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101. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Author: Tedja, Milly S, Wojciechowski, Robert, Hysi, Pirro G, Eriksson, Nicholas, Furlotte, Nicholas A, Verhoeven, Virginie J M, Iglesias, Adriana I, Meester-Smoor, Magda A, Tompson, Stuart W, Fan, Qiao, Khawaja, Anthony P, Cheng, Ching-Yu, Höhn, René, Yamashiro, Kenji, Wenocur, Adam, Grazal, Clare, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Jonas, Jost B, Wang, Ya Xing, Xie, Jing, Mitchell, Paul, Foster, Paul J, Klein, Barbara E K, Klein, Ronald, Paterson, Andrew D, Hosseini, S Mohsen, Shah, Rupal L, Williams, Cathy, Teo, Yik-Ying, Tham, Yih Chung, Gupta, Preeti, Zhao, Wanting, Shi, Yuan, Saw, Woei-Yuh, Tai, E-Shyong, Sim, Xue Ling, Huffman, Jennifer E, Polašek, Ozren, Hayward, Caroline, Bencic, Goran, Rudan, Igor, Wilson, James F, CREAM Consortium, Joshi, Peter K, Tsujikawa, Akitaka, Matsuda, Fumihiko, Whisenhunt, Kristina N, Zeller, Tanja, Van der Spek, P.J., Haak, R., Meijers-Heijboer, Hanne, van Leeuwen, Elisabeth M, Iyengar, Sudha K, Lass, J.H., Hofman, A., Rivadeneira, F., Uitterlinden, A.G., Vingerling, J.R., Lehtimaki, T., Raitakari, O.T., Biino, G., Concas, M.P., Schwantes-An, T.H., Igo, R.P., Cuellar-Partida, G., Martin, N.G., Craig, J.E., Gharahkhani, P., Williams, K.M., Naq, A., Rahi, J.S., Cumberland, P.M., Delcourt, C., Bellenquez, C., Ried, J.S., Bergen, Arthur A, Meitinger, T., Gieger, C., Wong, T.Y., Hewitt, A.W., Mackey, D.A., Simpson, C.L., Pfeiffer, N., Parssinen, O., Baird, P.N., Vitart, V., Amin, N., Van Duijn, C.M., Bailey-Wilson, J.E., Young, T.L., Saw, S.M., Stambolian, D., MacGregor, S., Guggenheim, J.A., Tung, J.Y., Hammond, C.J., Klaver, C.C.W., Tedja, Milly S, Wojciechowski, Robert, Hysi, Pirro G, Eriksson, Nicholas, Furlotte, Nicholas A, Verhoeven, Virginie J M, Iglesias, Adriana I, Meester-Smoor, Magda A, Tompson, Stuart W, Fan, Qiao, Khawaja, Anthony P, Cheng, Ching-Yu, Höhn, René, Yamashiro, Kenji, Wenocur, Adam, Grazal, Clare, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Jonas, Jost B, Wang, Ya Xing, Xie, Jing, Mitchell, Paul, Foster, Paul J, Klein, Barbara E K, Klein, Ronald, Paterson, Andrew D, Hosseini, S Mohsen, Shah, Rupal L, Williams, Cathy, Teo, Yik-Ying, Tham, Yih Chung, Gupta, Preeti, Zhao, Wanting, Shi, Yuan, Saw, Woei-Yuh, Tai, E-Shyong, Sim, Xue Ling, Huffman, Jennifer E, Polašek, Ozren, Hayward, Caroline, Bencic, Goran, Rudan, Igor, Wilson, James F, CREAM Consortium, Joshi, Peter K, Tsujikawa, Akitaka, Matsuda, Fumihiko, Whisenhunt, Kristina N, Zeller, Tanja, Van der Spek, P.J., Haak, R., Meijers-Heijboer, Hanne, van Leeuwen, Elisabeth M, Iyengar, Sudha K, Lass, J.H., Hofman, A., Rivadeneira, F., Uitterlinden, A.G., Vingerling, J.R., Lehtimaki, T., Raitakari, O.T., Biino, G., Concas, M.P., Schwantes-An, T.H., Igo, R.P., Cuellar-Partida, G., Martin, N.G., Craig, J.E., Gharahkhani, P., Williams, K.M., Naq, A., Rahi, J.S., Cumberland, P.M., Delcourt, C., Bellenquez, C., Ried, J.S., Bergen, Arthur A, Meitinger, T., Gieger, C., Wong, T.Y., Hewitt, A.W., Mackey, D.A., Simpson, C.L., Pfeiffer, N., Parssinen, O., Baird, P.N., Vitart, V., Amin, N., Van Duijn, C.M., Bailey-Wilson, J.E., Young, T.L., Saw, S.M., Stambolian, D., MacGregor, S., Guggenheim, J.A., Tung, J.Y., Hammond, C.J., and Klaver, C.C.W.
Abstract: Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.
Published: 2018

102. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: analysis in Two Large Datasets

Author: Bailey, JNC, Gharahkhani, P, Kang, JH, Butkiewicz, M, Sullivan, DA, Weinreb, RN, Aschard, H, Allingham, RR, Ashley-Koch, A, Lee, RK, Moroi, SE, Brilliant, MH, Wollstein, G, Schuman, JS, Fingert, JH, Budenz, DL, Realini, T, Gaasterland, T, Scott, WK, Singh, K, Sit, AJ, Igo, RP, Song, YE, Hark, L, Ritch, R, Rhee, DJ, Vollrath, D, Zack, DJ, Medeiros, F, Vajaranant, TS, Chasman, DI, Christen, WG, Pericak-Vance, MA, Liu, Y, Kraft, P, Richards, JE, Rosner, BA, Hauser, MA, Craig, JE, Burdon, KP, Hewitt, AW, Mackey, DA, Haines, JL, MacGregor, S, Wiggs, JL, Pasquale, LR, Bailey, JNC, Gharahkhani, P, Kang, JH, Butkiewicz, M, Sullivan, DA, Weinreb, RN, Aschard, H, Allingham, RR, Ashley-Koch, A, Lee, RK, Moroi, SE, Brilliant, MH, Wollstein, G, Schuman, JS, Fingert, JH, Budenz, DL, Realini, T, Gaasterland, T, Scott, WK, Singh, K, Sit, AJ, Igo, RP, Song, YE, Hark, L, Ritch, R, Rhee, DJ, Vollrath, D, Zack, DJ, Medeiros, F, Vajaranant, TS, Chasman, DI, Christen, WG, Pericak-Vance, MA, Liu, Y, Kraft, P, Richards, JE, Rosner, BA, Hauser, MA, Craig, JE, Burdon, KP, Hewitt, AW, Mackey, DA, Haines, JL, MacGregor, S, Wiggs, JL, and Pasquale, LR
Abstract: PURPOSE: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. METHODS: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). RESULTS: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. CONCLUSIONS: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.
Published: 2018

103. Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma

Author: Anderson, MG, King, R, Struebing, FL, Li, Y, Wang, J, Koch, AA, Bailey, JNC, Gharahkhani, P, MacGregor, S, Allingham, RR, Hauser, MA, Wiggs, JL, Geiser, EE, Anderson, MG, King, R, Struebing, FL, Li, Y, Wang, J, Koch, AA, Bailey, JNC, Gharahkhani, P, MacGregor, S, Allingham, RR, Hauser, MA, Wiggs, JL, and Geiser, EE
Abstract: Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10-6 for SNP rs7631
Published: 2018

104. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, and MacGregor, S
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, >20% 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.
Published: 2018

105. Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

Author: Gharahkhani, P, Burdon, KP, Bailey, JNC, Hewitt, AW, Law, MH, Pasquale, LR, Kang, JH, Haines, JL, Souzeau, E, Zhou, T, Siggs, OM, Landers, J, Awadalla, M, Sharma, S, Mills, RA, Ridge, B, Lynn, D, Casson, R, Graham, SL, Goldberg, I, White, A, Healey, PR, Grigg, J, Lawlor, M, Mitchell, P, Ruddle, J, Coote, M, Walland, M, Best, S, Vincent, A, Gale, J, RadfordSmith, G, Whiteman, DC, Montgomery, GW, Martin, NG, Mackey, DA, Wiggs, JL, MacGregor, S, Craig, JE, Gharahkhani, P, Burdon, KP, Bailey, JNC, Hewitt, AW, Law, MH, Pasquale, LR, Kang, JH, Haines, JL, Souzeau, E, Zhou, T, Siggs, OM, Landers, J, Awadalla, M, Sharma, S, Mills, RA, Ridge, B, Lynn, D, Casson, R, Graham, SL, Goldberg, I, White, A, Healey, PR, Grigg, J, Lawlor, M, Mitchell, P, Ruddle, J, Coote, M, Walland, M, Best, S, Vincent, A, Gale, J, RadfordSmith, G, Whiteman, DC, Montgomery, GW, Martin, NG, Mackey, DA, Wiggs, JL, MacGregor, S, and Craig, JE
Abstract: 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.
Published: 2018

106. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias Gonzalez, Adriana, Mishra, A, Vitart, V, Bykhovskaya, Y, Hohn, R, Springelkamp, Henriët, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, XH, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, Leeuwen, Elisa, Taylor, KD, Bonnemaijer, Pieter, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, André, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, Caroline, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, CY (Ching-Yu), Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, Duijn, Cornelia, Macgregor, S, Iglesias Gonzalez, Adriana, Mishra, A, Vitart, V, Bykhovskaya, Y, Hohn, R, Springelkamp, Henriët, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, XH, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, Leeuwen, Elisa, Taylor, KD, Bonnemaijer, Pieter, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, André, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, Caroline, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, CY (Ching-Yu), Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, Duijn, Cornelia, and Macgregor, S
Published: 2018

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

Author: Siggs, Owen M., Han, Xikun, Qassim, Ayub, Souzeau, Emmanuelle, Kuruvilla, Shilpa, Marshall, Henry N., Mullany, Sean, Mackey, David A., Hewitt, Alex W., Gharahkhani, Puya, MacGregor, Stuart, and Craig, Jamie E.
Abstract: 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.
Published: 2021
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108. Shared Genetic Etiology of Obesity-Related Traits and Barrett's Esophagus/Adenocarcinoma: Insights from Genome-Wide Association Studies.

Author: Böhmer, Anne C., Hecker, Julian, Schröder, Julia, Gharahkhani, Puya, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Hess, Timo, Kreuser, Nicole, Thieme, René, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Fuchs, Claudia, Izbicki, Jakob R., Hölscher, Arnulf H., Dietrich, Arne, and Moulla, Yusef
Abstract: 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 (rg = 0.13, P = 2 × 10-04) and a rg of 0.12 between WHR and BE/EA (P = 1 × 10-02). Sex-specific analyses revealed a pronounced genetic correlation between BMI and EA in females (rg = 0.17, P = 1.2 × 10-03), and WHR and EA in males (rg = 0.18, P = 1.51 × 10-02). On the single marker level, significant enrichment of concordant effects was observed for BMI and BE/EA risk variants (P = 8.45 × 10-03) and WHR and BE/EA risk variants (P = 2 × 10-02). 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. [ABSTRACT FROM AUTHOR]
Published: 2020
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109. Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Author: Iglesias, A.I., Lee, S.J. van der, Bonnemaijer, P.W.M., Hohn, R., Nag, A., Gharahkhani, P., Khawaja, A.P., Broer, L., Foster, P.J., Hammond, C.J., Hysi, P.G., Leeuwen, E.M. van, MacGregor, S., Mackey, D.A., Mazur, J., Nickels, S., Uitterlinden, A.G., Klaver, C.C.W., Amin, N., Duijn, C.M. van, Iglesias, A.I., Lee, S.J. van der, Bonnemaijer, P.W.M., Hohn, R., Nag, A., Gharahkhani, P., Khawaja, A.P., Broer, L., Foster, P.J., Hammond, C.J., Hysi, P.G., Leeuwen, E.M. van, MacGregor, S., Mackey, D.A., Mazur, J., Nickels, S., Uitterlinden, A.G., Klaver, C.C.W., Amin, N., and Duijn, C.M. van
Abstract: Contains fulltext : 177754.pdf (Publisher’s version ) (Open Access), Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 x 10-61 ), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers.
Published: 2017

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

Author: Springelkamp, H. (Henriët), Iglesias, A.I. (Adriana), Mishra, A. (Aniket), Höhn, R. (René), Wojciechowski, R. (Robert), Khawaja, A.P. (Anthony), Nag, A. (Abhishek), Wang, Y.X. (Ya Xing), Wang, J.J. (Jie Jin), Cuellar-Partida, G. (Gabriel), Gibson, J. (Jane), Cooke Bailey, J.N. (Jessica), Vithana, E.N. (Eranga), Gharahkhani, P. (Puya), Boutin, T. (Thibaud), Ramdas, W.D. (Wishal), Zeller, T. (Tanja), Luben, R.N. (Robert), Yonova-Doing, E. (Ekaterina), Viswanathan, A.C. (Ananth), Yazar, S. (Seyhan), Cree, A.J. (Angela), Haines, J.L. (Jonathan), Koh, J.Y. (Jia Yu), Souzeau, E. (Emmanuelle), Wilson, J.F. (James), Amin, N. (Najaf), Müller, C. (Christian), Venturini, C. (Cristina), Kearns, L.S. (Lisa), Hee Kang, J. (Jae), Consortium, N. (Neighborhood), Tham, Y.C. (Yih Chung), Zhou, T. (Tiger), van Leeuwen, E.M. (Elisabeth), Nickels, S. (Stefan), Sanfilippo, P. (Paul), Liao, J. (Jiemin), Linde, H.V. (Herma van der), Zhao, W. (Wanting), van Koolwijk, L.M. (Leonieke), Zheng, L. (Li), Rivadeneira, F. (Fernando), Baskaran, M. (Mani), van der Lee, S.J. (Sven), Perera, S. (Shamira), de Jong, P.T. (Paulus), Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Fan, Q. (Qiao), Hofman, A. (Albert), Shyong Tai, E. (E-), Vingerling, J.R. (Johannes), Sim, X. (Xueling), Wolfs, R.C. (Roger), Teo, Y.Y. (Yik Ying), Lemij, H.G. (Hans), Khor, C.C. (Chiea Chuen), Willemsen, R. (Rob), Lackner, K.J. (Karl), Aung, T. (Tin), Jansonius, N.M. (Nomdo), Montgomery, G. (Grant), Wild, P.S. (Philipp), Young, T.L. (Terri), Burdon, K.P. (Kathryn), Hysi, P.G. (Pirro), Pasquale, L.R. (Louis), Wong, T.Y. (Tien Yin), Klaver, C.C. (Caroline), Hewitt, A.W. (Alex), Jonas, J.B. (Jost), Mitchell, P. (Paul), Lotery, A.J. (Andrew), Foster, P.J. (Paul), Vitart, V. (Veronique), Pfeiffer, N. (Norbert), Craig, J.E. (Jamie), Mackey, D.A. (David), Hammond, C.J. (Christopher), Wiggs, J.L. (Janey), Cheng, C.Y. (Ching-Yu), van Duijn, C.M. (Cornelia), MacGregor, S. (Stuart), Springelkamp, H. (Henriët), Iglesias, A.I. (Adriana), Mishra, A. (Aniket), Höhn, R. (René), Wojciechowski, R. (Robert), Khawaja, A.P. (Anthony), Nag, A. (Abhishek), Wang, Y.X. (Ya Xing), Wang, J.J. (Jie Jin), Cuellar-Partida, G. (Gabriel), Gibson, J. (Jane), Cooke Bailey, J.N. (Jessica), Vithana, E.N. (Eranga), Gharahkhani, P. (Puya), Boutin, T. (Thibaud), Ramdas, W.D. (Wishal), Zeller, T. (Tanja), Luben, R.N. (Robert), Yonova-Doing, E. (Ekaterina), Viswanathan, A.C. (Ananth), Yazar, S. (Seyhan), Cree, A.J. (Angela), Haines, J.L. (Jonathan), Koh, J.Y. (Jia Yu), Souzeau, E. (Emmanuelle), Wilson, J.F. (James), Amin, N. (Najaf), Müller, C. (Christian), Venturini, C. (Cristina), Kearns, L.S. (Lisa), Hee Kang, J. (Jae), Consortium, N. (Neighborhood), Tham, Y.C. (Yih Chung), Zhou, T. (Tiger), van Leeuwen, E.M. (Elisabeth), Nickels, S. (Stefan), Sanfilippo, P. (Paul), Liao, J. (Jiemin), Linde, H.V. (Herma van der), Zhao, W. (Wanting), van Koolwijk, L.M. (Leonieke), Zheng, L. (Li), Rivadeneira, F. (Fernando), Baskaran, M. (Mani), van der Lee, S.J. (Sven), Perera, S. (Shamira), de Jong, P.T. (Paulus), Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Fan, Q. (Qiao), Hofman, A. (Albert), Shyong Tai, E. (E-), Vingerling, J.R. (Johannes), Sim, X. (Xueling), Wolfs, R.C. (Roger), Teo, Y.Y. (Yik Ying), Lemij, H.G. (Hans), Khor, C.C. (Chiea Chuen), Willemsen, R. (Rob), Lackner, K.J. (Karl), Aung, T. (Tin), Jansonius, N.M. (Nomdo), Montgomery, G. (Grant), Wild, P.S. (Philipp), Young, T.L. (Terri), Burdon, K.P. (Kathryn), Hysi, P.G. (Pirro), Pasquale, L.R. (Louis), Wong, T.Y. (Tien Yin), Klaver, C.C. (Caroline), Hewitt, A.W. (Alex), Jonas, J.B. (Jost), Mitchell, P. (Paul), Lotery, A.J. (Andrew), Foster, P.J. (Paul), Vitart, V. (Veronique), Pfeiffer, N. (Norbert), Craig, J.E. (Jamie), Mackey, D.A. (David), Hammond, C.J. (Christopher), Wiggs, J.L. (Janey), Cheng, C.Y. (Ching-Yu), van Duijn, C.M. (Cornelia), and MacGregor, S. (Stuart)
Abstract: 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.
Published: 2017
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111. Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Author: Iglesias González, A.I. (Adriana), Lee, S.J. (Sven) van der, Bonnemaijer, P.W. (Pieter W.M.), Höhn, R. (René), Nag, A. (Abhishek), Gharahkhani, P. (Puya), Khawaja, A.P. (Anthony P.), Broer, L. (Linda), Foster, P.J. (Paul J.), Hammond, C.J. (Christopher J.), Hysi, P.G. (Pirro), Leeuwen, E.M. (Elisa) van, Macgregor, S. (Stuart), Mackey, D.A. (David), Mazur, J. (Johanna), Nickels, S. (Stefan), Uitterlinden, A.G. (André), Klaver, C.C.W. (Caroline), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Iglesias González, A.I. (Adriana), Lee, S.J. (Sven) van der, Bonnemaijer, P.W. (Pieter W.M.), Höhn, R. (René), Nag, A. (Abhishek), Gharahkhani, P. (Puya), Khawaja, A.P. (Anthony P.), Broer, L. (Linda), Foster, P.J. (Paul J.), Hammond, C.J. (Christopher J.), Hysi, P.G. (Pirro), Leeuwen, E.M. (Elisa) van, Macgregor, S. (Stuart), Mackey, D.A. (David), Mazur, J. (Johanna), Nickels, S. (Stefan), Uitterlinden, A.G. (André), Klaver, C.C.W. (Caroline), Amin, N. (Najaf), and Duijn, C.M. (Cornelia) van
Abstract: Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 × 10-61), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers.
Published: 2017
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112. Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

Author: Chintalapudi, S.R. (Sumana R.), Maria, D. (Doaa), Di Wang, X. (Xiang), Bailey, J.N.C. (Jessica N. Cooke), Allingham, R. (Rand), Brilliant, M.H. (Murray H.), Budenz, D.L. (Donald L.), Fingert, J. (John), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Haines, J.L. (Jonathan), Hark, L. (Lisa), Hauser, M.A. (Michael), Igo Jr., R.P. (Robert), Hee Kang, J. (Jae), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Moroi, S. (Syoko), Pasquale, L.R. (Louis), Pericak-Vance, M.A. (Margaret), Realini, A. (Anthony), Rhee, D. (Doug), Richards, J.R. (Julia R.), Ritch, R. (Robert), Schuman, J.S. (Joel S.), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Wollstein, G. (Gadi), Zack, D.J. (Donald), Aung, T. (Tin), Bonnemaijer, P. (Peter), Cheng, C.-Y. (Cheng-Yu), Craig, J.E. (Jamie), Duijn, C.M. (Cornelia) van, Gharahkhani, P. (Puya), Iglesias Gonzalez, A. (Adriana), Hammond, C.J. (Christopher J.), Hewitt, A. (Alex), Hoehn, R. (Rene), Jonansson, F. (Fridbert), Khawaja, A.P. (Anthony), Chuen Khor, C. (Chiea), Klaver, C.C.W. (Caroline), Lotery, A.J. (Andrew), Mackey, D.A. (David), MacGregor, S. (Stuart), Pang, C. (Calvin), Pasutto, F. (Francesca), Zwart, J-A. (John-Anker), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnar), Vitart, V. (Veronique), Vithana, E.N. (Eranga), Young, T.L. (Terri L.), Zeller, T. (Tanja), Hysi, P.G. (Pirro), Wiggs, J.L. (Janey L.), Williams, R.W. (Robert W.), Jablonski, M.M. (Monica M.), Chintalapudi, S.R. (Sumana R.), Maria, D. (Doaa), Di Wang, X. (Xiang), Bailey, J.N.C. (Jessica N. Cooke), Allingham, R. (Rand), Brilliant, M.H. (Murray H.), Budenz, D.L. (Donald L.), Fingert, J. (John), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Haines, J.L. (Jonathan), Hark, L. (Lisa), Hauser, M.A. (Michael), Igo Jr., R.P. (Robert), Hee Kang, J. (Jae), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Moroi, S. (Syoko), Pasquale, L.R. (Louis), Pericak-Vance, M.A. (Margaret), Realini, A. (Anthony), Rhee, D. (Doug), Richards, J.R. (Julia R.), Ritch, R. (Robert), Schuman, J.S. (Joel S.), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Wollstein, G. (Gadi), Zack, D.J. (Donald), Aung, T. (Tin), Bonnemaijer, P. (Peter), Cheng, C.-Y. (Cheng-Yu), Craig, J.E. (Jamie), Duijn, C.M. (Cornelia) van, Gharahkhani, P. (Puya), Iglesias Gonzalez, A. (Adriana), Hammond, C.J. (Christopher J.), Hewitt, A. (Alex), Hoehn, R. (Rene), Jonansson, F. (Fridbert), Khawaja, A.P. (Anthony), Chuen Khor, C. (Chiea), Klaver, C.C.W. (Caroline), Lotery, A.J. (Andrew), Mackey, D.A. (David), MacGregor, S. (Stuart), Pang, C. (Calvin), Pasutto, F. (Francesca), Zwart, J-A. (John-Anker), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnar), Vitart, V. (Veronique), Vithana, E.N. (Eranga), Young, T.L. (Terri L.), Zeller, T. (Tanja), Hysi, P.G. (Pirro), Wiggs, J.L. (Janey L.), Williams, R.W. (Robert W.), and Jablonski, M.M. (Monica M.)
Abstract: Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with know
Published: 2017
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113. New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Author: Springelkamp, H., Iglesias, A.I., Mishra, A, Hohn, R., Wojciechowski, R., Khawaja, A.P., Nag, A., Wang, Y.X., Wang, J.J., Cuellar-Partida, G., Gibson, J., Bailey, J.N., Vithana, E.N., Gharahkhani, P., Boutin, T., Ramdas, W.D., Zeller, T., Luben, R.N., Yonova-Doing, E., Viswanathan, A.C., Yazar, S., Cree, A.J., Haines, J.L., Koh, J.Y., Souzeau, E., Wilson, J.F., Amin, N., Muller, C., Venturini, C., Kearns, L.S., Kang, J.H., Tham, Y.C., Zhou, T., Leeuwen, E.M. van, Nickels, S., Sanfilippo, P., Liao, J., Linde, H. van der, Zhao, W., Koolwijk, L.M. van, Zheng, L., Rivadeneira, F., Baskaran, M., Lee, S.J. van der, Perera, S., Jong, P.T., Oostra, B.A., Uitterlinden, A.G., Fan, Q., Hofman, A., Tai, E.S., Vingerling, J.R., Sim, X., Wolfs, R.C., Teo, Y.Y., Lemij, H.G., Khor, C.C., Willemsen, R., Lackner, K.J., Aung, T., Jansonius, N.M., Montgomery, G., Wild, P.S., Young, T.L., Burdon, K.P., Hysi, P.G., Pasquale, L.R., Wong, T.Y., Klaver, C.C.W., Hewitt, A.W., Jonas, J.B., Mitchell, P., Lotery, A.J., Foster, P.J., Vitart, V., Pfeiffer, N., Craig, J.E., Mackey, D.A., Hammond, C.J., Wiggs, J.L., Cheng, C.Y., Duijn, C.M. van, MacGregor, S., Springelkamp, H., Iglesias, A.I., Mishra, A, Hohn, R., Wojciechowski, R., Khawaja, A.P., Nag, A., Wang, Y.X., Wang, J.J., Cuellar-Partida, G., Gibson, J., Bailey, J.N., Vithana, E.N., Gharahkhani, P., Boutin, T., Ramdas, W.D., Zeller, T., Luben, R.N., Yonova-Doing, E., Viswanathan, A.C., Yazar, S., Cree, A.J., Haines, J.L., Koh, J.Y., Souzeau, E., Wilson, J.F., Amin, N., Muller, C., Venturini, C., Kearns, L.S., Kang, J.H., Tham, Y.C., Zhou, T., Leeuwen, E.M. van, Nickels, S., Sanfilippo, P., Liao, J., Linde, H. van der, Zhao, W., Koolwijk, L.M. van, Zheng, L., Rivadeneira, F., Baskaran, M., Lee, S.J. van der, Perera, S., Jong, P.T., Oostra, B.A., Uitterlinden, A.G., Fan, Q., Hofman, A., Tai, E.S., Vingerling, J.R., Sim, X., Wolfs, R.C., Teo, Y.Y., Lemij, H.G., Khor, C.C., Willemsen, R., Lackner, K.J., Aung, T., Jansonius, N.M., Montgomery, G., Wild, P.S., Young, T.L., Burdon, K.P., Hysi, P.G., Pasquale, L.R., Wong, T.Y., Klaver, C.C.W., Hewitt, A.W., Jonas, J.B., Mitchell, P., Lotery, A.J., Foster, P.J., Vitart, V., Pfeiffer, N., Craig, J.E., Mackey, D.A., Hammond, C.J., Wiggs, J.L., Cheng, C.Y., Duijn, C.M. van, and MacGregor, S.
Abstract: Item does not contain fulltext, Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.
Published: 2017

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

Author: Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Mishra, A, Hohn, R, Wojciechowski, R, Khawaja, AP, Nag, A, Wang, YX, Wang, JJ, Cuellar-Partida, G, Gibson, J, Bailey, JNC, Vithana, EN, Gharahkhani, P, Boutin, T, Ramdas, Wishal, Zeller, T, Luben, RN, Yonova-Doing, E, Viswanathan, AC, Yazar, S, Cree, AJ, Haines, JL, Koh, JY, Souzeau, E, Wilson, JF, Amin, Najaf, Muller, C, Venturini, C, Kearns, LS, Kang, JH, Tham, YC, Zhou, T, van Leeuwen, EM, Nickels, S, Sanfilippo, P, Liao, JM, van der Linde, HC, Zhao, WT, Koolwijk, Leonieke, Zheng, L, Rivadeneira, Fernando, Baskaran, M, van der Lee, Sven, Perera, S, Jong, P, Oostra, Ben, Uitterlinden, André, Fan, Q, Hofman, Bert, Tai, ES, Vingerling, Hans, Sim, XL, Wolfs, R.C.W., Teo, YY, Lemij, HG, Khor, CC, Willemsen, Rob, Lackner, KJ, Aung, T, Jansonius, NM, Montgomery, G, Wild, PS, Young, TL, Burdon, KP, Hysi, PG, Pasquale, LR, Wong, TY, Klaver, Caroline, Hewitt, AW, Jonas, JB, Mitchell, P, Lotery, AJ, Foster, PJ, Vitart, V, Pfeiffer, N, Craig, JE, Mackey, DA, Hammond, CJ, Wiggs, JL, Cheng, CY (Ching-Yu), Duijn, Cornelia, Macgregor, S, Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Mishra, A, Hohn, R, Wojciechowski, R, Khawaja, AP, Nag, A, Wang, YX, Wang, JJ, Cuellar-Partida, G, Gibson, J, Bailey, JNC, Vithana, EN, Gharahkhani, P, Boutin, T, Ramdas, Wishal, Zeller, T, Luben, RN, Yonova-Doing, E, Viswanathan, AC, Yazar, S, Cree, AJ, Haines, JL, Koh, JY, Souzeau, E, Wilson, JF, Amin, Najaf, Muller, C, Venturini, C, Kearns, LS, Kang, JH, Tham, YC, Zhou, T, van Leeuwen, EM, Nickels, S, Sanfilippo, P, Liao, JM, van der Linde, HC, Zhao, WT, Koolwijk, Leonieke, Zheng, L, Rivadeneira, Fernando, Baskaran, M, van der Lee, Sven, Perera, S, Jong, P, Oostra, Ben, Uitterlinden, André, Fan, Q, Hofman, Bert, Tai, ES, Vingerling, Hans, Sim, XL, Wolfs, R.C.W., Teo, YY, Lemij, HG, Khor, CC, Willemsen, Rob, Lackner, KJ, Aung, T, Jansonius, NM, Montgomery, G, Wild, PS, Young, TL, Burdon, KP, Hysi, PG, Pasquale, LR, Wong, TY, Klaver, Caroline, Hewitt, AW, Jonas, JB, Mitchell, P, Lotery, AJ, Foster, PJ, Vitart, V, Pfeiffer, N, Craig, JE, Mackey, DA, Hammond, CJ, Wiggs, JL, Cheng, CY (Ching-Yu), Duijn, Cornelia, and Macgregor, S
Published: 2017

115. Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Author: Iglesias Gonzalez, Adriana, van der Lee, Sven, Bonnemaijer, Pieter, Hohn, R, Nag, A, Gharahkhani, P, Khawaja, AP, Broer, Linda, Foster, PJ, Hammond, CJ, Hysi, PG, Leeuwen, Elisa, Macgregor, S, Mackey, DA, Mazur, J, Nickels, S, Uitterlinden, André, Klaver, Caroline, Amin, Najaf, Duijn, Cornelia, Iggc, Iglesias Gonzalez, Adriana, van der Lee, Sven, Bonnemaijer, Pieter, Hohn, R, Nag, A, Gharahkhani, P, Khawaja, AP, Broer, Linda, Foster, PJ, Hammond, CJ, Hysi, PG, Leeuwen, Elisa, Macgregor, S, Mackey, DA, Mazur, J, Nickels, S, Uitterlinden, André, Klaver, Caroline, Amin, Najaf, Duijn, Cornelia, and Iggc
Published: 2017

116. Large scale meta-analysis identifies new genetic risk loci for esophageal adenocarcinoma (EA) and the first EA risk locus independent of Barrett’s esophagus

Author: Palles, C, Tomlinson, I, Chegwidden, L, Gharahkhani, P, MacGregor, S, Vaughan, TL, Schumacher, J, Jankowski, J, Fitzgerald, R, Gockel, I, Buas, M, Knapp, M, Noethen, MM, Becker, J, Pharaoh, P, and Whiteman, DC
Abstract: Esophageal adenocarcinoma (EA) is an often fatal cancer with rising incidence in the developed world. Barrett’s esophagus (BE) is a pre-cancerous metaplastic precursor of EA. We performed the first genome-wide association study (GWAS) meta-analysis for BE and EA to date, using 6,167 BE cases, 4,112 EA cases, and 17,159 unscreened controls, all of European descent. We identified eight new genome-wide significant associated (P
Published: 2016

117. Germline genetic variants and risk of Barrett's esophagus and esophageal adenocarcinoma: a large scale meta-analysis of genome-wide association studies

Author: Palles, C, Tomlinson, I, Chegwidden, L, Gharahkhani, P, MacGregor, S, Vaughan, T, Schumacher, J, Jankowski, J, Fitzgerald, R, Gockel, I, Buas, M, May, A, Gerges, C, Anders, M, Becker, J, Kreuser, N, Noder, T, Venerito, M, Veits, L, Schmidt, T, Manner, H, Schmidt, C, Hess, T, Böhmer, A, Izbicki, J, Hölscher, A, Lang, H, Lorenz, D, Schumacher, B, Hackelsberger, A, Mayershofer, R, Pech, O, Vashist, Y, Ott, K, Vieth, M, Weismüller, J, Nöthen, M, Attwood, S, Barr, H, de Caestecker, J, Harrison, R, Love, S, MacDonald, D, Moayyed, P, Prenen, H, Watson, R, Iyer, P, Anderson, L, Bernstein, L, Chow, W, Hardie, L, Lagergren, J, Liu, G, Risch, H, Wu, A, Ye, W, Bird, N, Shaheen, N, Gammon, M, Corley, D, Caldas, C, Moebus, S, Knapp, M, Peters, W, Neuhaus, H, Rösch, T, Ell, C, Pharaoh, P, and Whiteman, D
Abstract: Background Esophageal adenocarcinoma (EA) is one of the fastest rising cancers in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Genetic risk factors for BE and EA are incompletely understood. This study aimed to identify novel genetic risk factors for BE and EA. Methods Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available, involving 6,167 BE patients, 4,112 EA patients, and 17,159 representative controls, all of European ancestry, genotyped on Illumina high-density SNP-arrays, collected from four separate studies within North America, Europe, and Australia. Meta-analysis was conducted using the fixed-effects inverse variance-weighting approach. We used the standard genome-wide significant threshold of 5×10-8 for this study. We also conducted an association analysis following reweighting of loci using an approach that investigates annotation enrichment among the genome-wide significant loci. The entire GWAS-data set was also analyzed using bioinformatics approaches including functional annotation databases as well as gene-based and pathway-based methods in order to identify pathophysiologically relevant cellular pathways. Findings We identified eight new associated risk loci for BE and EA, within or near the CFTR (rs17451754, P=4·8×10-10), MSRA (rs17749155, P=5·2×10-10), BLK (rs10108511, P=2·1×10-9), KHDRBS2 (rs62423175, P=3·0×10-9), TPPP/CEP72 (rs9918259, P=3·2×10-9), TMOD1 (rs7852462, P=1·5×10-8), SATB2 (rs139606545, P=2·0×10-8), and HTR3C/ABCC5 genes (rs9823696, P=1·6×10-8). A further novel risk locus at LPA (rs12207195, posteriori probability=0·925) was identified after re-weighting using significantly enriched annotations. This study thereby doubled the number of known risk loci. The strongest disease pathways identified (P Interpretation The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Mutations in CFTR, one of the new risk loci identified in this study, cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology.
Published: 2016

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

Author: Bailey, JNC, Loomis, SJ, Kang, JH, Allingham, RR, Gharahkhani, P, Khor, CC, Burdon, KP, Aschard, H, Chasman, DI, Igo, RP, Hysi, PG, Glastonbury, CA, Ashley-Koch, A, Brilliant, M, Brown, AA, Budenz, DL, Buil, A, Cheng, CY, Choi, H, Christen, WG, Curhan, G, De Vivo, I, Fingert, JH, Foster, PJ, Fuchs, C, Gaasterland, D, Gaasterland, T, Hewitt, AW, Hu, F, Hunter, DJ, Khawaja, AP, Lee, RK, Li, Z, Lichter, PR, Mackey, DA, McGuffin, P, Mitchell, P, Moroi, SE, Perera, SA, Pepper, KW, Qi, Q, Realini, T, Richards, JE, Ridker, PM, Rimm, E, Ritch, R, Ritchie, M, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Song, YE, Tamimi, RM, Topouzis, F, Viswanathan, AC, Verma, SS, Vollrath, D, Wang, JJ, Weisschuh, N, Wissinger, B, Wollstein, G, Wong, TY, Yaspan, BL, Zack, DJ, Zhang, K, Weinreb, RN, Pericak-Vance, MA, Small, K, Hammond, CJ, Aung, T, Liu, Y, Vithana, EN, MacGregor, S, Craig, JE, Kraft, P, Howell, G, Hauser, MA, and Pasquale, LR
Subjects: ANZRAG Consortium
Abstract: © 2016 Nature America, Inc. Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10 -11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10 -10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10 -10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.
Published: 2016

119. Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

Author: Springelkamp, H, Mishra, A, Hysi, PG, Gharahkhani, P, Höhn, R, Khor, CC, Cooke Bailey, JN, Luo, X, Ramdas, WD, Vithana, E, Koh, V, Yazar, S, Xu, L, Forward, H, Kearns, LS, Amin, N, Iglesias, AI, Sim, KS, van Leeuwen, EM, Demirkan, A, van der Lee, S, Loon, SC, Rivadeneira, F, Nag, A, Sanfilippo, PG, Schillert, A, de Jong, PTVM, Oostra, BA, Uitterlinden, AG, Hofman, A, Zhou, T, Burdon, KP, Spector, TD, Lackner, KJ, Saw, SM, Vingerling, JR, Teo, YY, Pasquale, LR, Wolfs, RCW, Lemij, HG, Tai, ES, Jonas, JB, Cheng, CY, Aung, T, Jansonius, NM, Klaver, CCW, Craig, JE, Young, TL, Haines, JL, Macgregor, S, Mackey, DA, Pfeiffer, N, Wong, TY, Wiggs, JL, Hewitt, AW, van Duijn, CM, Hammond, CJ, Allingham, RR, Brilliant, MH, Budenz, DL, Bailey, JNC, Christen, WG, and Fingert, J
Subjects: genetic structures, sense organs, eye diseases
Abstract: © 2015 Wiley Periodicals, Inc. Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.
Published: 2015

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

Author: Han, Xikun, Ong, Jue-Sheng, An, Jiyuan, Craig, Jamie E., Gharahkhani, Puya, Hewitt, Alex W., and MacGregor, Stuart
Abstract: 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.
Published: 2020
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121. Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Author: Craig, Jamie E., Han, Xikun, Qassim, Ayub, Hassall, Mark, Cooke Bailey, Jessica N., Kinzy, Tyler G., Khawaja, Anthony P., An, Jiyuan, Marshall, Henry, Gharahkhani, Puya, Igo, Robert P., Graham, Stuart L., Healey, Paul R., Ong, Jue-Sheng, Zhou, Tiger, Siggs, Owen, Law, Matthew H., Souzeau, Emmanuelle, Ridge, Bronwyn, Hysi, Pirro G., Burdon, Kathryn P., Mills, Richard A., Landers, John, Ruddle, Jonathan B., Agar, Ashish, Galanopoulos, Anna, White, Andrew J. R., Willoughby, Colin E., Andrew, Nicholas H., Best, Stephen, Vincent, Andrea L., Goldberg, Ivan, Radford-Smith, Graham, Martin, Nicholas G., Montgomery, Grant W., Vitart, Veronique, Hoehn, Rene, Wojciechowski, Robert, Jonas, Jost B., Aung, Tin, Pasquale, Louis R., Cree, Angela Jane, Sivaprasad, Sobha, Vallabh, Neeru A., Viswanathan, Ananth C., Pasutto, Francesca, Haines, Jonathan L., Klaver, Caroline C. W., van Duijn, Cornelia M., Casson, Robert J., Foster, Paul J., Khaw, Peng Tee, Hammond, Christopher J., Mackey, David A., Mitchell, Paul, Lotery, Andrew J., Wiggs, Janey L., Hewitt, Alex W., and MacGregor, Stuart
Abstract: 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 MYOCvariant 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 × 10−6). 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.
Published: 2020
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122. Mendelian Randomization Study for Genetically Predicted Polyunsaturated Fatty Acids Levels on Overall Cancer Risk and Mortality.

Author: Liyanage, Upekha E., Jue-Sheng Ong, Jiyuan An, Gharahkhani, Puya, Law, Matthew H., and MacGregor, Stuart
Abstract: Background: Observational studies evaluating the link between polyunsaturated fatty acids (PUFA) and cancers have yielded mixed findings. We used Mendelian randomization (MR) to evaluate whether genetic evidence supports a causal role for PUFAs on overall cancer outcomes. Methods: We identified genetic instruments for six PUFAs from previous literature and evaluated their association with overall cancer risk (46,155 cases, 270,342 controls) and cancer mortality (6,998 deaths, 270,342 controls) among the UK Biobank cohort. We used the inverse variance weighted model to combine SNP estimates, and derived log (OR) estimates per SD change in each PUFA. Results: None of the six PUFAs showed association with overall cancer risk or mortality, with narrow confidence interval (CI) ruling out all but very small effects, for example, arachidonic acid (AA) overall cancer risk (OR, 1.02; 95% CI, 1.00-1.03). Sex-specific analysis revealed no associations except α-linolenic acid for potentially reducing cancer risk in men (OR, 0.92; 95% CI, 0.86-0.98; P = 0.02); however, this was nonsignificant after multiple testing correction. From individual cancers, only colorectal cancer showed evidence for a causal association for higher AA levels (OR, 1.05; 95% CI, 1.03-1.07), with similar results for the other correlated PUFAs. Conclusions: Our study provides no support for the hypothesis that PUFAs reduce overall cancer risk or mortality. Higher AA levels increased the risk for colorectal cancer. Impact: Our well-powered MR study provides robust causal inferences for the PUFAs on overall cancer risk and mortality. Future larger studies are warranted to replicate the individual cancer findings. [ABSTRACT FROM AUTHOR]
Published: 2019
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123. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error

Author: Fan, Q., Verhoeven, V.J., Wojciechowski, R., Barathi, V.A., Hysi, P.G., Guggenheim, J.A., Hohn, R., Vitart, V., Khawaja, A.P., Yamashiro, K., Hosseini, S.M., Lehtimaki, T., Lu, Y., Haller, T., Xie, J., Delcourt, C, Pirastu, M., Wedenoja, J., Gharahkhani, P., Venturini, C., Miyake, M., Hewitt, A.W., Guo, X., Mazur, J., Huffman, J.E., Williams, K.M., Polasek, O., Campbell, H., Rudan, I., Vatavuk, Z., Wilson, J.F., Joshi, P.K., McMahon, G., St Pourcain, B., Evans, D.M., Simpson, C.L., Schwantes-An, T.H., Igo, R.P., Jr., Mirshahi, A., Cougnard-Gregoire, A., Bellenguez, C., Blettner, M., Raitakari, O., Kahonen, M., Seppala, I., Zeller, T., Meitinger, T., Ried, J.S., Gieger, C., Portas, L., Leeuwen, E.M. van, Amin, N., Uitterlinden, A.G., Rivadeneira, F., Hofman, A., Vingerling, J.R., Wang, Y.X., Wang, X., Boh, E.T.H., Ikram, M.K., Sabanayagam, C., Gupta, P., Tan, V., Zhou, L, Ho, C.E., Lim, W., Beuerman, R.W., Siantar, R., Tai, E.S., Vithana, E., Mihailov, E., Khor, C.C., Hayward, C., Luben, R.N., Foster, P.J., Klein, B.E., Klein, R., Wong, H.S., Mitchell, P., Metspalu, A., Aung, T., Young, T.L., He, M., Parssinen, O., Duijn, C.M. van, Wang, J.J., Williams, C., Jonas, J.B., Teo, Y.Y., Mackey, D.A., Oexle, K., Yoshimura, N., Paterson, A.D., Pfeiffer, N., Wong, T.Y., Baird, P.N., Stambolian, D., Wilson, J.E., Cheng, C.Y., Hammond, C.J., Klaver, C.C.W., et al., Fan, Q., Verhoeven, V.J., Wojciechowski, R., Barathi, V.A., Hysi, P.G., Guggenheim, J.A., Hohn, R., Vitart, V., Khawaja, A.P., Yamashiro, K., Hosseini, S.M., Lehtimaki, T., Lu, Y., Haller, T., Xie, J., Delcourt, C, Pirastu, M., Wedenoja, J., Gharahkhani, P., Venturini, C., Miyake, M., Hewitt, A.W., Guo, X., Mazur, J., Huffman, J.E., Williams, K.M., Polasek, O., Campbell, H., Rudan, I., Vatavuk, Z., Wilson, J.F., Joshi, P.K., McMahon, G., St Pourcain, B., Evans, D.M., Simpson, C.L., Schwantes-An, T.H., Igo, R.P., Jr., Mirshahi, A., Cougnard-Gregoire, A., Bellenguez, C., Blettner, M., Raitakari, O., Kahonen, M., Seppala, I., Zeller, T., Meitinger, T., Ried, J.S., Gieger, C., Portas, L., Leeuwen, E.M. van, Amin, N., Uitterlinden, A.G., Rivadeneira, F., Hofman, A., Vingerling, J.R., Wang, Y.X., Wang, X., Boh, E.T.H., Ikram, M.K., Sabanayagam, C., Gupta, P., Tan, V., Zhou, L, Ho, C.E., Lim, W., Beuerman, R.W., Siantar, R., Tai, E.S., Vithana, E., Mihailov, E., Khor, C.C., Hayward, C., Luben, R.N., Foster, P.J., Klein, B.E., Klein, R., Wong, H.S., Mitchell, P., Metspalu, A., Aung, T., Young, T.L., He, M., Parssinen, O., Duijn, C.M. van, Wang, J.J., Williams, C., Jonas, J.B., Teo, Y.Y., Mackey, D.A., Oexle, K., Yoshimura, N., Paterson, A.D., Pfeiffer, N., Wong, T.Y., Baird, P.N., Stambolian, D., Wilson, J.E., Cheng, C.Y., Hammond, C.J., Klaver, C.C.W., and et al.
Abstract: Contains fulltext : 167942.pdf (publisher's version ) (Open Access), Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP x education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 x 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Published: 2016

124. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error

Author: Fan, Q. (Qiao), Verhoeven, V.J.M. (Virginie), Wojciechowski, R. (Robert), Barathi, V.A. (Veluchamy), Hysi, P.G. (Pirro), Guggenheim, J. (Jean), Höhn, R. (René), Vitart, V. (Veronique), Khawaja, A.P. (Anthony P.), Yamashiro, K. (Kenji), Hosseini, S.M. (S Mohsen), Lehtimäki, T. (Terho), Lu, Y. (Yi), Haller, T. (Toomas), Xie, J. (Jing), Delcourt, C. (Cécile), Pirastu, M. (Mario), Wedenoja, J. (Juho), Gharahkhani, P. (Puya), Venturini, C. (Cristina), Miyake, M. (Masahiro), Hewit, A.W. (Alex), Guo, X. (Xiaobo), Mazur, J. (Johanna), Huffman, J.E. (Jenifer E.), Williams, K.M. (Katie M.), Polasek, O. (Ozren), Campbell, H. (Harry), Rudan, I. (Igor), Vatavuk, Z. (Zoran), Wilson, J.F. (James F), Joshi, P.K. (Peter), Mcmahon, G. (George), St Pourcain, B. (Beate), Evans, D.M. (David), Simpson, C.L. (Claire), Schwantes-An, T.-H. (Tae-Hwi), Igo Jr., R.P. (Robert), Mirshahi, A. (Alireza), Cougnard-Grégoire, A. (Audrey), Bellenguez, C. (Céline), Blettner, M. (Maria), Raitakari, O. (Olli), Kähönen, M. (Mika), Seppälä, I. (Ilkka), Zeller, T. (Tanja), Meitinger, T. (Thomas), Ried, J.S. (Janina), Gieger, C. (Christian), Portas, L. (Laura), Leeuwen, E.M. (Elisa) van, Amin, N. (Najaf), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Hofman, A. (Albert), Vingerling, J.R. (Hans), Wang, Y. (Ying), Wang, X. (Xu), Tai-Hui Boh, E. (Eileen), Ikram, M.K. (Kamran), Sabanayagam, C. (Charumathi), Gupta, P. (Preeti), Tan, V. (Vincent), Zhou, L. (Lei), Ho, C.E.H. (Candice E. H.), Lim, W. (Wan'E), Beuerman, R.W. (Roger W.), Siantar, R. (Rosalynn), Tai, E.-S. (E-Shyong), Vithana, E.N. (Eranga), Mihailov, E. (Evelin), Khor, C.C., Hayward, C. (Caroline), Luben, R.N. (Robert), Foster, P.J. (Paul), Klein, B.E.K. (Barbara), Klein, R. (Ronald), Wong, H.-S. (Hoi-Suen), Mitchell, P. (Paul), Metspalu, A. (Andres), Aung, T. (Tin), Young, T.L. (Terri L.), He, M. (Mingguang), Pärssinen, O. (Olavi), Duijn, C.M. (Cornelia) van, Jin Wang, J. (Jie), Williams, C. (Cathy), Jonas, J.B. (Jost B.), Teo, Y.Y. (Yik Ying), Mackey, D.A. (David), Oexle, K. (Konrad), Yoshimura, N., Paterson, A.D. (Andrew D.), Pfeiffer, N. (Norbert), Wong, T.Y. (Tien Yin), Baird, P.N. (Paul), Stambolian, D. (Dwight), Wilson, J.E.B. (Joan E. Bailey), Cheng, C-Y. (Ching-Yu), Hammond, C.J. (Christopher J.), Klaver, C.C.W. (Caroline), Saw, S-M. (Seang-Mei), Rahi, J.S. (Jugnoo), Korobelnik, J.-F. (Jean-François), Kemp, J.P. (John), Timpson, N.J. (Nicholas), Smith, A.V. (Davey), Craig, J.E. (Jamie E.), Burdon, K.P. (Kathryn P.), Fogarty, R. (Rhys), Iyengar, S.K. (Sudha), Chew, E.Y. (Emily), Janmahasatian, S. (Sarayut), Martin, N.G. (Nicholas), MacGregor, S. (Stuart), Xu, L. (Liang), Schache, M. (Maria), Nangia, M. (Monika), Panda-Jonas, S. (Songhomitra), Wright, A.F. (Alan), Fondran, J.R. (Jeremy R.), Lass, J.H. (Jonathan H.), Feng, S. (Sheng), Zhao, J.H. (Jing Hua), Khaw, K.T., Wareham, N.J. (Nick), Rantanen, T. (Taina), Kaprio, J. (Jaakko), Pang, C.P. (Chi Pui), Chen, L.J. (Li Jia), Tam, P.O. (Pancy O.), Jhanji, V. (Vishal), Young, A.L. (Alvin L.), Döring, A. (Angela), Raffel, L.J. (Leslie), Cotch, M.-F. (Mary-Frances), Li, X. (Xiaohui), Yip, S.P. (Shea Ping), Yap, M.K.H. (Maurice K.H.), Biino, G. (Ginevra), Vaccargiu, S. (Simona), Fossarello, M. (Maurizio), Fleck, B. (Brian), Yazar, S. (Seyhan), Tideman, J.W.L. (Willem), Tedja, M. (Milly), Léveillard, T. (Thierry), Morrison, M.A. (Margaux A.), Farrer, L.A. (Lindsay), Zhou, X. (Xiangtian), Chen, W. (Wei), Mizuki, N. (Nobuhisa), Meguro, A. (Akira), Makela, K.M. (Kari Matti), Fan, Q. (Qiao), Verhoeven, V.J.M. (Virginie), Wojciechowski, R. (Robert), Barathi, V.A. (Veluchamy), Hysi, P.G. (Pirro), Guggenheim, J. (Jean), Höhn, R. (René), Vitart, V. (Veronique), Khawaja, A.P. (Anthony P.), Yamashiro, K. (Kenji), Hosseini, S.M. (S Mohsen), Lehtimäki, T. (Terho), Lu, Y. (Yi), Haller, T. (Toomas), Xie, J. (Jing), Delcourt, C. (Cécile), Pirastu, M. (Mario), Wedenoja, J. (Juho), Gharahkhani, P. (Puya), Venturini, C. (Cristina), Miyake, M. (Masahiro), Hewit, A.W. (Alex), Guo, X. (Xiaobo), Mazur, J. (Johanna), Huffman, J.E. (Jenifer E.), Williams, K.M. (Katie M.), Polasek, O. (Ozren), Campbell, H. (Harry), Rudan, I. (Igor), Vatavuk, Z. (Zoran), Wilson, J.F. (James F), Joshi, P.K. (Peter), Mcmahon, G. (George), St Pourcain, B. (Beate), Evans, D.M. (David), Simpson, C.L. (Claire), Schwantes-An, T.-H. (Tae-Hwi), Igo Jr., R.P. (Robert), Mirshahi, A. (Alireza), Cougnard-Grégoire, A. (Audrey), Bellenguez, C. (Céline), Blettner, M. (Maria), Raitakari, O. (Olli), Kähönen, M. (Mika), Seppälä, I. (Ilkka), Zeller, T. (Tanja), Meitinger, T. (Thomas), Ried, J.S. (Janina), Gieger, C. (Christian), Portas, L. (Laura), Leeuwen, E.M. (Elisa) van, Amin, N. (Najaf), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Hofman, A. (Albert), Vingerling, J.R. (Hans), Wang, Y. (Ying), Wang, X. (Xu), Tai-Hui Boh, E. (Eileen), Ikram, M.K. (Kamran), Sabanayagam, C. (Charumathi), Gupta, P. (Preeti), Tan, V. (Vincent), Zhou, L. (Lei), Ho, C.E.H. (Candice E. H.), Lim, W. (Wan'E), Beuerman, R.W. (Roger W.), Siantar, R. (Rosalynn), Tai, E.-S. (E-Shyong), Vithana, E.N. (Eranga), Mihailov, E. (Evelin), Khor, C.C., Hayward, C. (Caroline), Luben, R.N. (Robert), Foster, P.J. (Paul), Klein, B.E.K. (Barbara), Klein, R. (Ronald), Wong, H.-S. (Hoi-Suen), Mitchell, P. (Paul), Metspalu, A. (Andres), Aung, T. (Tin), Young, T.L. (Terri L.), He, M. (Mingguang), Pärssinen, O. (Olavi), Duijn, C.M. (Cornelia) van, Jin Wang, J. (Jie), Williams, C. (Cathy), Jonas, J.B. (Jost B.), Teo, Y.Y. (Yik Ying), Mackey, D.A. (David), Oexle, K. (Konrad), Yoshimura, N., Paterson, A.D. (Andrew D.), Pfeiffer, N. (Norbert), Wong, T.Y. (Tien Yin), Baird, P.N. (Paul), Stambolian, D. (Dwight), Wilson, J.E.B. (Joan E. Bailey), Cheng, C-Y. (Ching-Yu), Hammond, C.J. (Christopher J.), Klaver, C.C.W. (Caroline), Saw, S-M. (Seang-Mei), Rahi, J.S. (Jugnoo), Korobelnik, J.-F. (Jean-François), Kemp, J.P. (John), Timpson, N.J. (Nicholas), Smith, A.V. (Davey), Craig, J.E. (Jamie E.), Burdon, K.P. (Kathryn P.), Fogarty, R. (Rhys), Iyengar, S.K. (Sudha), Chew, E.Y. (Emily), Janmahasatian, S. (Sarayut), Martin, N.G. (Nicholas), MacGregor, S. (Stuart), Xu, L. (Liang), Schache, M. (Maria), Nangia, M. (Monika), Panda-Jonas, S. (Songhomitra), Wright, A.F. (Alan), Fondran, J.R. (Jeremy R.), Lass, J.H. (Jonathan H.), Feng, S. (Sheng), Zhao, J.H. (Jing Hua), Khaw, K.T., Wareham, N.J. (Nick), Rantanen, T. (Taina), Kaprio, J. (Jaakko), Pang, C.P. (Chi Pui), Chen, L.J. (Li Jia), Tam, P.O. (Pancy O.), Jhanji, V. (Vishal), Young, A.L. (Alvin L.), Döring, A. (Angela), Raffel, L.J. (Leslie), Cotch, M.-F. (Mary-Frances), Li, X. (Xiaohui), Yip, S.P. (Shea Ping), Yap, M.K.H. (Maurice K.H.), Biino, G. (Ginevra), Vaccargiu, S. (Simona), Fossarello, M. (Maurizio), Fleck, B. (Brian), Yazar, S. (Seyhan), Tideman, J.W.L. (Willem), Tedja, M. (Milly), Léveillard, T. (Thierry), Morrison, M.A. (Margaux A.), Farrer, L.A. (Lindsay), Zhou, X. (Xiangtian), Chen, W. (Wei), Mizuki, N. (Nobuhisa), Meguro, A. (Akira), and Makela, K.M. (Kari Matti)
Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10-5), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Published: 2016
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125. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium

Author: Fan, Q. (Qiao), Guo, X. (Xiaobo), Tideman, J.W.L. (Willem), Williams, K.M. (Katie M.), Yazar, S. (Seyhan), Hosseini, S.M. (S. Mohsen), Howe, L.D. (Laura), Pourcain, B.S. (Beate), Evans, D.M. (David), Timpson, N.J. (Nicholas), Mcmahon, G. (George), Hysi, P.G. (Pirro), Krapohl, E. (Eva), Wang, Y.X. (Ya Xing), Jonas, J.B., Baird, P.N. (Paul), Wang, J.J. (Jie Jin), Cheng, C.-Y. (Ching-Yu), Teo, Y.Y. (Yik Ying), Wong, T.-Y. (Tien-Yin), Ding, X. (Xiaohu), Wojciechowski, R. (Robert), Young, T.L. (Terri), Pärssinen, O. (Olavi), Oexle, K. (Konrad), Pfeiffer, A.F.H. (Andreas), Bailey-Wilson, J.E. (Joan E.), Paterson, A.D. (Andrew), Klaver, C.C.W. (Caroline C. W.), Plomin, R. (Robert), Hammond, C.J. (Christopher J.), He, M. (Mingguang), Saw, S-M. (Seang-Mei), Guggenheim, J. (Jean), Meguro, A. (Akira), Wright, A.F. (Alan), Hewit, A.W. (Alex), Young, A.L. (Alvin L.), Veluchamy, A.B. (Amutha Barathi), Metspalu, A. (Andres), Döring, A. (Angela), Khawaja, A.P. (Anthony P.), Klein, B.E.K. (Barbara), St Pourcain, B. (Beate), Fleck, B. (Brian), Klaver, C.C.W. (Caroline), Hayward, C. (Caroline), Williams, C. (Cathy), Delcourt, C. (Cécile), Pang, C.P. (Chi Pui), Khor, C.C., Gieger, C. (Christian), Simpson, C.L. (Claire), Duijn, C.M. (Cornelia) van, Mackey, D.A. (David), Stambolian, D. (Dwight), Chew, E.Y. (Emily), Tai, E.-S. (E.-Shyong), Mihailov, E. (Evelin), Smith, A.V. (Davey), Biino, G. (Ginevra), Campbell, H. (Harry), Rudan, I. (Igor), Seppälä, I. (Ilkka), Kaprio, J. (Jaakko), Wilson, J.F. (James F.), Craig, J.E. (Jamie E.), Ried, J.S. (Janina), Korobelnik, J.-F. (Jean-François), Fondran, J.R. (Jeremy R.), Liao, J. (Jie), Zhao, J.H. (Jing Hua), Xie, J. (Jing), Kemp, J.P. (John), Lass Jr., J.H. (Jonathan), Rahi, J.S. (Jugnoo), Wedenoja, J. (Juho), Makela, K.M. (Kari Matti), Burdon, K.P. (Kathryn P.), Khaw, K.T., Yamashiro, K. (Kenji), Chen, L.J. (Li Jia), Xu, L. (Liang), Farrer, L.A. (Lindsay), Ikram, M.K. (M. Kamran), DeAngelis, M.M. (Margaret), Morrison, M.A. (Margaux A.), Schache, M. (Maria), Pirastu, M. (Mario), Miyake, M. (Masahiro), Yap, M.K.H. (Maurice K. H.), Fossarello, M. (Maurizio), Kähönen, M. (Mika), Tedja, M. (Milly), Yoshimura, N., Martin, N.G. (Nicholas), Wareham, N.J. (Nick), Mizuki, N. (Nobuhisa), Raitakari, O. (Olli), Polasek, O. (Ozren), Tam, P.O. (Pancy O.), Foster, P.J. (Paul), Mitchell, P. (Paul), Chen, P. (Peng), Cumberland, P. (Phillippa), Gharahkhani, P. (Puya), Höhn, R. (René), Fogarty, R.D. (Rhys D.), Luben, R.N. (Robert), Igo Jr., R.P. (Robert), Klein, R. (Ronald), Janmahasatian, S. (Sarayut), Yip, S.P. (Shea Ping), Feng, S. (Sheng), Vaccargiu, S. (Simona), Panda-Jonas, S. (Songhomitra), MacGregor, S. (Stuart), Iyengar, S.K. (Sudha), Rantanen, T. (Taina), Lehtimäki, T. (Terho), Meitinger, T. (Thomas), Aung, T. (Tin), Haller, T. (Toomas), Vitart, V. (Veronique), Nangia, M. (Monika), Verhoeven, V.J.M. (Virginie), Jhanji, V. (Vishal), Zhao, W. (Wanting), Chen, W. (Wei), Zhou, X. (Xiangtian), Lu, Y. (Yi), Vatavuk, Z. (Zoran), Fan, Q. (Qiao), Guo, X. (Xiaobo), Tideman, J.W.L. (Willem), Williams, K.M. (Katie M.), Yazar, S. (Seyhan), Hosseini, S.M. (S. Mohsen), Howe, L.D. (Laura), Pourcain, B.S. (Beate), Evans, D.M. (David), Timpson, N.J. (Nicholas), Mcmahon, G. (George), Hysi, P.G. (Pirro), Krapohl, E. (Eva), Wang, Y.X. (Ya Xing), Jonas, J.B., Baird, P.N. (Paul), Wang, J.J. (Jie Jin), Cheng, C.-Y. (Ching-Yu), Teo, Y.Y. (Yik Ying), Wong, T.-Y. (Tien-Yin), Ding, X. (Xiaohu), Wojciechowski, R. (Robert), Young, T.L. (Terri), Pärssinen, O. (Olavi), Oexle, K. (Konrad), Pfeiffer, A.F.H. (Andreas), Bailey-Wilson, J.E. (Joan E.), Paterson, A.D. (Andrew), Klaver, C.C.W. (Caroline C. W.), Plomin, R. (Robert), Hammond, C.J. (Christopher J.), He, M. (Mingguang), Saw, S-M. (Seang-Mei), Guggenheim, J. (Jean), Meguro, A. (Akira), Wright, A.F. (Alan), Hewit, A.W. (Alex), Young, A.L. (Alvin L.), Veluchamy, A.B. (Amutha Barathi), Metspalu, A. (Andres), Döring, A. (Angela), Khawaja, A.P. (Anthony P.), Klein, B.E.K. (Barbara), St Pourcain, B. (Beate), Fleck, B. (Brian), Klaver, C.C.W. (Caroline), Hayward, C. (Caroline), Williams, C. (Cathy), Delcourt, C. (Cécile), Pang, C.P. (Chi Pui), Khor, C.C., Gieger, C. (Christian), Simpson, C.L. (Claire), Duijn, C.M. (Cornelia) van, Mackey, D.A. (David), Stambolian, D. (Dwight), Chew, E.Y. (Emily), Tai, E.-S. (E.-Shyong), Mihailov, E. (Evelin), Smith, A.V. (Davey), Biino, G. (Ginevra), Campbell, H. (Harry), Rudan, I. (Igor), Seppälä, I. (Ilkka), Kaprio, J. (Jaakko), Wilson, J.F. (James F.), Craig, J.E. (Jamie E.), Ried, J.S. (Janina), Korobelnik, J.-F. (Jean-François), Fondran, J.R. (Jeremy R.), Liao, J. (Jie), Zhao, J.H. (Jing Hua), Xie, J. (Jing), Kemp, J.P. (John), Lass Jr., J.H. (Jonathan), Rahi, J.S. (Jugnoo), Wedenoja, J. (Juho), Makela, K.M. (Kari Matti), Burdon, K.P. (Kathryn P.), Khaw, K.T., Yamashiro, K. (Kenji), Chen, L.J. (Li Jia), Xu, L. (Liang), Farrer, L.A. (Lindsay), Ikram, M.K. (M. Kamran), DeAngelis, M.M. (Margaret), Morrison, M.A. (Margaux A.), Schache, M. (Maria), Pirastu, M. (Mario), Miyake, M. (Masahiro), Yap, M.K.H. (Maurice K. H.), Fossarello, M. (Maurizio), Kähönen, M. (Mika), Tedja, M. (Milly), Yoshimura, N., Martin, N.G. (Nicholas), Wareham, N.J. (Nick), Mizuki, N. (Nobuhisa), Raitakari, O. (Olli), Polasek, O. (Ozren), Tam, P.O. (Pancy O.), Foster, P.J. (Paul), Mitchell, P. (Paul), Chen, P. (Peng), Cumberland, P. (Phillippa), Gharahkhani, P. (Puya), Höhn, R. (René), Fogarty, R.D. (Rhys D.), Luben, R.N. (Robert), Igo Jr., R.P. (Robert), Klein, R. (Ronald), Janmahasatian, S. (Sarayut), Yip, S.P. (Shea Ping), Feng, S. (Sheng), Vaccargiu, S. (Simona), Panda-Jonas, S. (Songhomitra), MacGregor, S. (Stuart), Iyengar, S.K. (Sudha), Rantanen, T. (Taina), Lehtimäki, T. (Terho), Meitinger, T. (Thomas), Aung, T. (Tin), Haller, T. (Toomas), Vitart, V. (Veronique), Nangia, M. (Monika), Verhoeven, V.J.M. (Virginie), Jhanji, V. (Vishal), Zhao, W. (Wanting), Chen, W. (Wei), Zhou, X. (Xiangtian), Lu, Y. (Yi), and Vatavuk, Z. (Zoran)
Abstract: Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).
Published: 2016
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126. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error

Author: Fan, Q, Verhoeven, VJM, Wojciechowski, R, Barathi, VA, Hysi, PG, Guggenheim, JA, Hoehn, R, Vitart, V, Khawaja, AP, Yamashiro, K, Hosseini, SM, Lehtimaki, T, Lu, Y, Haller, T, Xie, J, Delcourt, C, Pirastu, M, Wedenoja, J, Gharahkhani, P, Venturini, C, Miyake, M, Hewitt, AW, Guo, X, Mazur, J, Huffman, JE, Williams, KM, Polasek, O, Campbell, H, Rudan, I, Vatavuk, Z, Wilson, JF, Joshi, PK, McMahon, G, St Pourcain, B, Evans, DM, Simpson, CL, Schwantes-An, T-H, Igo, RP, Mirshahi, A, Cougnard-Gregoire, A, Bellenguez, C, Blettner, M, Raitakari, O, Kaehoenen, M, Seppala, I, Zeller, T, Meitinger, T, Ried, JS, Gieger, C, Portas, L, van Leeuwen, EM, Amin, N, Uitterlinden, AG, Rivadeneira, F, Hofman, A, Vingerling, JR, Wang, YX, Wang, X, Boh, ET-H, Ikram, MK, Sabanayagam, C, Gupta, P, Tan, V, Zhou, L, Ho, CEH, Lim, W, Beuerman, RW, Siantar, R, Tai, E-S, Vithana, E, Mihailov, E, Khor, C-C, Hayward, C, Luben, RN, Foster, PJ, Klein, BEK, Klein, R, Wong, H-S, Mitchell, P, Metspalu, A, Aung, T, Young, TL, He, M, Paerssinen, O, van Duijn, CM, Wang, JJ, Williams, C, Jonas, JB, Teo, Y-Y, David, AMM, Oexle, K, Yoshimura, N, Paterson, AD, Pfeiffer, N, Wong, T-Y, Baird, PN, Stambolian, D, Bailey-Wilson, JE, Cheng, C-Y, Hammond, CJ, Klaver, CCW, Saw, S-M, Rahi, JS, Korobelnik, J-F, Kemp, JP, Timpson, NJ, Smith, GD, Craig, JE, Burdon, KP, Fogarty, RD, Iyengar, SK, Chew, E, Janmahasatian, S, Martin, NG, MacGregor, S, Xu, L, Schache, M, Nangia, V, Panda-Jonas, S, Wright, AF, Fondran, JR, Lass, JH, Feng, S, Zhao, JH, Khaw, K-T, Wareham, NJ, Rantanen, T, Kaprio, J, Pang, CP, Chen, LJ, Tam, PO, Jhanji, V, Young, AL, Doering, A, Raffel, LJ, Cotch, M-F, Li, X, Yip, SP, Yap, MKH, Biino, G, Vaccargiu, S, Fossarello, M, Fleck, B, Yazar, S, Tideman, JWL, Tedja, M, Deangelis, MM, Morrison, M, Farrer, L, Zhou, X, Chen, W, Mizuki, N, Meguro, A, Makela, KM, Fan, Q, Verhoeven, VJM, Wojciechowski, R, Barathi, VA, Hysi, PG, Guggenheim, JA, Hoehn, R, Vitart, V, Khawaja, AP, Yamashiro, K, Hosseini, SM, Lehtimaki, T, Lu, Y, Haller, T, Xie, J, Delcourt, C, Pirastu, M, Wedenoja, J, Gharahkhani, P, Venturini, C, Miyake, M, Hewitt, AW, Guo, X, Mazur, J, Huffman, JE, Williams, KM, Polasek, O, Campbell, H, Rudan, I, Vatavuk, Z, Wilson, JF, Joshi, PK, McMahon, G, St Pourcain, B, Evans, DM, Simpson, CL, Schwantes-An, T-H, Igo, RP, Mirshahi, A, Cougnard-Gregoire, A, Bellenguez, C, Blettner, M, Raitakari, O, Kaehoenen, M, Seppala, I, Zeller, T, Meitinger, T, Ried, JS, Gieger, C, Portas, L, van Leeuwen, EM, Amin, N, Uitterlinden, AG, Rivadeneira, F, Hofman, A, Vingerling, JR, Wang, YX, Wang, X, Boh, ET-H, Ikram, MK, Sabanayagam, C, Gupta, P, Tan, V, Zhou, L, Ho, CEH, Lim, W, Beuerman, RW, Siantar, R, Tai, E-S, Vithana, E, Mihailov, E, Khor, C-C, Hayward, C, Luben, RN, Foster, PJ, Klein, BEK, Klein, R, Wong, H-S, Mitchell, P, Metspalu, A, Aung, T, Young, TL, He, M, Paerssinen, O, van Duijn, CM, Wang, JJ, Williams, C, Jonas, JB, Teo, Y-Y, David, AMM, Oexle, K, Yoshimura, N, Paterson, AD, Pfeiffer, N, Wong, T-Y, Baird, PN, Stambolian, D, Bailey-Wilson, JE, Cheng, C-Y, Hammond, CJ, Klaver, CCW, Saw, S-M, Rahi, JS, Korobelnik, J-F, Kemp, JP, Timpson, NJ, Smith, GD, Craig, JE, Burdon, KP, Fogarty, RD, Iyengar, SK, Chew, E, Janmahasatian, S, Martin, NG, MacGregor, S, Xu, L, Schache, M, Nangia, V, Panda-Jonas, S, Wright, AF, Fondran, JR, Lass, JH, Feng, S, Zhao, JH, Khaw, K-T, Wareham, NJ, Rantanen, T, Kaprio, J, Pang, CP, Chen, LJ, Tam, PO, Jhanji, V, Young, AL, Doering, A, Raffel, LJ, Cotch, M-F, Li, X, Yip, SP, Yap, MKH, Biino, G, Vaccargiu, S, Fossarello, M, Fleck, B, Yazar, S, Tideman, JWL, Tedja, M, Deangelis, MM, Morrison, M, Farrer, L, Zhou, X, Chen, W, Mizuki, N, Meguro, A, and Makela, KM
Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Published: 2016

127. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Author: Springelkamp, H, Höhn, R, Mishra, A, Hysi, PG, Khor, CC, Loomis, SJ, Bailey, JNC, Gibson, J, Thorleifsson, G, Janssen, SF, Luo, X, Ramdas, WD, Vithana, E, Nongpiur, ME, Montgomery, GW, Xu, L, Mountain, JE, Gharahkhani, P, Lu, Y, Amin, N, Karssen, LC, Sim, KS, Van Leeuwen, EM, Iglesias, AI, Verhoeven, VJM, Hauser, MA, Loon, SC, Despriet, DDG, Nag, A, Venturini, C, Sanfilippo, PG, Schillert, A, Kang, JH, Landers, J, Jonasson, F, Cree, AJ, Van Koolwijk, LME, Rivadeneira, F, Souzeau, E, Jonsson, V, Menon, G, Mitchell, P, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Weinreb, RN, De Jong, PTVM, Oostra, BA, Uitterlinden, AG, Hofman, A, Ennis, S, Thorsteinsdottir, U, Burdon, KP, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Haines, JL, Kraft, P, Lee, RK, Lichter, PR, and Liu, Y
Subjects: genetic structures, sense organs, eye diseases
Abstract: © 2014 Macmillan Publishers Limited. All rights reserved. Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
Published: 2014

128. Genetic evidence that the causal association of educational attainment with reduced risk of Alzheimer's disease is driven by intelligence.

Author: Thorp, Jackson G, Mitchell, Brittany L, Gerring, Zachary F, Ong, Jue‐Sheng, Gharahkhani, Puya, Derks, Eske M, and Lupton, Michelle K
Abstract: Background: Alzheimer's disease (AD) is predicted to affect 132 million people by 2050. Targeting modifiable lifestyle risk factors that are associated with an increased risk of AD could prevent a large proportion of dementia cases, allowing people to reach the end of their life dementia free. However, evidence obtained from observational studies does not take into account how risk factors are correlated with one another, and whether they causally contribute to increased AD risk. In this study, we determine whether the relationship between twelve previously speculated AD risk factors and AD susceptibility is consistent with causality using large‐scale genetic data (table 1). Method: We conduct multivariable Mendelian Randomization (MR) analyses to identify causal risk factors of AD while controlling for genetic pleiotropy, using genetic instruments from the most well powered GWAS studies currently available. We also use GWAS‐by‐subtraction implemented with genomic structural equation modelling (genomic SEM) to understand the cognitive and non‐cognitive components of the causal association of EA on AD risk. Result: We identified significant positive correlations between AD and physical activity and loneliness, and significant negative correlations with educational attainment (EA), intelligence and household income. Using GWAS‐by‐subtraction to partition EA into cognitive (intelligence) and noncognitive genetic factors, we showed a significant genetic correlation between AD and the cognitive factor, but not the noncognitive factor (figure 1). Univariable MR found EA, intelligence, household income and the cognitive factor to all be causally protective against AD. Multivariable MR analysis showed that higher intelligence lowers AD risk, independent of EA and household income. There was no evidence that EA lowers AD risk, independent of intelligence. In addition the cognitive (intelligence) component of EA decreased AD risk with no significant influence of the noncognitive factor (table 2). Conclusion: From the risk factors tested only the cognitive component of EA (i.e., intelligence) is an independent causal risk factor for AD. To reduce incidence of AD this cognitive aspect of EA would need to be modified. It is questionable whether substantial modification of intelligence is achievable through simple interventions such as improving access to extended education. [ABSTRACT FROM AUTHOR]
Published: 2022
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129. Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

Author: Springelkamp, H. (Henriët), Mishra, A. (Aniket), Hysi, P.G. (Pirro), Gharahkhani, P. (Puya), Höhn, R. (René), Khor, C.C., Cooke Bailey, J.N. (Jessica N.), Luo, X. (Xiaoyan), Ramdas, W.D. (Wishal), Vithana, E.N. (Eranga), Koh, V. (Victor), Yazar, S. (Seyhan), Xu, L. (Liang), Forward, H. (Hannah), Kearns, L.S. (Lisa S.), Amin, N. (Najaf), Iglesias González, A.I. (Adriana), Sim, K.S., Leeuwen, E.M. (Elisa) van, Demirkan, A. (Ayşe), Lee, S.J. (Sven) van der, Loon, S.-C. (Seng-Chee), Rivadeneira Ramirez, F. (Fernando), Nag, A. (Abhishek), Sanfilippo, P.G. (Paul G.), Schillert, A. (Arne), Jong, P.T.V.M. (Paulus) de, Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Hofman, A. (Albert), Zhou, T. (Tiger), Burdon, K.P. (Kathryn), Spector, T.D. (Timothy), Lackner, K.J. (Karl), Saw, S-M. (Seang-Mei), Vingerling, J.R. (Hans), Teo, Y.Y. (Yik Ying), Pasquale, L.R. (Louis), Wolfs, R.C.W. (Roger), Lemij, H.G. (Hans), Tai, E.S. (Shyong), Jonas, J.B. (Jost B.), Cheng, C-Y. (Ching-Yu), Aung, T. (Tin), Jansonius, N.M. (Nomdo), Klaver, C.C.W. (Caroline), Craig, J.E. (Jamie), Young, T.L. (Terri), Haines, J.L. (Jonathan), MacGregor, S. (Stuart), Mackey, D.A. (David), Pfeiffer, A.F.H. (Andreas), Wong, T.Y. (Tien Yin), Wiggs, J.L. (Janey), Hewit, A.W. (Alex), Duijn, C.M. (Cornelia) van, Hammond, C.J. (Christopher), Springelkamp, H. (Henriët), Mishra, A. (Aniket), Hysi, P.G. (Pirro), Gharahkhani, P. (Puya), Höhn, R. (René), Khor, C.C., Cooke Bailey, J.N. (Jessica N.), Luo, X. (Xiaoyan), Ramdas, W.D. (Wishal), Vithana, E.N. (Eranga), Koh, V. (Victor), Yazar, S. (Seyhan), Xu, L. (Liang), Forward, H. (Hannah), Kearns, L.S. (Lisa S.), Amin, N. (Najaf), Iglesias González, A.I. (Adriana), Sim, K.S., Leeuwen, E.M. (Elisa) van, Demirkan, A. (Ayşe), Lee, S.J. (Sven) van der, Loon, S.-C. (Seng-Chee), Rivadeneira Ramirez, F. (Fernando), Nag, A. (Abhishek), Sanfilippo, P.G. (Paul G.), Schillert, A. (Arne), Jong, P.T.V.M. (Paulus) de, Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Hofman, A. (Albert), Zhou, T. (Tiger), Burdon, K.P. (Kathryn), Spector, T.D. (Timothy), Lackner, K.J. (Karl), Saw, S-M. (Seang-Mei), Vingerling, J.R. (Hans), Teo, Y.Y. (Yik Ying), Pasquale, L.R. (Louis), Wolfs, R.C.W. (Roger), Lemij, H.G. (Hans), Tai, E.S. (Shyong), Jonas, J.B. (Jost B.), Cheng, C-Y. (Ching-Yu), Aung, T. (Tin), Jansonius, N.M. (Nomdo), Klaver, C.C.W. (Caroline), Craig, J.E. (Jamie), Young, T.L. (Terri), Haines, J.L. (Jonathan), MacGregor, S. (Stuart), Mackey, D.A. (David), Pfeiffer, A.F.H. (Andreas), Wong, T.Y. (Tien Yin), Wiggs, J.L. (Janey), Hewit, A.W. (Alex), Duijn, C.M. (Cornelia) van, and Hammond, C.J. (Christopher)
Abstract: Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed
Published: 2015
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130. A common variant near TGFBR3 is associated with primary open angle glaucoma

Author: Li, Z, Allingham, RR, Nakano, M, Jia, L, Chen, Y, Ikeda, Y, Mani, B, Chen, L-J, Kee, C, Garway-Heath, DF, Sripriya, S, Fuse, N, Abu-Amero, KK, Huang, C, Namburi, P, Burdon, K, Perera, SA, Gharahkhani, P, Lin, Y, Ueno, M, Ozaki, M, Mizoguchi, T, Krishnadas, SR, Osman, EA, Lee, MC, Chan, ASY, Tajudin, L-SA, Do, T, Goncalves, A, Reynier, P, Zhang, H, Bourne, R, Goh, D, Broadway, D, Husain, R, Negi, AK, Su, DH, Ho, C-L, Blanco, AA, Leung, CKS, Wong, TT, Yakub, A, Liu, Y, Nongpiur, ME, Han, JC, Hon, DN, Shantha, B, Zhao, B, Sang, J, Zhang, N, Sato, R, Yoshii, K, Panda-Jonas, S, Koch, AEA, Herndon, LW, Moroi, SE, Challa, P, Foo, JN, Bei, J-X, Zeng, Y-X, Simmons, CP, Tran, NBC, Sharmila, PF, Chew, M, Lim, B, Tam, POS, Chua, E, Ng, XY, Yong, VHK, Chong, YF, Meah, WY, Vijayan, S, Seongsoo, S, Xu, W, Teo, YY, Bailey, JNC, Kang, JH, Haines, JL, Cheng, CY, Saw, S-M, Tai, E-S, Richards, JE, Ritch, R, Gaasterland, DE, Pasquale, LR, Liu, J, Jonas, JB, Milea, D, George, R, Al-Obeidan, SA, Mori, K, Macgregor, S, Hewitt, AW, Girkin, CA, Zhang, M, Sundaresan, P, Vijaya, L, Mackey, DA, Wong, TY, Craig, JE, Sun, X, Kinoshita, S, Wiggs, JL, Khor, C-C, Yang, Z, Pang, CP, Wang, N, Hauser, MA, Tashiro, K, Aung, T, Vithana, EN, Li, Z, Allingham, RR, Nakano, M, Jia, L, Chen, Y, Ikeda, Y, Mani, B, Chen, L-J, Kee, C, Garway-Heath, DF, Sripriya, S, Fuse, N, Abu-Amero, KK, Huang, C, Namburi, P, Burdon, K, Perera, SA, Gharahkhani, P, Lin, Y, Ueno, M, Ozaki, M, Mizoguchi, T, Krishnadas, SR, Osman, EA, Lee, MC, Chan, ASY, Tajudin, L-SA, Do, T, Goncalves, A, Reynier, P, Zhang, H, Bourne, R, Goh, D, Broadway, D, Husain, R, Negi, AK, Su, DH, Ho, C-L, Blanco, AA, Leung, CKS, Wong, TT, Yakub, A, Liu, Y, Nongpiur, ME, Han, JC, Hon, DN, Shantha, B, Zhao, B, Sang, J, Zhang, N, Sato, R, Yoshii, K, Panda-Jonas, S, Koch, AEA, Herndon, LW, Moroi, SE, Challa, P, Foo, JN, Bei, J-X, Zeng, Y-X, Simmons, CP, Tran, NBC, Sharmila, PF, Chew, M, Lim, B, Tam, POS, Chua, E, Ng, XY, Yong, VHK, Chong, YF, Meah, WY, Vijayan, S, Seongsoo, S, Xu, W, Teo, YY, Bailey, JNC, Kang, JH, Haines, JL, Cheng, CY, Saw, S-M, Tai, E-S, Richards, JE, Ritch, R, Gaasterland, DE, Pasquale, LR, Liu, J, Jonas, JB, Milea, D, George, R, Al-Obeidan, SA, Mori, K, Macgregor, S, Hewitt, AW, Girkin, CA, Zhang, M, Sundaresan, P, Vijaya, L, Mackey, DA, Wong, TY, Craig, JE, Sun, X, Kinoshita, S, Wiggs, JL, Khor, C-C, Yang, Z, Pang, CP, Wang, N, Hauser, MA, Tashiro, K, Aung, T, and Vithana, EN
Abstract: Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.
Published: 2015

131. ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

Author: Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Cuellar-Partida, G, Amin, Najaf, Burdon, KP, Leeuwen, Elisa, Gharahkhani, P, Mishra, A, van der Lee, Sven, Hewitt, AW, Rivadeneira, Fernando, Viswanathan, AC, Wolfs, R.C.W., Martin, NG, Ramdas, Wishal, van Koolwijk, LM, Pennell, CE, Vingerling, Hans, Mountain, JE, Uitterlinden, André, Hofman, Bert, Mitchell, P, Lemij, HG, Wang, JJ, Klaver, Caroline, Mackey, DA, Craig, JE, Duijn, Cornelia, Macgregor, S, Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Cuellar-Partida, G, Amin, Najaf, Burdon, KP, Leeuwen, Elisa, Gharahkhani, P, Mishra, A, van der Lee, Sven, Hewitt, AW, Rivadeneira, Fernando, Viswanathan, AC, Wolfs, R.C.W., Martin, NG, Ramdas, Wishal, van Koolwijk, LM, Pennell, CE, Vingerling, Hans, Mountain, JE, Uitterlinden, André, Hofman, Bert, Mitchell, P, Lemij, HG, Wang, JJ, Klaver, Caroline, Mackey, DA, Craig, JE, Duijn, Cornelia, and Macgregor, S
Abstract: Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (beta = 0.44, P-value = 1.87 x 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (beta = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 x 10(-)8], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 x 10(-9); for normal-tension glaucoma OR = 1.29, P-value = 4.23 x 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.
Published: 2015

132. Myocilin Gene Gln368Ter Variant Penetrance and Association With Glaucoma in Population-Based and Registry-Based Studies

Author: Han, Xikun, Souzeau, Emmanuelle, Ong, Jue-Sheng, An, Jiyuan, Siggs, Owen M., Burdon, Kathryn P., Best, Stephen, Goldberg, Ivan, Healey, Paul R., Graham, Stuart L., Ruddle, Jonathan B., Mills, Richard A., Landers, John, Galanopoulos, Anna, White, Andrew J.R., Casson, Robert, Mackey, David A., Hewitt, Alex W., Gharahkhani, Puya, Craig, Jamie E., and MacGregor, Stuart
Abstract: IMPORTANCE: The p.Gln368Ter (rs74315329) risk allele in the myocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom. OBJECTIVES: To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT). DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018. MAIN OUTCOMES AND MEASURES: The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT. RESULTS: A total of 411 337 UKBB participants of white British ancestry (mean [SD] age, 56.6 [8.0] years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13%). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95% CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95% CI, 3.38-5.71); OHT, 3.56 (95% CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95% CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6% in patients with glaucoma, 24.3% in patients with OHT, and 30.8% in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95% CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95% CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1%, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5%. CONCLUSIONS AND RELEVANCE: The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50% of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.
Published: 2019
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133. ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

Author: Springelkamp, H., primary, Iglesias, A. I., additional, Cuellar-Partida, G., additional, Amin, N., additional, Burdon, K. P., additional, van Leeuwen, E. M., additional, Gharahkhani, P., additional, Mishra, A., additional, van der Lee, S. J., additional, Hewitt, A. W., additional, Rivadeneira, F., additional, Viswanathan, A. C., additional, Wolfs, R. C. W., additional, Martin, N. G., additional, Ramdas, W. D., additional, van Koolwijk, L. M., additional, Pennell, C. E., additional, Vingerling, J. R., additional, Mountain, J. E., additional, Uitterlinden, A. G., additional, Hofman, A., additional, Mitchell, P., additional, Lemij, H. G., additional, Wang, J. J., additional, Klaver, C. C. W., additional, Mackey, D. A., additional, Craig, J. E., additional, van Duijn, C. M., additional, and MacGregor, S., additional
Published: 2015
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134. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Author: Springelkamp, H. (Henriët), Höhn, R. (René), Mishra, A. (Aniket), Hysi, P.G. (Pirro), Khor, C.C., Loomis, S.J. (Stephanie J.), Bailey, J.N.C. (Jessica N. Cooke), Gibson, J. (Jane), Thorleifsson, G. (Gudmar), Janssen, S.F. (Sarah), Luo, X. (Xiaoyan), Ramdas, W.D. (Wishal), Vithana, E.N. (Eranga), Nongpiur, M.E. (Monisha E.), Montgomery, G.W. (Grant), Xu, L. (Liang), Mountain, J.E. (Jenny E.), Gharahkhani, P. (Puya), Lu, Y. (Yi), Amin, N. (Najaf), Karssen, L.C. (Lennart), Sim, K.S., Leeuwen, E.M. (Elisa) van, Iglesias González, A.I. (Adriana), Verhoeven, V.J.M. (Virginie), Hauser, M.A. (Michael), Loon, S.-C. (Seng-Chee), Despriet, D.D.G. (Dominique), Nag, A. (Abhishek), Venturini, C. (Cristina), Sanfilippo, P.G. (Paul G.), Schillert, A. (Arne), Kang, J.H. (Jae), Landers, J. (John), Jonasson, F. (Fridbert), Cree, A.J. (Angela), Koolwijk, L.M.E. (Leonieke) van, Rivadeneira Ramirez, F. (Fernando), Souzeau, E. (Emmanuelle), Jonsson, V. (Vesteinn), Menon, G. (Geeta), Mitchell, P. (Paul), Wang, J.J. (Jie Jin), Rochtchina, E. (Elena), Attia, J. (John), Scott, R. (Rodney), Holliday, E.G. (Elizabeth), Baird, P.N. (Paul), Xie, J. (Jing), Inouye, M. (Michael), Viswanathan, A.C. (Ananth), Sim, X. (Xueling), Weinreb, R.N. (Robert N.), Jong, P.T.V.M. (Paulus) de, Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Hofman, A. (Albert), Ennis, S. (Sarah), Thorsteinsdottir, U. (Unnur), Burdon, K.P. (Kathryn), Spector, T.D. (Timothy), Mirshahi, A. (Alireza), Saw, S-M. (Seang-Mei), Vingerling, J.R. (Hans), Teo, Y.Y. (Yik Ying), Wolfs, R.C.W. (Roger), Lemij, H.G. (Hans), Tai, E.S. (Shyong), Jansonius, N.M. (Nomdo), Jonas, J.B. (Jost B.), Cheng, C-Y. (Ching-Yu), Aung, T. (Tin), Klaver, C.C.W. (Caroline), Craig, J.E. (Jamie), MacGregor, S. (Stuart), Mackey, D.A. (David), Lotery, A.J. (Andrew), Zwart, J-A. (John-Anker), Bergen, A.A.B. (Arthur), Young, T.L. (Terri), Wiggs, J.L. (Janey), Pfeiffer, A.F.H. (Andreas), Wong, T.Y. (Tien Yin), Pasquale, L.R. (Louis), Hewit, A.W. (Alex), Duijn, C.M. (Cornelia) van, Hammond, C.J. (Christopher), Springelkamp, H. (Henriët), Höhn, R. (René), Mishra, A. (Aniket), Hysi, P.G. (Pirro), Khor, C.C., Loomis, S.J. (Stephanie J.), Bailey, J.N.C. (Jessica N. Cooke), Gibson, J. (Jane), Thorleifsson, G. (Gudmar), Janssen, S.F. (Sarah), Luo, X. (Xiaoyan), Ramdas, W.D. (Wishal), Vithana, E.N. (Eranga), Nongpiur, M.E. (Monisha E.), Montgomery, G.W. (Grant), Xu, L. (Liang), Mountain, J.E. (Jenny E.), Gharahkhani, P. (Puya), Lu, Y. (Yi), Amin, N. (Najaf), Karssen, L.C. (Lennart), Sim, K.S., Leeuwen, E.M. (Elisa) van, Iglesias González, A.I. (Adriana), Verhoeven, V.J.M. (Virginie), Hauser, M.A. (Michael), Loon, S.-C. (Seng-Chee), Despriet, D.D.G. (Dominique), Nag, A. (Abhishek), Venturini, C. (Cristina), Sanfilippo, P.G. (Paul G.), Schillert, A. (Arne), Kang, J.H. (Jae), Landers, J. (John), Jonasson, F. (Fridbert), Cree, A.J. (Angela), Koolwijk, L.M.E. (Leonieke) van, Rivadeneira Ramirez, F. (Fernando), Souzeau, E. (Emmanuelle), Jonsson, V. (Vesteinn), Menon, G. (Geeta), Mitchell, P. (Paul), Wang, J.J. (Jie Jin), Rochtchina, E. (Elena), Attia, J. (John), Scott, R. (Rodney), Holliday, E.G. (Elizabeth), Baird, P.N. (Paul), Xie, J. (Jing), Inouye, M. (Michael), Viswanathan, A.C. (Ananth), Sim, X. (Xueling), Weinreb, R.N. (Robert N.), Jong, P.T.V.M. (Paulus) de, Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Hofman, A. (Albert), Ennis, S. (Sarah), Thorsteinsdottir, U. (Unnur), Burdon, K.P. (Kathryn), Spector, T.D. (Timothy), Mirshahi, A. (Alireza), Saw, S-M. (Seang-Mei), Vingerling, J.R. (Hans), Teo, Y.Y. (Yik Ying), Wolfs, R.C.W. (Roger), Lemij, H.G. (Hans), Tai, E.S. (Shyong), Jansonius, N.M. (Nomdo), Jonas, J.B. (Jost B.), Cheng, C-Y. (Ching-Yu), Aung, T. (Tin), Klaver, C.C.W. (Caroline), Craig, J.E. (Jamie), MacGregor, S. (Stuart), Mackey, D.A. (David), Lotery, A.J. (Andrew), Zwart, J-A. (John-Anker), Bergen, A.A.B. (Arthur), Young, T.L. (Terri), Wiggs, J.L. (Janey), Pfeiffer, A.F.H. (Andreas), Wong, T.Y. (Tien Yin), Pasquale, L.R. (Louis), Hewit, A.W. (Alex), Duijn, C.M. (Cornelia) van, and Hammond, C.J. (Christopher)
Abstract: Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
Published: 2014
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135. Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma

Author: Gharahkhani, P, Burdon, KP, Fogarty, R, Sharma, S, Hewitt, AW, Martin, S, Law, MH, Cremin, K, Bailey, JNC, Loomis, SJ, Pasquale, LR, Haines, JL, Hauser, MA, Viswanathan, AC, McGuffin, P, Topouzis, F, Foster, PJ, Graham, SL, Casson, RJ, Chehade, M, White, AJ, Zhou, T, Souzeau, E, Landers, J, Fitzgerald, JT, Klebe, S, Ruddle, JB, Goldberg, I, Healey, PR, Mills, RA, Wang, JJ, Montgomery, GW, Martin, NG, Radford-Smith, G, Whiteman, DC, Brown, MA, Wiggs, JL, Mackey, DA, Mitchell, P, MacGregor, S, Craig, JE, Gharahkhani, P, Burdon, KP, Fogarty, R, Sharma, S, Hewitt, AW, Martin, S, Law, MH, Cremin, K, Bailey, JNC, Loomis, SJ, Pasquale, LR, Haines, JL, Hauser, MA, Viswanathan, AC, McGuffin, P, Topouzis, F, Foster, PJ, Graham, SL, Casson, RJ, Chehade, M, White, AJ, Zhou, T, Souzeau, E, Landers, J, Fitzgerald, JT, Klebe, S, Ruddle, JB, Goldberg, I, Healey, PR, Mills, RA, Wang, JJ, Montgomery, GW, Martin, NG, Radford-Smith, G, Whiteman, DC, Brown, MA, Wiggs, JL, Mackey, DA, Mitchell, P, MacGregor, S, and Craig, JE
Abstract: Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
Published: 2014

136. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias, Adriana I., Mishra, Aniket, Vitart, Veronique, Bykhovskaya, Yelena, Höhn, René, Springelkamp, Henriët, Cuellar-Partida, Gabriel, Gharahkhani, Puya, Bailey, Jessica N. Cooke, Willoughby, Colin E., Li, Xiaohui, Yazar, Seyhan, Nag, Abhishek, Khawaja, Anthony P., Polašek, Ozren, Siscovick, David, Mitchell, Paul, Tham, Yih Chung, Haines, Jonathan L., Kearns, Lisa S., Hayward, Caroline, Shi, Yuan, van Leeuwen, Elisabeth M., Taylor, Kent D., Wang, Jie Jin, Rochtchina, Elena, Attia, John, Scott, Rodney, Holliday, Elizabeth G., Wong, Tien Yin, Baird, Paul N., Xie, Jing, Inouye, Michael, Viswanathan, Ananth, Sim, Xueling, Bonnemaijer, Pieter, Rotter, Jerome I., Martin, Nicholas G., Zeller, Tanja, Mills, Richard A., Staffieri, Sandra E., Jonas, Jost B., Schmidtmann, Irene, Boutin, Thibaud, Kang, Jae H., Lucas, Sionne E. M., Beutel, Manfred E., Wilson, James F., Allingham, R. Rand, Brilliant, Murray H., Budenz, Donald L., Christen, William G., Fingert, John, Friedman, David S., Gaasterland, Douglas, Gaasterland, Terry, Hauser, Michael A., Kraft, Peter, Lee, Richard K., Lichter, Paul R., Liu, Yutao, Loomis, Stephanie J., Moroi, Sayoko E., Pericak-Vance, Margaret A., Realini, Anthony, Richards, Julia E., Schuman, Joel S., Scott, William K., Singh, Kuldev, Sit, Arthur J., Vollrath, Douglas, Weinreb, Robert N., Wollstein, Gadi, Zack, Donald J., Zhang, Kang, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M., Bramon, Elvira, Brown, Matthew A., Casas, Juan P., Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S., Mathew, Christopher G., Palmer, Colin N. A., Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J., Trembath, Richard C., Wood, Nicholas W., Spencer, Chris C. A., Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E., Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J., Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T., Liddle, Jennifer, Potter, Simon C., Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Uitterlinden, André G., Vithana, Eranga N., Foster, Paul J., Hysi, Pirro G., Hewitt, Alex W., Khor, Chiea Chuen, Pasquale, Louis R., Montgomery, Grant W., Klaver, Caroline C. W., Aung, Tin, Pfeiffer, Norbert, Mackey, David A., Hammond, Christopher J., Cheng, Ching-Yu, Craig, Jamie E., Rabinowitz, Yaron S., Wiggs, Janey L., Burdon, Kathryn P., van Duijn, Cornelia M., and MacGregor, Stuart
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, >20% 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.
Published: 2018
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137. Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

Author: Gharahkhani, Puya, Burdon, Kathryn P., Cooke Bailey, Jessica N., Hewitt, Alex W., Law, Matthew H., Pasquale, Louis R., Kang, Jae H., Haines, Jonathan L., Souzeau, Emmanuelle, Zhou, Tiger, Siggs, Owen M., Landers, John, Awadalla, Mona, Sharma, Shiwani, Mills, Richard A., Ridge, Bronwyn, Lynn, David, Casson, Robert, Graham, Stuart L., Goldberg, Ivan, White, Andrew, Healey, Paul R., Grigg, John, Lawlor, Mitchell, Mitchell, Paul, Ruddle, Jonathan, Coote, Michael, Walland, Mark, Best, Stephen, Vincent, Andrea, Gale, Jesse, RadfordSmith, Graham, Whiteman, David C., Montgomery, Grant W., Martin, Nicholas G., Mackey, David A, Wiggs, Janey L., MacGregor, Stuart, Craig, Jamie E., Allingham, R. Rand, Brilliant, Murray, Budenz, Donald L., Fingert, John H., Gaasterland, Douglas, Gaasterland, Teresa, Hark, Lisa, Hauser, Michael, Igo, Robert P., Kraft, Peter, Lee, Richard K., Lichter, Paul R., Liu, Yutao, Moroi, Syoko, Pericak-Vance, Margaret, Realini, Anthony, Rhee, Doug, Richards, Julia E., Ritch, Robert, Schuman, Joel S., Scott, William K., Singh, Kuldev, Sit, Arthur J., Vollrath, Douglas, Wollstein, Gadi, and Zack, Donald J.
Abstract: 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.
Published: 2018
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138. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

Author: Cooke Bailey, Jessica N., Gharahkhani, Puya, Kang, Jae H., Butkiewicz, Mariusz, Sullivan, David A., Weinreb, Robert N., Aschard, Hugues, Allingham, R. Rand, Ashley-Koch, Allison, Lee, Richard K., Moroi, Sayoko E., Brilliant, Murray H., Wollstein, Gadi, Schuman, Joel S., Fingert, John H., Budenz, Donald L., Realini, Tony, Gaasterland, Terry, Scott, William K., Singh, Kuldev, Sit, Arthur J., Igo, Robert P., Song, Yeunjoo E., Hark, Lisa, Ritch, Robert, Rhee, Douglas J., Vollrath, Douglas, Zack, Donald J., Medeiros, Felipe, Vajaranant, Thasarat S., Chasman, Daniel I., Christen, William G., Pericak-Vance, Margaret A., Liu, Yutao, Kraft, Peter, Richards, Julia E., Rosner, Bernard A., Hauser, Michael A., Craig, Jamie E., Burdon, Kathryn P., Hewitt, Alex W., Mackey, David A., Haines, Jonathan L., MacGregor, Stuart, Wiggs, Janey L., and Pasquale, Louis R.
Subjects: primary open-angle glaucoma, testosterone, genetics, pathway analysis
Abstract: Purpose Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.
Published: 2018
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139. Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma

Author: Buas, Matthew F, He, Qianchuan, Johnson, Lisa G, Onstad, Lynn, Levine, David M, Thrift, Aaron P, Gharahkhani, Puya, Palles, Claire, Lagergren, Jesper, Fitzgerald, Rebecca C, Ye, Weimin, Caldas, Carlos, Bird, Nigel C, Shaheen, Nicholas J, Bernstein, Leslie, Gammon, Marilie D, Wu, Anna H, Hardie, Laura J, Pharoah, Paul D, Liu, Geoffrey, Iyer, Prassad, Corley, Douglas A, Risch, Harvey A, Chow, Wong-Ho, Prenen, Hans, Chegwidden, Laura, Love, Sharon, Attwood, Stephen, Moayyedi, Paul, MacDonald, David, Harrison, Rebecca, Watson, Peter, Barr, Hugh, deCaestecker, John, Tomlinson, Ian, Jankowski, Janusz, Whiteman, David C, MacGregor, Stuart, Vaughan, Thomas L, and Madeleine, Margaret M
Abstract: ObjectiveOesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA.DesignWe used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk.ResultsWe identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10−5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk.ConclusionsThis study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1influence disease susceptibility.
Published: 2017
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140. A common variant near TGFBR3 is associated with primary open angle glaucoma

Author: Li, Zheng, Allingham, R. Rand, Nakano, Masakazu, Jia, Liyun, Chen, Yuhong, Ikeda, Yoko, Mani, Baskaran, Chen, Li-Jia, Kee, Changwon, Garway-Heath, David F., Sripriya, Sarangapani, Fuse, Nobuo, Abu-Amero, Khaled K., Huang, Chukai, Namburi, Prasanthi, Burdon, Kathryn, Perera, Shamira A., Gharahkhani, Puya, Lin, Ying, Ueno, Morio, Ozaki, Mineo, Mizoguchi, Takanori, Krishnadas, Subbiah Ramasamy, Osman, Essam A., Lee, Mei Chin, Chan, Anita S.Y., Tajudin, Liza-Sharmini A., Do, Tan, Goncalves, Aurelien, Reynier, Pascal, Zhang, Hong, Bourne, Rupert, Goh, David, Broadway, David, Husain, Rahat, Negi, Anil K., Su, Daniel H, Ho, Ching-Lin, Blanco, Augusto Azuara, Leung, Christopher K.S., Wong, Tina T., Yakub, Azhany, Liu, Yutao, Nongpiur, Monisha E., Han, Jong Chul, Hon, Do Nhu, Shantha, Balekudaru, Zhao, Bowen, Sang, Jinghong, Zhang, NiHong, Sato, Ryuichi, Yoshii, Kengo, Panda-Jonas, Songhomita, Ashley Koch, Allison E., Herndon, Leon W., Moroi, Sayoko E., Challa, Pratap, Foo, Jia Nee, Bei, Jin-Xin, Zeng, Yi-Xin, Simmons, Cameron P., Bich Chau, Tran Nguyen, Sharmila, Philomenadin Ferdinamarie, Chew, Merwyn, Lim, Blanche, Tam, Pansy O.S., Chua, Elaine, Ng, Xiao Yu, Yong, Victor H.K., Chong, Yaan Fun, Meah, Wee Yang, Vijayan, Saravanan, Seongsoo, Sohn, Xu, Wang, Teo, Yik Ying, Cooke Bailey, Jessica N., Kang, Jae H., Haines, Jonathan L., Cheng, Ching Yu, Saw, Seang-Mei, Tai, E-Shyong, Richards, Julia E., Ritch, Robert, Gaasterland, Douglas E., Pasquale, Louis R., Liu, Jianjun, Jonas, Jost B., Milea, Dan, George, Ronnie, Al-Obeidan, Saleh A., Mori, Kazuhiko, Macgregor, Stuart, Hewitt, Alex W., Girkin, Christopher A., Zhang, Mingzhi, Sundaresan, Periasamy, Vijaya, Lingam, Mackey, David A., Wong, Tien Yin, Craig, Jamie E., Sun, Xinghuai, Kinoshita, Shigeru, Wiggs, Janey L., Khor, Chiea-Chuen, Yang, Zhenglin, Pang, Chi Pui, Wang, Ningli, Hauser, Michael A., Tashiro, Kei, Aung, Tin, and Vithana, Eranga N.
Abstract: Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10−33), we observed one SNP showing significant association to POAG (CDC7–TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10−8). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.
Published: 2015
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141. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open angle glaucoma

Author: Cooke Bailey, Jessica N., Loomis, Stephanie J., Kang, Jae H., Allingham, R. Rand, Gharahkhani, Puya, Khor, Chiea Chuen, Burdon, Kathryn P., Aschard, Hugues, Chasman, Daniel I., Igo, Robert P., Hysi, Pirro G., Glastonbury, Craig A., Ashley-Koch, Allison, Brilliant, Murray, Brown, Andrew A., Budenz, Donald L., Buil, Alfonso, Cheng, Ching-Yu, Choi, Hyon, Christen, William G., Curhan, Gary, De Vivo, Immaculata, Fingert, John H., Foster, Paul J., Fuchs, Charles, Gaasterland, Douglas, Gaasterland, Terry, Hewitt, Alex W., Hu, Frank, Hunter, David J., Khawaja, Anthony P., Lee, Richard K., Li, Zheng, Lichter, Paul R., Mackey, David A., McGuffin, Peter, Mitchell, Paul, Moroi, Sayoko E., Perera, Shamira A., Pepper, Keating W., Qi, Qibin, Realini, Tony, Richards, Julia E., Ridker, Paul M, Rimm, Eric, Ritch, Robert, Ritchie, Marylyn, Schuman, Joel S., Scott, William K., Singh, Kuldev, Sit, Arthur J., Song, Yeunjoo E., Tamimi, Rulla M., Topouzis, Fotis, Viswanathan, Ananth C., Verma, Shefali Setia, Vollrath, Douglas, Wang, Jie Jin, Weisschuh, Nicole, Wissinger, Bernd, Wollstein, Gadi, Wong, Tien Y., Yaspan, Brian L., Zack, Donald J., Zhang, Kang, Weinreb, Robert N., Pericak-Vance, Margaret A., Small, Kerrin, Hammond, Christopher J., Aung, Tin, Liu, Yutao, Vithana, Eranga N., MacGregor, Stuart, Craig, Jamie E., Kraft, Peter, Howell, Gareth, Hauser, Michael A., Pasquale, Louis R., Haines, Jonathan L., and Wiggs, Janey L.
Abstract: Primary open angle glaucoma (POAG) is a leading cause of blindness world-wide. To identify new susceptibility loci, we meta-analyzed GWAS results from 8 independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significant SNPs in two Australian studies (1,252 cases and 2,592 controls), 3 European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of top SNPs identified three novel loci: rs35934224[T] within TXNRD2 (odds ratio (OR) = 0.78, P = 4.05×10−11 encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] within ATXN2 (OR = 1.17, P = 8.73×10−10), and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76×10−10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest novel targets for preventative therapies.
Published: 2015
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142. Pleiotropic Analysis of Cancer Risk Loci on Esophageal Adenocarcinoma Risk.

Author: Eunjung Lee, Stram, Daniel O., Ek, Weronica E., Onstad, Lynn E., MacGregor, Stuart, Gharahkhani, Puya, Weimin Ye, Lagergren, Jesper, Shaheen, Nicholas J., Murray, Liam J., Hardie, Laura J., Gammon, Marilie D., Wong-Ho Chow, Risch, Harvey A., Corley, Douglas A., Levine, David M., Whiteman, David C., Bernstein, Leslie, Bird, Nigel C., and Vaughan, Thomas L.
Abstract: Background: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus. Methods: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. Results: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. Conclusions: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus. Impact: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks ofEAand Barrett's esophagus. [ABSTRACT FROM AUTHOR]
Published: 2015
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143. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Author: Springelkamp, Henriët., Höhn, René, Mishra, Aniket, Hysi, Pirro G., Khor, Chiea-Chuen, Loomis, Stephanie J., Bailey, Jessica N. Cooke, Gibson, Jane, Thorleifsson, Gudmar, Janssen, Sarah F., Luo, Xiaoyan, Ramdas, Wishal D., Vithana, Eranga, Nongpiur, Monisha E., Montgomery, Grant W., Xu, Liang, Mountain, Jenny E., Gharahkhani, Puya, Lu, Yi, Amin, Najaf, Karssen, Lennart C., Sim, Kar-Seng, van Leeuwen, Elisabeth M., Iglesias, Adriana I., Verhoeven, Virginie J. M., Hauser, Michael A., Loon, Seng-Chee, Despriet, Dominiek D. G., Nag, Abhishek, Venturini, Cristina, Sanfilippo, Paul G., Schillert, Arne, Kang, Jae H., Landers, John, Jonasson, Fridbert, Cree, Angela J., van Koolwijk, Leonieke M. E., Rivadeneira, Fernando, Souzeau, Emmanuelle, Jonsson, Vesteinn, Menon, Geeta, Mitchell, Paul, Wang, Jie Jin, Rochtchina, Elena, Attia, John, Scott, Rodney, Holliday, Elizabeth G., Wong, Tien-Yin, Baird, Paul N., Xie, Jing, Inouye, Michael, Viswanathan, Ananth, Sim, Xueling, Weinreb, Robert N., de Jong, Paulus T. V. M., Oostra, Ben A., Uitterlinden, André G., Hofman, Albert, Ennis, Sarah, Thorsteinsdottir, Unnur, Burdon, Kathryn P., Allingham, R. Rand, Brilliant, Murray H., Budenz, Donald L., Cooke Bailey, Jessica N., Christen, William G., Fingert, John, Friedman, David S., Gaasterland, Douglas, Gaasterland, Terry, Haines, Jonathan L., Kang, Jae Hee, Kraft, Peter, Lee, Richard K., Lichter, Paul R., Liu, Yutao, Moroi, Sayoko E., Pasquale, Louis R., Pericak-Vance, Margaret A., Realini, Anthony, Richards, Julia E., Schuman, Joel S., Scott, William K., Singh, Kuldev, Sit, Arthur J., Vollrath, Douglas, Wiggs, Janey L., Wollstein, Gadi, Zack, Donald J., Zhang, Kang, Donnelly (Chair), Peter, Barroso (Deputy Chair), Ines, Blackwell, Jenefer M., Bramon, Elvira, Brown, Matthew A., Casas, Juan P., Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S., Mathew, Christopher G., Palmer, Colin N. A., Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J., Trembath, Richard C., Viswanathan, Ananth C., Wood, Nicholas W., Spencer, Chris C. A., Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Donnelly, Peter, Langford, Cordelia, Hunt, Sarah E., Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J., Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T., Liddle, Jennifer, Potter, Simon C., Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Barroso, Ines, Mathew (Chair), Christopher G., Spector, Timothy D., Mirshahi, Alireza, Saw, Seang-Mei, Vingerling, Johannes R., Teo, Yik-Ying, Wolfs, Roger C. W., Lemij, Hans G., Tai, E-Shyong, Jansonius, Nomdo M., Jonas, Jost B., Cheng, Ching-Yu, Aung, Tin, Klaver, Caroline C. W., Craig, Jamie E., Macgregor, Stuart, Mackey, David A., Lotery, Andrew J., Stefansson, Kari, Bergen, Arthur A. B., Young, Terri L., Pfeiffer, Norbert, Hewitt, Alex W., van Duijn, Cornelia M., and Hammond, Christopher J.
Abstract: Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
Published: 2014
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144. Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma

Author: Gharahkhani, Puya, Burdon, Kathryn P, Fogarty, Rhys, Sharma, Shiwani, Hewitt, Alex W., Martin, Sarah, Law, Matthew H., Cremin, Katie, Bailey, Jessica N. Cooke, Loomis, Stephanie J., Pasquale, Louis R., Haines, Jonathan L., Hauser, Michael A., Viswanathan, Ananth C., McGuffin, Peter, Topouzis, Fotis, Foster, Paul J., Graham, Stuart L, Casson, Robert J, Chehade, Mark, White, Andrew J, Zhou, Tiger, Souzeau, Emmanuelle, Landers, John, Fitzgerald, Jude T, Klebe, Sonja, Ruddle, Jonathan B, Goldberg, Ivan, Healey, Paul R, Mills, Richard A., Wang, Jie Jin, Montgomery, Grant W., Martin, Nicholas G., RadfordSmith, Graham, Whiteman, David C., Brown, Matthew A., Wiggs, Janey L., Mackey, David A, Mitchell, Paul, MacGregor, Stuart, and Craig, Jamie E.
Abstract: Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 advanced POAG cases and 1,992 controls. Association of the top SNPs from the discovery stage was investigated in two Australian replication cohorts (total 932 cases, 6,862 controls) and two US replication cohorts (total 2,616 cases, 2,634 controls). Meta-analysis of all cohorts revealed three novel loci associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493 [G] OR=1.31, P= 2.1 × 10-19), within AFAP1 (rs4619890 [G] OR=1.20, P= 7.0 × 10-10) and within GMDS (rs11969985 [G] OR=1.31, and P= 7.7 × 10-10). Using RT-PCR and immunolabelling, we also showed that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
Published: 2014
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145. Polygenic Risk Scores Stratify Keratinocyte Cancer Risk among Solid Organ Transplant Recipients with Chronic Immunosuppression in a High Ultraviolet Radiation Environment

Author: Seviiri, Mathias, Law, Matthew H., Ong, Jue Sheng, Gharahkhani, Puya, Nyholt, Dale R., Hopkins, Peter, Chambers, Daniel, Campbell, Scott, Isbel, Nicole M., Soyer, H. Peter, Olsen, Catherine M., Ellis, Jonathan J., Whiteman, David C., Green, Adele C., and MacGregor, Stuart
Abstract: 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 R2 = 0.21 vs. 0.19, P = 3.2 × 10–3; SCC R2 = 0.30 vs. 0.27, P = 4.6 × 10–4).
Published: 2021
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146. Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma.

Author: Dong, Jing, Maj, Carlo, Tsavachidis, Spiridon, Ostrom, Quinn T., Gharahkhani, Puya, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bernstein, Leslie, Borisov, Oleg, Schröder, Julia, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., May, Andrea, Gerges, Christian, and Anders, Mario
Abstract: 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. 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 s ex-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. 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 BONF =.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 BONF = 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. 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. [ABSTRACT FROM AUTHOR]
Published: 2020
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147. Polygenic Risk Scores Allow Risk Stratification for Keratinocyte Cancer in Organ-Transplant Recipients

Author: Seviiri, Mathias, Law, Matthew H., Ong, Jue Sheng, Gharahkhani, Puya, Nyholt, Dale R., Olsen, Catherine M., Whiteman, David C., and MacGregor, Stuart
Abstract: 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 × 10-3) 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%.
Published: 2021
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148. No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study.

Author: Dong, Jing, Gharahkhani, Puya, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Wu, Anna H., Ye, Weimin, Onstad, Lynn, Anderson, Lesley A., Bernstein, Leslie, Pharoah, Paul D., Risch, Harvey A., Corley, Douglas A., Fitzgerald, Rebecca C., Iyer, Prasad G., Reid, Brian J., Lagergren, Jesper, Shaheen, Nicholas J., and Vaughan, Thomas L.
Abstract: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77–1.92; P =.41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39–1.19; P =.18). In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC. [ABSTRACT FROM AUTHOR]
Published: 2019
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149. Determining Risk of Barrett’s Esophagus and Esophageal Adenocarcinoma Based on Epidemiologic Factors and Genetic Variants.

Author: Dong, Jing, Buas, Matthew F., Gharahkhani, Puya, Kendall, Bradley J., Onstad, Lynn, Zhao, Shanshan, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Bernstein, Leslie, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., Iyer, Prasad G., Reid, Brian J., and Hardie, Laura J.
Abstract: Background & Aims We developed comprehensive models to determine risk of Barrett’s esophagus (BE) or esophageal adenocarcinoma (EAC) based on genetic and non-genetic factors. Methods We used pooled data from 3288 patients with BE, 2511 patients with EAC, and 2177 individuals without either (controls) from participants in the international Barrett’s and EAC consortium as well as the United Kingdom’s BE gene study and stomach and esophageal cancer study. We collected data on 23 genetic variants associated with risk for BE or EAC, and constructed a polygenic risk score (PRS) for cases and controls by summing the risk allele counts for the variants weighted by their natural log-transformed effect estimates (odds ratios) extracted from genome-wide association studies. We also collected data on demographic and lifestyle factors (age, sex, smoking, body mass index, use of nonsteroidal anti-inflammatory drugs) and symptoms of gastroesophageal reflux disease (GERD). Risk models with various combinations of non-genetic factors and the PRS were compared for their accuracy in identifying patients with BE or EAC using the area under the receiver operating characteristic curve (AUC) analysis. Results Individuals in the highest quartile of risk, based on genetic factors (PRS), had a 2-fold higher risk of BE (odds ratio, 2.22; 95% confidence interval, 1.89–2.60) or EAC (odds ratio, 2.46; 95% confidence interval, 2.07–2.92) than individual in the lowest quartile of risk based on PRS. Risk models developed based on only demographic or lifestyle factors or GERD symptoms identified patients with BE or EAC with AUC values ranging from 0.637 to 0.667. Combining data on demographic or lifestyle factors with data on GERD symptoms identified patients with BE with an AUC of 0.793 and patients with EAC with an AUC of 0.745. Including PRSs with these data only minimally increased the AUC values for BE (to 0.799) and EAC (to 0.754). Including the PRSs in the model developed based on non-genetic factors resulted in a net reclassification improvement for BE of 3.0% and for EAC of 5.6%. Conclusions We used data from 3 large databases of patients from studies of BE or EAC to develop a risk prediction model based on genetic, clinical, and demographic/lifestyle factors. We identified a PRS that increases discrimination and net reclassification of individuals with vs without BE and EAC. However, the absolute magnitude of improvement is not sufficient to justify its clinical use. [ABSTRACT FROM AUTHOR]
Published: 2018
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150. Developing and validating a comprehensive polygenic risk score to enhance keratoconus risk prediction.

Author: He W, Võsa U, Palumaa T, Ong JS, Torres SD, Hewitt AW, Mackey DA, Gharahkhani P, Esko T, and MacGregor S
Abstract: Purpose: This study aimed to develop and validate a comprehensive polygenic risk score (PRS) for keratoconus, enhancing the predictive accuracy for identifying individuals at increased risk, which is crucial for preventing keratoconus-associated visual impairment such as post-Laser-assisted in situ keratomileusis (LASIK) ectasia., Methods: We applied a multi-trait analysis approach (MTAG) to genome-wide association study data on keratoconus and quantitative keratoconus-related traits and used this to construct PRS models for keratoconus risk using several PRS methodologies. We evaluated the predictive performance of the PRSs in two biobanks: Estonian Biobank (EstBB; 375 keratoconus cases and 17 902 controls) and UK Biobank (UKB: 34 keratoconus cases and 1000 controls). Scores were compared using the area under the curve (AUC) and odds ratios (ORs) for various PRS models., Results: The PRS models demonstrated significant predictive capabilities in EstBB, with the SBayesRC model achieving the highest OR of 2.28 per standard deviation increase in PRS, with a model containing age, sex and PRS showing good predictive accuracy (AUC = 0.72). In UKB, we found that adding the best-performing PRS to a model containing corneal measurements increased the AUC from 0.84 to 0.88 (P = 0.012 for difference), with an OR of 4.26 per standard deviation increase in the PRS. These models showed improved predictive capability compared to previous keratoconus PRS., Conclusion: The PRS models enhanced prediction of keratoconus risk, even with corneal measurements, showing potential for clinical use to identify individuals at high risk of keratoconus, and potentially help reduce the risk of post-LASIK ectasia., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Published: 2024
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