australia.

Purpose: Intraocular pressure (IOP) elevations may occur in early morning or outside office hours and can be missed during routine in-clinic IOP measurements. Such fluctuations or peaks likely contribute to glaucoma progression. We sought to investigate the relationship between an IOP polygenic risk score (PRS) and short-term IOP profile.

Design: Cross-sectional study.

Participants: Four hundred seventy-three eyes from 239 participants with suspected or established primary open-angle glaucoma sampled from 4 outpatient clinics in Australia between August 2016 and December 2019.

Methods: Participants underwent Icare HOME (Icare Oy, Vanda, Finland) tonometer measurements to record IOP 4 times daily for 5 days. Unreliable measurements were excluded. A minimum of 2 days with at least 3 reliable measurements were required. We used a validated IOP PRS derived from 146 IOP-associated variants in a linear regression model adjusted for central corneal thickness and age.

Main Outcome Measures: Highest recorded early morning IOP and mean IOP within and outside office hours. Early morning IOP spikes were defined by a higher early morning IOP than the maximum in-office hours IOP.

Results: Reliable measurements were obtained from 334 eyes of 176 participants (mean age, 64 ± 9 years). Eyes in the highest IOP PRS quintile showed an early morning IOP increase of 4.3 mmHg (95% confidence interval [CI], 1.4-7.3; P = 0.005) and mean increase in IOP outside office hours of 2.7 mmHg (95% CI, 0.61-4.7; P = 0.013) than the lowest quintile, which were significant independently after accounting for a recent in-clinic IOP measured by Goldmann applanation tonometry. Eyes in the highest PRS quintile were 5.4-fold more likely to show early morning IOP spikes than the lowest quintile (odds ratio 95% CI, 1.3-23.6; P = 0.023).

Conclusions: A validated IOP PRS was associated with higher early morning IOP and mean IOP outside office hours. These findings support a role for genetic risk prediction of susceptibility to elevated IOP that may not be apparent during in-clinic hours, requiring more detailed clinical phenotyping using home tonometry, the results of which may guide additional interventions to improve IOP control.
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http://dx.doi.org/10.1016/j.ogla.2020.12.002DOI Listing
December 2020

Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.

Carcinogenesis 2021 04;42(3):369-377

Department of Medicine, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK.

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.
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http://dx.doi.org/10.1093/carcin/bgaa132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052954PMC
April 2021

The effects of eight serum lipid biomarkers on age-related macular degeneration risk: a Mendelian randomization study.

Int J Epidemiol 2021 03;50(1):325-336

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Background: Age-related macular degeneration (AMD) is a leading cause of vision loss. Whereas lipids have been studied extensively to understand their effects on cardiovascular diseases, their relationship with AMD remains unclear.

Methods: Two-sample Mendelian randomization (MR) analyses were performed to systematically evaluate the causal relationships between eight serum lipid biomarkers, consisting of apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], triglycerides (TG) and non-HDL cholesterol (non-HDL-C), and the risk of different AMD stages and subtypes. We derived 64-407 genetic instruments for eight serum lipid biomarkers in 419 649 participants of European descent from the UK Biobank cohort. We conducted genome-wide association studies (GWAS) for 12 711 advanced AMD cases [8544 choroidal neovascularization (CNV) and 2656 geographic atrophy (GA) specific AMD subtypes] and 5336 intermediate AMD cases with 14 590 controls of European descent from the International AMD Genomics Consortium.

Results: Higher genetically predicted HDL-C and ApoA1 levels increased the risk of all AMD subtypes. LDL-C, ApoB, CHOL and non-HDL-C levels were associated with decreased risk of intermediate and GA AMD but not with CNV. Genetically predicted TG levels were associated with decreased risk of different AMD subtypes. Sensitivity analyses revealed no evidence for directional pleiotropy effects. In our multivariable MR analyses, adjusting for the effects of correlated lipid biomarkers yielded similar results.

Conclusion: These results suggest the role of lipid metabolism in drusen formation and particularly in AMD development at the early and intermediate stages. Mechanistic studies are warranted to investigate the utility of lipid pathways for therapeutic treatment in preventing AMD.
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http://dx.doi.org/10.1093/ije/dyaa178DOI Listing
March 2021

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma.

Gastroenterology 2020 12 9;159(6):2065-2076.e1. Epub 2020 Sep 9.

Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Germany.

Background & Aims: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored.

Methods: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits.

Results: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals.

Conclusions: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.
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http://dx.doi.org/10.1053/j.gastro.2020.08.052DOI Listing
December 2020

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Nat Commun 2020 07 3;11(1):3353. Epub 2020 Jul 3.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
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http://dx.doi.org/10.1038/s41467-020-16483-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335068PMC
July 2020

Polygenic Risk Scores Allow Risk Stratification for Keratinocyte Cancer in Organ-Transplant Recipients.

J Invest Dermatol 2021 02 29;141(2):325-333.e6. Epub 2020 Jun 29.

Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.

Organ-transplant recipients have an elevated risk of keratinocyte cancers: basal cell carcinoma (BCC) and squamous cell carcinoma. We assessed whether polygenic risk scores (PRSs) generated in nontransplantees from the UK Biobank and 23andMe (13,981 squamous cell carcinoma, 33,736 BCC, and >560,000 controls) can predict keratinocyte cancer risk in an independent organ-transplant recipient cohort. After adjusting for traditional risk factors, compared with the bottom 20%, organ-transplant recipients in the top 20% PRS had an increased risk of BCC (OR = 3.25, 95% confidence interval = 1.44-7.31, P = 4.4 × 10) and squamous cell carcinoma (OR = 2.11, 95% confidence interval = 0.98-4.53, P = 0.055). For BCC, the top 20% PRS individuals had an absolute risk of 23%, whereas the risk in the bottom 20% was similar to that in the general nontransplantee population. Adding PRS to a model containing traditional skin cancer risk factors yielded a 3% increase in the area under the curve for receiver operating characteristic curve for BCC (0.73 vs. 0.70); adding the PRS did not significantly increase the area under the curve for receiver operating characteristic curve for squamous cell carcinoma. Organ-transplant recipients in the highest genetic risk quintile could benefit from more intense keratinocyte cancer screening and preventive strategies compared with their counterparts. The BCC PRS improves prediction over and above the traditional skin cancer risk factors by 3%.
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http://dx.doi.org/10.1016/j.jid.2020.06.017DOI Listing
February 2021

Association of Myopia and Intraocular Pressure With Retinal Detachment in European Descent Participants of the UK Biobank Cohort: A Mendelian Randomization Study.

JAMA Ophthalmol 2020 06;138(6):671-678

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Importance: Rhegmatogenous retinal detachment is a potentially sight-threatening condition. The role of myopia or intraocular pressure (IOP) in retinal detachment remains unclear.

Objective: To determine if myopia or IOP is associated with retinal detachment risk using genetic data.

Design, Setting, And Participants: Observational analyses and 2-sample mendelian randomization were used to evaluate the associations between myopia, IOP, and retinal detachment risk in European descent participants from the UK Biobank (UKBB) cohort (n = 405 692). For retinal detachment, a genome-wide association study on 4257 cases and 39 181 controls in the UKBB was conducted. Genetic variants associated with mean spherical equivalent (MSE) refractive error (n = 95 827) and IOP (n = 101 939) were derived using independent participants from the retinal detachment genome-wide association study. Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from February 2019 to March 2020.

Main Outcomes And Measures: The odds ratio (OR) of retinal detachment caused by per-unit increases in MSE refractive error (in diopters [D]) and IOP (in mm Hg).

Results: Of the 405 692 participants in the UKBB cohort, the mean (SD) age was 56.87 (7.96) years, the mean (SD) MSE was -0.31 (2.65) D, the mean (SD) corneal-compensated IOP was 16.05 (3.49) mm Hg, and 4253 participants (1.0%) had retinal detachment. Genetic analyses of the 4257 cases and 39 181 controls identified 2 novel retinal detachment genes: COL22A1 (lead single-nucleotide variant rs11992725; P = 4.8 × 10-10) and FAT3 (lead single-nucleotide variant rs10765568; P = 1.2 × 10-15). Genetically assessed MSE refractive error was negatively associated with retinal detachment (per-unit [D] increase in MSE refractive error: OR, 0.72; 95% CI, 0.69-0.76; P = 3.8 × 10-44). For each 6-D decrease in MSE refractive error (representing the move of refractive error from emmetropia to high myopia), retinal detachment risk increased 7.2-fold (95% CI, 5.19-9.27). For per-unit (mm Hg) genetically assessed increase in IOP, the risk of retinal detachment increased by 8% (OR, 1.08; 95% CI, 1.03-1.14; P = .001).

Conclusions And Relevance: This study provides genetic support for the assertion that myopia and IOP are associated with the risk of retinal detachment and that myopia prevention efforts may help prevent retinal detachment.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.1231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193520PMC
June 2020

Genome-wide meta-analysis identifies novel loci associated with age-related macular degeneration.

J Hum Genet 2020 Aug 10;65(8):657-665. Epub 2020 Apr 10.

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly population. To accelerate the understanding of the genetics of AMD, we conducted a meta-analysis of genome-wide association studies (GWAS) combining data from the International AMD Genomics Consortium AMD-2016 GWAS (16,144 advanced AMD cases and 17,832 controls), AMD-2013 GWAS (17,181 cases and 60,074 controls), and new data on 4017 AMD cases and 14,984 controls from Genetic Epidemiology Research on Aging study. We identified 12 novel AMD loci near or within C4BPA-CD55, ZNF385B, ZBTB38, NFKB1, LINC00461, ADAM19, CPN1, ACSL5, CSK, RLBP1, CLUL1, and LBP. We then replicated the associations of the novel loci in independent cohorts, UK Biobank (5860 cases and 126,726 controls) and FinnGen (1266 cases and 47,560 control). In general, the concordance in effect sizes was very high (correlation in effect size estimates 0.89), 11 of 12 novel loci were in the expected direction, 5 were associated with AMD at a nominal significance level, and rs3825991 (near gene RLBP1) after Bonferroni correction. We identified an additional 21 novel genes using a gene-based test. Most of the novel genes are expressed in retinal tissue and could be involved in the pathogenesis of AMD (i.e., complement, inflammation, and lipid pathways). These findings enhance our understanding of the genetic architecture of AMD and shed light on the biological process underlying AMD pathogenesis.
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http://dx.doi.org/10.1038/s10038-020-0750-xDOI Listing
August 2020

Author Correction: Understanding the role of bitter taste perception in coffee, tea and alcohol consumption through Mendelian randomization.

Sci Rep 2020 Mar 11;10(1):4778. Epub 2020 Mar 11.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-60488-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066143PMC
March 2020

An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity.

Ophthalmology 2020 07 7;127(7):901-907. Epub 2020 Jan 7.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, Australia.

Purpose: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification.

Design: Cross-sectional study.

Participants: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients.

Methods: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group.

Main Outcome Measures: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity.

Results: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01).

Conclusions: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.
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http://dx.doi.org/10.1016/j.ophtha.2019.12.025DOI Listing
July 2020

Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression.

Nat Genet 2020 02 20;52(2):160-166. Epub 2020 Jan 20.

Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.
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http://dx.doi.org/10.1038/s41588-019-0556-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056672PMC
February 2020

Using Mendelian randomization to evaluate the causal relationship between serum C-reactive protein levels and age-related macular degeneration.

Eur J Epidemiol 2020 Feb 3;35(2):139-146. Epub 2020 Jan 3.

Statistical Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Serum C-reactive protein (CRP), an important inflammatory marker, has been associated with age-related macular degeneration (AMD) in observational studies; however, the findings are inconsistent. It remains unclear whether the association between circulating CRP levels and AMD is causal. We used two-sample Mendelian randomization (MR) to evaluate the potential causal relationship between serum CRP levels and AMD risk. We derived genetic instruments for serum CRP levels in 418,642 participants of European ancestry from UK Biobank, and then conducted a genome-wide association study for 12,711 advanced AMD cases and 14,590 controls of European descent from the International AMD Genomics Consortium. Genetic variants which predicted elevated serum CRP levels were associated with advanced AMD (odds ratio [OR] for per standard deviation increase in serum CRP levels: 1.31, 95% confidence interval [CI]: 1.19-1.44, P = 5.2 × 10). The OR for the increase in advanced AMD risk when moving from low (< 3 mg/L) to high (> 3 mg/L) CRP levels is 1.29 (95% CI: 1.17-1.41). Our results were unchanged in sensitivity analyses using MR models which make different modelling assumptions. Our findings were broadly similar across the different forms of AMD (intermediate AMD, choroidal neovascularization, and geographic atrophy). We used multivariable MR to adjust for the effects of other potential AMD risk factors including smoking, body mass index, blood pressure and cholesterol; this did not alter our findings. Our study provides strong genetic evidence that higher circulating CRP levels lead to increases in risk for all forms of AMD. These findings highlight the potential utility for using circulating CRP as a biomarker in future trials aimed at modulating AMD risk via systemic therapies.
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http://dx.doi.org/10.1007/s10654-019-00598-zDOI Listing
February 2020

Genome-wide association analysis of 95 549 individuals identifies novel loci and genes influencing optic disc morphology.

Hum Mol Genet 2019 11;28(21):3680-3690

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Optic nerve head morphology is affected by several retinal diseases. We measured the vertical optic disc diameter (DD) of the UK Biobank (UKBB) cohort (N = 67 040) and performed the largest genome-wide association study (GWAS) of DD to date. We identified 81 loci (66 novel) for vertical DD. We then replicated the novel loci in International Glaucoma Genetic Consortium (IGGC, N = 22 504) and European Prospective Investigation into Cancer-Norfolk (N = 6005); in general the concordance in effect sizes was very high (correlation in effect size estimates 0.90): 44 of the 66 novel loci were significant at P < 0.05, with 19 remaining significant after Bonferroni correction. We identified another 26 novel loci in the meta-analysis of UKBB and IGGC data. Gene-based analyses identified an additional 57 genes. Human ocular tissue gene expression analysis showed that most of the identified genes are enriched in optic nerve head tissue. Some of the identified loci exhibited pleiotropic effects with vertical cup-to-disc ratio, intraocular pressure, glaucoma and myopia. These results can enhance our understanding of the genetics of optic disc morphology and shed light on the genetic findings for other ophthalmic disorders such as glaucoma and other optic nerve diseases.
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http://dx.doi.org/10.1093/hmg/ddz193DOI Listing
November 2019

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters.

Commun Biol 2019 27;2:435. Epub 2019 Nov 27.

1Department of Ophthalmology, Erasmus MC, Rotterdam, The Netherlands.

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in and rs1028727 near at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.
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http://dx.doi.org/10.1038/s42003-019-0634-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881308PMC
July 2020

Shared Genetic Etiology of Obesity-Related Traits and Barrett's Esophagus/Adenocarcinoma: Insights from Genome-Wide Association Studies.

Cancer Epidemiol Biomarkers Prev 2020 02 20;29(2):427-433. Epub 2019 Nov 20.

Centre of Urban Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, University of Essen, Essen, Germany.

Background: Obesity is a major risk factor for esophageal adenocarcinoma (EA) and its precursor Barrett's esophagus (BE). Research suggests that individuals with high genetic risk to obesity have a higher BE/EA risk. To facilitate understanding of biological factors that lead to progression from BE to EA, the present study investigated the shared genetic background of BE/EA and obesity-related traits.

Methods: Cross-trait linkage disequilibrium score regression was applied to summary statistics from genome-wide association meta-analyses on BE/EA and on obesity traits. Body mass index (BMI) was used as a proxy for general obesity, and waist-to-hip ratio (WHR) for abdominal obesity. For single marker analyses, all genome-wide significant risk alleles for BMI and WHR were compared with summary statistics of the BE/EA meta-analyses.

Results: Sex-combined analyses revealed a significant genetic correlation between BMI and BE/EA ( = 0.13, = 2 × 10) and a of 0.12 between WHR and BE/EA ( = 1 × 10). Sex-specific analyses revealed a pronounced genetic correlation between BMI and EA in females ( = 0.17, = 1.2 × 10), and WHR and EA in males ( = 0.18, = 1.51 × 10). On the single marker level, significant enrichment of concordant effects was observed for BMI and BE/EA risk variants ( = 8.45 × 10) and WHR and BE/EA risk variants ( = 2 × 10).

Conclusions: Our study provides evidence for sex-specific genetic correlations that might reflect specific biological mecha-nisms. The data demonstrate that shared genetic factors are particularly relevant in progression from BE to EA.

Impact: Our study quantifies the genetic correlation between BE/EA and obesity. Further research is now warranted to elucidate these effects and to understand the shared pathophysiology.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0374DOI Listing
February 2020
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