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4. Häufigkeit der Katarakt-Operation und deren Einfluss auf die visuelle Funktion - Ergebnisse der Gutenberg-Gesundheitsstudie (GHS)

Author

Schuster, Alexander K., Nickels, S., Pfeiffer, N., Schmidtmann, I., Wild, P.S., Münzel, T., Beutel, M.E., Lackner, K.J., and Voßmerbäumer, U.

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Fragestellung: Die Katarakt-Operation gilt als die häufigste Operation in Deutschland. Zahlen hierzu basieren bisher auf Umfragen oder Verkaufszahlen von Intraokularlinsen. Wir berichten nun die Häufigkeit von Kataraktoperationen über ein Fünfjahresintervall bei Personen im Alter[zum vollständigen Text gelangen Sie über die oben angegebene URL], 34. Kongress der Deutschsprachigen Gesellschaft für Intraokularlinsen-Implantation, interventionelle und refraktive Chirurgie

Published
2020

5. Niedriges Geburtsgewicht ist assoziiert mit der altersbedingten Makuladegeneration im Erwachsenenalter – Ergebnisse der Gutenberg-Gesundheitsstudie

Author

Fieß, A, Elbaz, H, Korb, CA, Nickels, S, Schulz, A, Münzel, T, Wild, PS, Beutel, ME, Schmidtmann, I, Lackner, KJ, Peto, T, Pfeiffer, N, and Schuster, AK

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Ziel: Diese Studie analysiert, ob ein niedriges Geburtsgewicht (GG) mit der Prävalenz und Inzidenz der altersbedingten Makuladeneration (AMD) im Erwachsenenalter zusammenhängt. Methoden: Die Gutenberg-Gesundheitsstudie (GHS) ist eine bevölkerungsbezogene, beobachtende Kohortenstudie[zum vollständigen Text gelangen Sie über die oben angegebene URL], 92. Versammlung des Vereins Rhein-Mainischer Augenärzte

Published
2020
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8. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Author

Fan, Q. (Qiao), Pozarickij, A. (Alfred), Tan, N.Y.Q. (Nicholas Y. Q.), Guo, X. (Xiaobo), Verhoeven, V.J.M. (Virginie), Vitart, V. (Veronique), Guggenheim, J. (Jean), Miyake, M. (Masahiro), Tideman, J.W.L. (Willem), Khawaja, A.P. (Anthony), Zhang, L. (Liang), MacGregor, S. (Stuart), Höhn, R. (René), Chen, P. (Peng), Biino, G. (Ginevra), Wedenoja, J. (Juho), Saffari, S.E. (Seyed Ehsan), Tedja, M. (Milly), Xie, J. (Jing), Lanca, C. (Carla), Wang, Y.X. (Ya Xing), Sahebjada, S. (Srujana), Mazur, J. (Johanna), Mirshahi, A. (Alireza), Martin, N.G. (Nicholas), Yazar, S. (Seyhan), Pennell, C.E. (Craig), Yap, M.K.H. (Maurice K. H.), Haarman, A.E.G. (Annechien E. G.), Enthoven, C.A. (Clair A.), Polling, J.R. (Jan Roelof), Bailey-Wilson, J.E. (Joan E.), Veluchamy, A.B. (Amutha Barathi), Burdon, K.P. (Kathryn P.), Campbell, H. (Harry), Chen, L.J. (Li Jia), Chew, E.Y. (Emily Y.), Craig, J.E. (Jamie), Cumberland, P.M. (Phillippa M.), DeAngelis, M.M. (Margaret), Delcourt, C. (Cécile), Ding, X. (Xiaohu), Evans, D.M. (David M.), Gharahkhani, P. (Puya), Iglesias, A.I. (Adriana I.), Haller, T. (Toomas), Han, X. (Xikun), Hoang, Q. (Quan), Igo Jr., R.P. (Robert), Iyengar, S.K. (Sudha), Kähönen, M. (Mika), Kaprio, J. (Jaakko), Klein, B.E. (Barbara E.), Klein, R. (Ronald), Lass Jr., J.H. (Jonathan), Lee, K. (Kris), Lehtimäki, T. (Terho), Lewis, D.D. (Deyana D.), Li, Q. (Qing), Li, S.-M. (Shi-Ming), Lyytikäinen, L.-P. (Leo-Pekka), Meguro, A. (Akira), Metspalu, A. (Andres), Middlebrooks, C.D. (Candace D.), Mizuki, N. (Nobuhisa), Musolf, A.M. (Anthony M.), Nickels, S. (Stefan), Oexle, K. (Konrad), Pang, C.P. (Chi Pui), Paterson, A.D. (Andrew), Rahi, J.S. (Jugnoo S.), Raitakari, O. (Olli), Rudan, I. (Igor), Stambolian, D.E. (Dwight), Simpson, C.L. (Claire), Wang, N. (Ningli), Bin Wei, W. (Wen), Williams, K.M. (Katie M.), Wilson, J.F. (James), Wojciechowski, R. (Robert), Yamashiro, K. (Kenji), Yam, J.C.S. (Jason C. S.), Zhou, X. (Xiangtian), Aslam, T. (Tariq), Barman, S.A. (Sarah A.), Barrett, J.H. (Jenny H.), Bishop, P.N. (Paul), Blows, P. (Peter), Bunce, C. (Catey), Carare, R.O. (Roxana O.), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chua, S.Y.L. (Sharon Y. L.), Crabb, D.P. (David), Cumberland, P.M. (Philippa M.), Day, A. (Alexander), Desai, P. (Parul), Dhillon, B. (Bal), Dick, A.D. (Andrew D.), Egan, C. (Cathy), Ennis, S. (Sarah), Fruttiger, M. (Marcus), Gallacher, J. (John), Garway-Heath, D.F. (David F.), Gibson, J. (Jane), Gore, D. (Dan), Hardcastle, A. (Alison), Harding, S.P. (Simon), Hogg, R. (Ruth), Keane, P.A. (Pearse A.), Khaw, S.P.T. (Sir Peng T.), Lascaratos, G. (Gerassimos), Lotery, A.J. (Andrew), Macgillivray, T. (Tom), Mackie, S. (Sarah), Martin, K. (Keith), McGaughey, M. (Michelle), McGuinness, B. (Bernadette), McKay, G.J. (Gareth), McKibbin, M. (Martin), Mitry, D. (Danny), Moore, T. (Tony), Morgan, J.E. (James E.), Muthy, Z.A. (Zaynah A.), O’Sullivan, E. (Eoin), Owen, C.G. (Chris G.), Patel, P. (Praveen), Paterson, E. (Euan), Peto, T. (Tünde), Petzold, A. (Axel), Rudnikca, A.R. (Alicja R.), Self, J. (Jay), Sivaprasad, S., Steel, D. (David), Stratton, I. (Irene), Strouthidis, N. (Nicholas), Sudlow, C. (Cathie), Thomas, D. (Dhanes), Trucco, E. (Emanuele), Tufail, A. (Adnan), Vernon, S.A. (Stephen A.), Viswanathan, A.C. (Ananth C.), Williams, K. (Katie), Woodside, J.V. (J.), Yates, M.M. (Max M.), Yip, J. (Jennifer), Zheng, Y. (Yalin), Hewit, A.W. (Alex), Jaddoe, V.W.V. (Vincent), Duijn, C.M. (Cornelia) van, Hayward, C. (Caroline), Polasek, O. (Ozren), Tai, E.S. (Shyong), Yoshikatsu, H. (Hosoda), Hysi, P.G. (Pirro G.), Young, T.L. (Terri L.), Tsujikawa, A. (Akitaka), Wang, J.J. (Jie Jing), Mitchell, P. (Paul), Pfeiffer, A.F.H. (Andreas), Pärssinen, O. (Olavi), Foster, P.J. (Paul), Fossarello, M. (Maurizio), Yip, S.P. (Shea Ping), Williams, C. (Cathy), Hammond, C.J. (Christopher), Jonas, J.B., He, M. (Mingguang), Mackey, D.A. (David), Wong, T.-Y. (Tien-Yin), Klaver, C.C.W. (Caroline), Saw, S-M. (Seang-Mei), Baird, P.N. (Paul), Cheng, C.-Y. (Ching-Yu), Fan, Q. (Qiao), Pozarickij, A. (Alfred), Tan, N.Y.Q. (Nicholas Y. Q.), Guo, X. (Xiaobo), Verhoeven, V.J.M. (Virginie), Vitart, V. (Veronique), Guggenheim, J. (Jean), Miyake, M. (Masahiro), Tideman, J.W.L. (Willem), Khawaja, A.P. (Anthony), Zhang, L. (Liang), MacGregor, S. (Stuart), Höhn, R. (René), Chen, P. (Peng), Biino, G. (Ginevra), Wedenoja, J. (Juho), Saffari, S.E. (Seyed Ehsan), Tedja, M. (Milly), Xie, J. (Jing), Lanca, C. (Carla), Wang, Y.X. (Ya Xing), Sahebjada, S. (Srujana), Mazur, J. (Johanna), Mirshahi, A. (Alireza), Martin, N.G. (Nicholas), Yazar, S. (Seyhan), Pennell, C.E. (Craig), Yap, M.K.H. (Maurice K. H.), Haarman, A.E.G. (Annechien E. G.), Enthoven, C.A. (Clair A.), Polling, J.R. (Jan Roelof), Bailey-Wilson, J.E. (Joan E.), Veluchamy, A.B. (Amutha Barathi), Burdon, K.P. (Kathryn P.), Campbell, H. (Harry), Chen, L.J. (Li Jia), Chew, E.Y. (Emily Y.), Craig, J.E. (Jamie), Cumberland, P.M. (Phillippa M.), DeAngelis, M.M. (Margaret), Delcourt, C. (Cécile), Ding, X. (Xiaohu), Evans, D.M. (David M.), Gharahkhani, P. (Puya), Iglesias, A.I. (Adriana I.), Haller, T. (Toomas), Han, X. (Xikun), Hoang, Q. (Quan), Igo Jr., R.P. (Robert), Iyengar, S.K. (Sudha), Kähönen, M. (Mika), Kaprio, J. (Jaakko), Klein, B.E. (Barbara E.), Klein, R. (Ronald), Lass Jr., J.H. (Jonathan), Lee, K. (Kris), Lehtimäki, T. (Terho), Lewis, D.D. (Deyana D.), Li, Q. (Qing), Li, S.-M. (Shi-Ming), Lyytikäinen, L.-P. (Leo-Pekka), Meguro, A. (Akira), Metspalu, A. (Andres), Middlebrooks, C.D. (Candace D.), Mizuki, N. (Nobuhisa), Musolf, A.M. (Anthony M.), Nickels, S. (Stefan), Oexle, K. (Konrad), Pang, C.P. (Chi Pui), Paterson, A.D. (Andrew), Rahi, J.S. (Jugnoo S.), Raitakari, O. (Olli), Rudan, I. (Igor), Stambolian, D.E. (Dwight), Simpson, C.L. (Claire), Wang, N. (Ningli), Bin Wei, W. (Wen), Williams, K.M. (Katie M.), Wilson, J.F. (James), Wojciechowski, R. (Robert), Yamashiro, K. (Kenji), Yam, J.C.S. (Jason C. S.), Zhou, X. (Xiangtian), Aslam, T. (Tariq), Barman, S.A. (Sarah A.), Barrett, J.H. (Jenny H.), Bishop, P.N. (Paul), Blows, P. (Peter), Bunce, C. (Catey), Carare, R.O. (Roxana O.), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chua, S.Y.L. (Sharon Y. L.), Crabb, D.P. (David), Cumberland, P.M. (Philippa M.), Day, A. (Alexander), Desai, P. (Parul), Dhillon, B. (Bal), Dick, A.D. (Andrew D.), Egan, C. (Cathy), Ennis, S. (Sarah), Fruttiger, M. (Marcus), Gallacher, J. (John), Garway-Heath, D.F. (David F.), Gibson, J. (Jane), Gore, D. (Dan), Hardcastle, A. (Alison), Harding, S.P. (Simon), Hogg, R. (Ruth), Keane, P.A. (Pearse A.), Khaw, S.P.T. (Sir Peng T.), Lascaratos, G. (Gerassimos), Lotery, A.J. (Andrew), Macgillivray, T. (Tom), Mackie, S. (Sarah), Martin, K. (Keith), McGaughey, M. (Michelle), McGuinness, B. (Bernadette), McKay, G.J. (Gareth), McKibbin, M. (Martin), Mitry, D. (Danny), Moore, T. (Tony), Morgan, J.E. (James E.), Muthy, Z.A. (Zaynah A.), O’Sullivan, E. (Eoin), Owen, C.G. (Chris G.), Patel, P. (Praveen), Paterson, E. (Euan), Peto, T. (Tünde), Petzold, A. (Axel), Rudnikca, A.R. (Alicja R.), Self, J. (Jay), Sivaprasad, S., Steel, D. (David), Stratton, I. (Irene), Strouthidis, N. (Nicholas), Sudlow, C. (Cathie), Thomas, D. (Dhanes), Trucco, E. (Emanuele), Tufail, A. (Adnan), Vernon, S.A. (Stephen A.), Viswanathan, A.C. (Ananth C.), Williams, K. (Katie), Woodside, J.V. (J.), Yates, M.M. (Max M.), Yip, J. (Jennifer), Zheng, Y. (Yalin), Hewit, A.W. (Alex), Jaddoe, V.W.V. (Vincent), Duijn, C.M. (Cornelia) van, Hayward, C. (Caroline), Polasek, O. (Ozren), Tai, E.S. (Shyong), Yoshikatsu, H. (Hosoda), Hysi, P.G. (Pirro G.), Young, T.L. (Terri L.), Tsujikawa, A. (Akitaka), Wang, J.J. (Jie Jing), Mitchell, P. (Paul), Pfeiffer, A.F.H. (Andreas), Pärssinen, O. (Olavi), Foster, P.J. (Paul), Fossarello, M. (Maurizio), Yip, S.P. (Shea Ping), Williams, C. (Cathy), Hammond, C.J. (Christopher), Jonas, J.B., He, M. (Mingguang), Mackey, D.A. (David), Wong, T.-Y. (Tien-Yin), Klaver, C.C.W. (Caroline), Saw, S-M. (Seang-Mei), Baird, P.N. (Paul), and Cheng, C.-Y. (Ching-Yu)

Abstract

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Published
2020
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9. No evidence for an association of plasma homocysteine levels and refractive error - Results from the population-based Gutenberg Health Study (GHS)

Author

Nickels, S. (Stefan), Blom, H.J. (Henk J.), Schulz, A. (Andreas), Joachimsen, L. (Lutz), Münzel, T. (Thomas), Wild, P.S. (Philipp), Beutel, M.E. (Manfred E.), Blettner, M. (Maria), Lackner, K.J. (Karl), Pfeiffer, A.F.H. (Andreas), Lagrèze, W.A. (Wolf Alexander), Nickels, S. (Stefan), Blom, H.J. (Henk J.), Schulz, A. (Andreas), Joachimsen, L. (Lutz), Münzel, T. (Thomas), Wild, P.S. (Philipp), Beutel, M.E. (Manfred E.), Blettner, M. (Maria), Lackner, K.J. (Karl), Pfeiffer, A.F.H. (Andreas), and Lagrèze, W.A. (Wolf Alexander)

Abstract

Purpose There is a strong association between severe hyperhomocysteinemia and myopia. Thus we studied the hypothesis that even moderately increased levels of homocysteine (Hcy) might be a potentially treatable risk factor for myopia. Methods The Gutenberg Health Study (GHS) is a population-based, prospective, observational cohort study in Germany, including 15,010 participants aged between 35 and 74 at recruitment. The baseline examination was conducted from 2007-2012. Refraction was measured using autorefraction (HARK 599, Carl Zeiss AG, Jena, Germany). Hcy was measured by an immunoassay. We included only phakic participants without a history of corneal surgery or corneal laser treatment. We used linear regression models to evaluate the potential association between Hcy and refraction at baseline, and between Hcy and change in refraction between baseline and 5-year-follow-up examination. We used generalized estimating equation models to account for the correlation between fellow eyes. Results We included 13,749 participants, categorized as having no myopia (spherical equivalent > -0.75 D, 65.2%), low myopia (-0.75 D-2.75 D, 21.5%), moderate myopia (-3.00 D- 5.75 D, 9.8%) and high myopia (≤ -6 D

Published
2020
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11. The Decreasing Prevalence of Nonrefractive Visual Impairment in Older Europeans: A Meta-analysis of Published and Unpublished Data

Author

Delcourt, C., Le Goff, M., von Hanno, T., Mirshahi, A., Khawaja, A. P., Verhoeven, V. J. M., Hogg, R. E., Anastosopoulos, E., Cachulo, M. L., Hohn, R., Wolfram, C., Bron, A., Miotto, S., Carriere, I., Colijn, J. M., Buitendijk, G. H. S., Evans, J., Nitsch, D., Founti, P., Yip, J. L. Y., Pfeiffer, N., Creuzot-Garcher, C., Silva, R., Piermarocchi, S., Topouzis, F., Bertelsen, G., Foster, P. J., Fletcher, A., Klaver, C. C. W., Korobelnik, J. -F., Acar, N., Azuara-Blanco, A., Berendschot, T., Bergen, A., Binquet, C., Bird, A., Bobak, M., Boon, C., Bretillon, L., Broe, R., Buitendijk, G., Capuano, V., Chakravarthy, U., Chan, M., Chang, P., Colijn, J., Cougnard-Gregoire, A., Cree, A., Cumberland, P., Cunha-Vaz, J., Daien, V., De Jong, E., Deak, G., Delyfer, M. -N., den Hollander, A., Dietzel, M., Erke, M. G., Faria, P., Farinha, C., Fauser, S., Finger, R., Foster, P., Gorgels, T., Grauslund, J., Grus, F., Hammond, C., Hansen, M., Helmer, C., Hense, H. -W., Hermann, M., Hoehn, R., Hogg, R., Holz, F., Hoyng, C., Jansonius, N., Janssen, S., Kersten, E., Khawaja, A., Klaver, C., Lamparter, J., Lechanteur, Y., Lehtimaki, T., Leung, I., Lotery, A., Mauschitz, M., Meester, M., Merle, B., Meyer zu Westrup, V., Midena, E., Mohan-Said, S., Mueller, M., Muldrew, A., Murta, J., Nickels, S., Nunes, S., Owen, C., Peto, T., Prokofyeva, E., Rahi, J., Raitakari, O., Rauscher, F., Ribeiro, L., Rougier, M. -B., Rudnicka, A., Randjvar, Sahel, Salonikiou, A., Sanchez, C., Schmitz-Valckenberg, S., Schouten, J., Schuster, A., Schweitzer, C., Segato, T., Shehata, J., Silvestri, G., Simader, C., Souied, E., Speckauskas, M., Springelkamp, H., Tapp, R., van Leeuwen, E., Verhoeven, V., Verzijden, T., Von Hanno, T., Vujosevic, S., Wiedemann, P., Williams, K., Yip, J., and Zerbib, J.

Subjects
Europe, Aged, Humans, Prevalence, Vision, Low, Visually Impaired Persons, Visual Acuity, Vision, Low
Abstract

TOPIC: To estimate the prevalence of nonrefractive visual impairment and blindness in European persons 55 years of age and older. CLINICAL RELEVANCE: Few visual impairment and blindness prevalence estimates are available for the European population. In addition, many of the data collected in European population-based studies currently are unpublished and have not been included in previous estimates. METHODS: Fourteen European population-based studies participating in the European Eye Epidemiology Consortium (n = 70 723) were included. Each study provided nonrefractive visual impairment and blindness prevalence estimates stratified by age (10-year strata) and gender. Nonrefractive visual impairment and blindness were defined as best-corrected visual acuity worse than 20/60 and 20/400 in the better eye, respectively. Using random effects meta-analysis, prevalence rates were estimated according to age, gender, geographical area, and period (1991-2006 and 2007-2012). Because no data were available for Central and Eastern Europe, population projections for numbers of affected people were estimated using Eurostat population estimates for European high-income countries in 2000 and 2010. RESULTS: The age-standardized prevalence of nonrefractive visual impairment in people 55 years of age or older decreased from 2.22% (95% confidence interval [CI], 1.34-3.10) from 1991 through 2006 to 0.92% (95% CI, 0.42-1.42) from 2007 through 2012. It strongly increased with age in both periods (up to 15.69% and 4.39% in participants 85 years of age or older from 1991 through 2006 and from 2007 through 2012, respectively). Age-standardized prevalence of visual impairment tended to be higher in women than men from 1991 through 2006 (2.67% vs. 1.88%), but not from 2007 through 2012 (0.87% vs. 0.88%). No differences were observed between northern, western, and southern regions of Europe. The projected numbers of affected older inhabitants in European high-income countries decreased from 2.5 million affected individuals in 2000 to 1.2 million in 2010. Of those, 584 000 were blind in 2000, in comparison with 170 000 who were blind in 2010. CONCLUSIONS: Despite the increase in the European older population, our study indicated that the number of visually impaired people has decreased in European high-income countries in the last 20 years. This may be the result of major improvements in eye care and prevention, the decreasing prevalence of eye diseases, or both.

Published
2018

12. Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration Evidence from the EYE-RISK and European Eye Epidemiology Consortia

Author

Colijn, J.M., Hollander, A.I. den, Demirkan, A., Cougnard-Gregoire, A., Verzijden, T., Kersten, E., Meester-Smoor, M.A., Merle, B.M.J., Papageorgiou, G., Ahmad, S., Mulder, M.T., Costa, M.A., Benlian, P., Bertelsen, G., Bron, A.M., Claes, B., Creuzot-Garcher, C., Erke, M.G., Fauser, S., Foster, P.J., Hammond, C.J., Hense, H.W., Hoyng, C.B., Khawaja, A.P., Korobelnik, J.F., Piermarocchi, S., Segato, T., Silva, R., Souied, E.H., Williams, K.M., Duijn, C.M. van, Delcourt, C., Klaver, C.C.W., Acar, N., Altay, L., Anastosopoulos, E., Azuara-Blanco, A., Berendschot, T., Bergen, A., Binquet, C., Bird, A., Bobak, M., Larsen, M.B., Boon, C., Bourne, R., Bretillon, L., Broe, R., Bron, A., Buitendijk, G., Cachulo, M.L., Capuano, V., Carriere, I., Chakravarthy, U., Chan, M., Chang, P., Colijn, J., Cree, A., Cumberland, P., Cunha-Vaz, J., Daien, V., Jong, E. de, Deak, G., Delyfer, M.N., Hollander, A. den, Dietzel, M., Faria, P., Farinha, C., Finger, R., Fletcher, A., Foster, P., Founti, P., Gorgels, T., Grauslund, J., Grus, F., Hammond, C., Heesterbeek, T., Hermann, M., Hoehn, R., Hogg, R., Holz, F., Hoyng, C., Jansonius, N., Janssen, S., Khawaja, A., Klaver, C., Lamparter, J., Goff, M. le, Lehtimaki, T., Leung, I., Lotery, A., Mauschitz, M., Meester, M., Merle, B., Westrup, V.M.Z., Midena, E., Miotto, S., Mirshahi, A., Mohan-Said, S., Mueller, M., Muldrew, A., Murta, J., Nickels, S., Nunes, S., Owen, C., Peto, T., Pfeiffer, N., Prokofyeva, E., Rahi, J., Raitakari, O., Rauscher, F., Ribeiro, L., Rougier, M.B., Rudnicka, A., Sahel, J., Salonikiou, A., Sanchez, C., Schick, T., Schmitz-Valckenberg, S., Schuster, A., Schweitzer, C., Shehata, J., Silvestri, G., Simader, C., Souied, E., Speckauskas, M., Springelkamp, H., Tapp, R., Topouzis, F., Leeuwen, E. van, Verhoeven, V., Vingerling, H., Hanno, T. von, Williams, K., Wolfram, C., Yip, J., Zerbib, J., Ajana, S., Arango-Gonzalez, B., Arndt, V., Bhatia, V., Bhattacharya, S.S., Biarnes, M., Borrell, A., Buhren, S., Calado, S.M., Dammeier, S., Jong, E.K. de, Cerda, B. de la, Diaz-Corrales, F.J., Diether, S., Emri, E., Endermann, T., Ferraro, L.L., Garcia, M., Heesterbeek, T.J., Honisch, S., Kilger, E., Langen, H., Lengyel, I., Luthert, P., Maugeais, C., Meester-Smoor, M., Inserm, B.M.J.M., Mones, J., Nogoceke, E., Pool, F.M., Rodriguez, E., Ueffing, M., Bartz-Schmidt, K.U.U., Leeuwen, E.M. van, Zumbansen, M., European Eye Epidemiology Consorti, and EYE-RISK Consortium

Published
2019

13. Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium

Author

Wong, Y.L., Hysi, P., Cheung, G., Tedja, M., Hoang, Q.V., Tompson, S.W., Whisenhunt, K.N., Verhoeven, V., Zhao, W., Hess, M., Wong, C.W., Kifley, A., Hosoda, Y., Haarman, A.E.G., Hopf, S., Laspas, P., Sensaki, S., Sim, X., Miyake, M., Tsujikawa, A., Lamoureux, E., Ohno-Matsui, K., Nickels, S., Mitchell, P., Wong, T.Y., Wang, J.J., Hammond, C.J., Barathi, V.A., Cheng, C.Y., Yamashiro, K., Young, T.L., Klaver, C.C.W., Saw, S.M., Wong, Y.L., Hysi, P., Cheung, G., Tedja, M., Hoang, Q.V., Tompson, S.W., Whisenhunt, K.N., Verhoeven, V., Zhao, W., Hess, M., Wong, C.W., Kifley, A., Hosoda, Y., Haarman, A.E.G., Hopf, S., Laspas, P., Sensaki, S., Sim, X., Miyake, M., Tsujikawa, A., Lamoureux, E., Ohno-Matsui, K., Nickels, S., Mitchell, P., Wong, T.Y., Wang, J.J., Hammond, C.J., Barathi, V.A., Cheng, C.Y., Yamashiro, K., Young, T.L., Klaver, C.C.W., and Saw, S.M.

Abstract

Contains fulltext : 208643.pdf (publisher's version ) (Open Access), PURPOSE: To evaluate the roles of known myopia-associated genetic variants for development of myopic macular degeneration (MMD) in individuals with high myopia (HM), using case-control studies from the Consortium of Refractive Error and Myopia (CREAM). METHODS: A candidate gene approach tested 50 myopia-associated loci for association with HM and MMD, using meta-analyses of case-control studies comprising subjects of European and Asian ancestry aged 30 to 80 years from 10 studies. Fifty loci with the strongest associations with myopia were chosen from a previous published GWAS study. Highly myopic (spherical equivalent [SE]

Published
2019

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

Author

Bonnemaijer, P.W.M., Leeuwen, E.M. van, Iglesias, A.I., Gharahkhani, P., Vitart, V., Khawaja, A.P., Simcoe, M., Hohn, R., Cree, A.J., Igo, R.P., Jr., Gerhold-Ay, A., Nickels, S., Wilson, J.F., Hayward, C., Boutin, T.S., Polasek, O., Aung, T., Khor, C.C., Amin, N., Lotery, A.J., Wiggs, J.L., Cheng, C.Y., Hysi, P.G., Hammond, C.J., Thiadens, A., MacGregor, S., Klaver, C.C.W., Duijn, C.M. van, Bonnemaijer, P.W.M., Leeuwen, E.M. van, Iglesias, A.I., Gharahkhani, P., Vitart, V., Khawaja, A.P., Simcoe, M., Hohn, R., Cree, A.J., Igo, R.P., Jr., Gerhold-Ay, A., Nickels, S., Wilson, J.F., Hayward, C., Boutin, T.S., Polasek, O., Aung, T., Khor, C.C., Amin, N., Lotery, A.J., Wiggs, J.L., Cheng, C.Y., Hysi, P.G., Hammond, C.J., Thiadens, A., MacGregor, S., Klaver, C.C.W., and Duijn, C.M. van

Abstract

Contains fulltext : 215476.pdf (publisher's version ) (Open Access), A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.

Published
2019

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

Author

Bonnemaijer, P.W.M. (Pieter), Leeuwen, E.M. (Elisabeth M. van), Iglesias, A.I. (Adriana I.), Gharahkhani, P. (Puya), Vitart, V. (Veronique), Khawaja, A.P. (Anthony), Simcoe, M. (Mark), Höhn, R. (René), Cree, A.J. (Angela), Igo Jr., R.P. (Robert), Burdon, K.P. (Kathryn P.), Craig, J.E. (Jamie), Hewit, A.W. (Alex), Jonas, J.B., Khor, C.-C. (Chiea-Cheun), Pasutto, F. (Francesca), Mackey, D.A. (David), Mitchell, P. (Paul), Mishra, A. (Aniket), Pang, C.P. (Chi Pui), Pasquale, L.R. (Louis R), Springelkamp, H. (Henriët), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Viswanathan, A.C. (Ananth C.), Wojciechowski, R. (Robert), Wong, T.Y. (Tien Yin), Young, T.L. (Terrri L), Zeller, T. (Tanja), Allingham, R.R. (R Rand), Budenz, D.L. (Donald L.), Bailey, J.C. (Jessica Cooke), Fingert, J. (John), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Haines, J.L. (Jonathan), Hark, L. (Lisa), Hauser, M.A. (Michael), Kang, J.H. (Jae Hee), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Moroi, S. (Syoko), Pasquale, L.R. (Louis), Pericak, M. (Margaret), Realini, A. (Anthony), Rhee, D. (Doug), Richards, J.R. (Julia R.), Ritch, R. (Robert), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Weinreb, R.N. (Robert N.), Wollstein, G. (Gadi), Wilmer, D.Z. (Don Zack), Atan, D. (Denize), Aslam, T. (Tariq), Barman, S.A. (Sarah A.), Barrett, J.H. (Jennifer H.), Bishop, P.N. (Paul), Blows, P. (Peter), Bunce, C. (Catey), Carare, R.O. (Roxana O.), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chua, S.Y.L. (Sharon Y. L.), Crabb, D.P. (David), Cumberland, P.M. (Philippa M.), Day, A. (Alexander), Desai, P. (Parul), Dhillon, B. (Bal), Dick, A.D. (Andrew D.), Egan, C. (Cathy), Ennis, S. (Sarah), Foster, P.J. (Paul), Fruttiger, M. (Marcus), Gallacher, J.E.J. (John E. J.), Garway, D.F. (David F.), Gibson, J. (Jane), Dan Gore, (), Guggenheim, J. (Jean), Hardcastle, A. (Alison), Harding, S.P. (Simon), Hogg, R. (Ruth), Keane, P.A. (Pearse A.), Khaw, P.T. (Peng T.), Lascaratos, G. (Gerassimos), Macgillivray, T. (Tom), Mackie, S. (Sarah), Martin, K. (Keith), McGaughey, M. (Michelle), McGuinness, B. (Bernadette), McKay, G.J. (Gareth), McKibbin, M. (Martin), Mitry, D. (Danny), Moore, T. (Tony), Morgan, J.E. (James E.), Muthy, Z.A. (Zaynah A.), O’Sullivan, E. (Eoin), Owen, C.G. (Chris G.), Patel, P. (Praveen), Paterson, E. (Euan), Peto, T. (Tünde), Petzold, A. (Axel), Rahi, J.S. (Jugnoo S.), Rudnikca, A.R. (Alicja R.), Self, J. (Jay), Sivaprasad, S., Steel, D. (David), Stratton, I. (Irene), Strouthidis, N. (Nicholas), Sudlow, C. (Cathie), Thomas, D. (Dhanes), Trucco, E. (Emanuele), Tufail, A. (Adnan), Vernon, S.A. (Stephen A.), Williams, C. (Cathy), Williams, K.M. (Katie M.), Woodside, J.V. (J.), Yates, M.M. (Max M.), Yip, J. (Jennifer), Zheng, Y. (Yalin), Gerhold-Ay, A. (Aslihan), Nickels, S. (Stefan), Wilson, J.F. (James), Hayward, C. (Caroline), Boutin, T.S. (Thibaud S.), Polasek, O. (Ozren), Aung, T. (Tin), Khor, C.C., Amin, N. (Najaf), Lotery, A.J. (Andrew), Wiggs, J.L. (Janey L.), Cheng, C.-Y. (Ching-Yu), Hysi, P.G. (Pirro G.), Hammond, C.J. (Christopher), Thiadens, A.A.H.J. (Alberta), MacGregor, S. (Stuart), Klaver, C.C.W. (Caroline), Duijn, C.M. (Cornelia) van, Bonnemaijer, P.W.M. (Pieter), Leeuwen, E.M. (Elisabeth M. van), Iglesias, A.I. (Adriana I.), Gharahkhani, P. (Puya), Vitart, V. (Veronique), Khawaja, A.P. (Anthony), Simcoe, M. (Mark), Höhn, R. (René), Cree, A.J. (Angela), Igo Jr., R.P. (Robert), Burdon, K.P. (Kathryn P.), Craig, J.E. (Jamie), Hewit, A.W. (Alex), Jonas, J.B., Khor, C.-C. (Chiea-Cheun), Pasutto, F. (Francesca), Mackey, D.A. (David), Mitchell, P. (Paul), Mishra, A. (Aniket), Pang, C.P. (Chi Pui), Pasquale, L.R. (Louis R), Springelkamp, H. (Henriët), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Viswanathan, A.C. (Ananth C.), Wojciechowski, R. (Robert), Wong, T.Y. (Tien Yin), Young, T.L. (Terrri L), Zeller, T. (Tanja), Allingham, R.R. (R Rand), Budenz, D.L. (Donald L.), Bailey, J.C. (Jessica Cooke), Fingert, J. (John), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Haines, J.L. (Jonathan), Hark, L. (Lisa), Hauser, M.A. (Michael), Kang, J.H. (Jae Hee), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Moroi, S. (Syoko), Pasquale, L.R. (Louis), Pericak, M. (Margaret), Realini, A. (Anthony), Rhee, D. (Doug), Richards, J.R. (Julia R.), Ritch, R. (Robert), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Weinreb, R.N. (Robert N.), Wollstein, G. (Gadi), Wilmer, D.Z. (Don Zack), Atan, D. (Denize), Aslam, T. (Tariq), Barman, S.A. (Sarah A.), Barrett, J.H. (Jennifer H.), Bishop, P.N. (Paul), Blows, P. (Peter), Bunce, C. (Catey), Carare, R.O. (Roxana O.), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chua, S.Y.L. (Sharon Y. L.), Crabb, D.P. (David), Cumberland, P.M. (Philippa M.), Day, A. (Alexander), Desai, P. (Parul), Dhillon, B. (Bal), Dick, A.D. (Andrew D.), Egan, C. (Cathy), Ennis, S. (Sarah), Foster, P.J. (Paul), Fruttiger, M. (Marcus), Gallacher, J.E.J. (John E. J.), Garway, D.F. (David F.), Gibson, J. (Jane), Dan Gore, (), Guggenheim, J. (Jean), Hardcastle, A. (Alison), Harding, S.P. (Simon), Hogg, R. (Ruth), Keane, P.A. (Pearse A.), Khaw, P.T. (Peng T.), Lascaratos, G. (Gerassimos), Macgillivray, T. (Tom), Mackie, S. (Sarah), Martin, K. (Keith), McGaughey, M. (Michelle), McGuinness, B. (Bernadette), McKay, G.J. (Gareth), McKibbin, M. (Martin), Mitry, D. (Danny), Moore, T. (Tony), Morgan, J.E. (James E.), Muthy, Z.A. (Zaynah A.), O’Sullivan, E. (Eoin), Owen, C.G. (Chris G.), Patel, P. (Praveen), Paterson, E. (Euan), Peto, T. (Tünde), Petzold, A. (Axel), Rahi, J.S. (Jugnoo S.), Rudnikca, A.R. (Alicja R.), Self, J. (Jay), Sivaprasad, S., Steel, D. (David), Stratton, I. (Irene), Strouthidis, N. (Nicholas), Sudlow, C. (Cathie), Thomas, D. (Dhanes), Trucco, E. (Emanuele), Tufail, A. (Adnan), Vernon, S.A. (Stephen A.), Williams, C. (Cathy), Williams, K.M. (Katie M.), Woodside, J.V. (J.), Yates, M.M. (Max M.), Yip, J. (Jennifer), Zheng, Y. (Yalin), Gerhold-Ay, A. (Aslihan), Nickels, S. (Stefan), Wilson, J.F. (James), Hayward, C. (Caroline), Boutin, T.S. (Thibaud S.), Polasek, O. (Ozren), Aung, T. (Tin), Khor, C.C., Amin, N. (Najaf), Lotery, A.J. (Andrew), Wiggs, J.L. (Janey L.), Cheng, C.-Y. (Ching-Yu), Hysi, P.G. (Pirro G.), Hammond, C.J. (Christopher), Thiadens, A.A.H.J. (Alberta), MacGregor, S. (Stuart), Klaver, C.C.W. (Caroline), and Duijn, C.M. (Cornelia) van

Abstract

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.

Published
2019
Full Text
View/download PDF

16. Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium

Author

Wong, Y.-L. (Yee-Ling), Hysi, P. (Pirro), Cheung, G. (Gemmy), Tedja, M. (Milly), Hoang, Q.V. (Quan V.), Tompson, S.W.J. (Stuart W.J.), Whisenhunt, K.N. (Kristina N.), Verhoeven, V.J.M. (Virginie), Zhao, W. (Wanting), Hess, M. (Moritz), Wong, C.-W. (Chee-Wai), Kifley, A. (Annette), Hosoda, Y. (Yoshikatsu), Haarman, A.E.G. (Annechien E.G.), Hopf, S. (Susanne), Laspas, P. (Panagiotis), Sensaki, S. (Sonoko), Sim, X. (Xueling), Miyake, M. (Masahiro), Tsujikawa, A. (Akitaka), Lamoureux, E.L. (Ecosse), Ohno-Matsui, K. (Kyoko), Nickels, S. (Stefan), Mitchell, P. (Paul), Wong, T.-Y. (Tien-Yin), Wang, J.J. (Jie Jin), Hammond, C.J. (Christopher), Barathi, V.A. (Veluchamy), Cheng, C.-Y. (Ching-Yu), Yamashiro, K. (Kenji), Young, T.L. (Terri), Klaver, C.C.W. (Caroline), Saw, S-M. (Seang-Mei), Wong, Y.-L. (Yee-Ling), Hysi, P. (Pirro), Cheung, G. (Gemmy), Tedja, M. (Milly), Hoang, Q.V. (Quan V.), Tompson, S.W.J. (Stuart W.J.), Whisenhunt, K.N. (Kristina N.), Verhoeven, V.J.M. (Virginie), Zhao, W. (Wanting), Hess, M. (Moritz), Wong, C.-W. (Chee-Wai), Kifley, A. (Annette), Hosoda, Y. (Yoshikatsu), Haarman, A.E.G. (Annechien E.G.), Hopf, S. (Susanne), Laspas, P. (Panagiotis), Sensaki, S. (Sonoko), Sim, X. (Xueling), Miyake, M. (Masahiro), Tsujikawa, A. (Akitaka), Lamoureux, E.L. (Ecosse), Ohno-Matsui, K. (Kyoko), Nickels, S. (Stefan), Mitchell, P. (Paul), Wong, T.-Y. (Tien-Yin), Wang, J.J. (Jie Jin), Hammond, C.J. (Christopher), Barathi, V.A. (Veluchamy), Cheng, C.-Y. (Ching-Yu), Yamashiro, K. (Kenji), Young, T.L. (Terri), Klaver, C.C.W. (Caroline), and Saw, S-M. (Seang-Mei)

Abstract

Purpose To evaluate the roles of known myopia-associated genetic variants for development of myopic macular degeneration (MMD) in individuals with high myopia (HM), using case-control studies from the Consortium of Refractive Error and Myopia (CREAM). Methods A candidate gene approach tested 50 myopia-associated loci for association with HM and MMD, using meta-analyses of case-control studies comprising subjects of European and Asian ancestry aged 30 to 80 years from 10 studies. Fifty loci with the strongest associations with myopia were chosen from a previous published GWAS study. Highly myopic (spherical equivalent [SE] -5.0 diopters [D]) cases with MMD (N = 348), and two sets of controls were enrolled: (1) the first set included 16,275 emmetropes (SE -0.5 D); and (2) second set included 898 highly myopic subjects (SE -5.0 D) without MMD. MMD was classified based on the International photographic classification for pathologic myopia (META-PM). Results In the first analysis, comprising highly myopic cases with MMD (N = 348) versus emmetropic controls without MMD (N = 16,275), two SNPs were significantly associated with high myopia in adults with HM and MMD: (1) rs10824518 (P = 6.20E-07) in KCNMA1, which is highly expressed in human retinal and scleral tissues; and (2) rs524952 (P = 2.32E-16) near GJD2. In the second analysis, comprising highly myopic cases with MMD (N = 348) versus highly myopic controls without MMD (N = 898), none of the SNPs studied reached Bonferroni-corrected significance. Conclusions Of the 50 myopia-associated loci, we did not find any variant specifically associated with MMD, but the KCNMA1 and GJD2 loci were significantly associated with HM in highly myopic subjects with MMD, compared to emmetropes.

Published
2019
Full Text
View/download PDF

17. Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium.

Author

Yao, Y-G, Wong, Y-L, Hysi, P, Cheung, G, Tedja, M, Hoang, QV, Tompson, SWJ, Whisenhunt, KN, Verhoeven, V, Zhao, W, Hess, M, Wong, C-W, Kifley, A, Hosoda, Y, Haarman, AEG, Hopf, S, Laspas, P, Sensaki, S, Sim, X, Miyake, M, Tsujikawa, A, Lamoureux, E, Ohno-Matsui, K, Nickels, S, Mitchell, P, Wong, T-Y, Wang, JJ, Hammond, CJ, Barathi, VA, Cheng, C-Y, Yamashiro, K, Young, TL, Klaver, CCW, Saw, S-M, Consortium of Refractive Error, Myopia (CREAM), Yao, Y-G, Wong, Y-L, Hysi, P, Cheung, G, Tedja, M, Hoang, QV, Tompson, SWJ, Whisenhunt, KN, Verhoeven, V, Zhao, W, Hess, M, Wong, C-W, Kifley, A, Hosoda, Y, Haarman, AEG, Hopf, S, Laspas, P, Sensaki, S, Sim, X, Miyake, M, Tsujikawa, A, Lamoureux, E, Ohno-Matsui, K, Nickels, S, Mitchell, P, Wong, T-Y, Wang, JJ, Hammond, CJ, Barathi, VA, Cheng, C-Y, Yamashiro, K, Young, TL, Klaver, CCW, Saw, S-M, and Consortium of Refractive Error, Myopia (CREAM)

Abstract

PURPOSE: To evaluate the roles of known myopia-associated genetic variants for development of myopic macular degeneration (MMD) in individuals with high myopia (HM), using case-control studies from the Consortium of Refractive Error and Myopia (CREAM). METHODS: A candidate gene approach tested 50 myopia-associated loci for association with HM and MMD, using meta-analyses of case-control studies comprising subjects of European and Asian ancestry aged 30 to 80 years from 10 studies. Fifty loci with the strongest associations with myopia were chosen from a previous published GWAS study. Highly myopic (spherical equivalent [SE] ≤ -5.0 diopters [D]) cases with MMD (N = 348), and two sets of controls were enrolled: (1) the first set included 16,275 emmetropes (SE ≤ -0.5 D); and (2) second set included 898 highly myopic subjects (SE ≤ -5.0 D) without MMD. MMD was classified based on the International photographic classification for pathologic myopia (META-PM). RESULTS: In the first analysis, comprising highly myopic cases with MMD (N = 348) versus emmetropic controls without MMD (N = 16,275), two SNPs were significantly associated with high myopia in adults with HM and MMD: (1) rs10824518 (P = 6.20E-07) in KCNMA1, which is highly expressed in human retinal and scleral tissues; and (2) rs524952 (P = 2.32E-16) near GJD2. In the second analysis, comprising highly myopic cases with MMD (N = 348) versus highly myopic controls without MMD (N = 898), none of the SNPs studied reached Bonferroni-corrected significance. CONCLUSIONS: Of the 50 myopia-associated loci, we did not find any variant specifically associated with MMD, but the KCNMA1 and GJD2 loci were significantly associated with HM in highly myopic subjects with MMD, compared to emmetropes.

Published
2019

18. Correction: Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium.

Author

Wong, Y-L, Hysi, P, Cheung, G, Tedja, M, Hoang, QV, Tompson, SWJ, Whisenhunt, KN, Verhoeven, VJM, Zhao, W, Hess, M, Wong, C-W, Kifley, A, Hosoda, Y, Haarman, AEG, Hopf, S, Laspas, P, Sensaki, S, Sim, X, Miyake, M, Tsujikawa, A, Lamoureux, E, Ohno-Matsui, K, Nickels, S, Mitchell, P, Wong, T-Y, Wang, JJ, Hammond, CJ, Barathi, VA, Cheng, C-Y, Yamashiro, K, Young, TL, Klaver, CCW, Saw, S-M, Consortium of Refractive Error, Myopia (CREAM), Wong, Y-L, Hysi, P, Cheung, G, Tedja, M, Hoang, QV, Tompson, SWJ, Whisenhunt, KN, Verhoeven, VJM, Zhao, W, Hess, M, Wong, C-W, Kifley, A, Hosoda, Y, Haarman, AEG, Hopf, S, Laspas, P, Sensaki, S, Sim, X, Miyake, M, Tsujikawa, A, Lamoureux, E, Ohno-Matsui, K, Nickels, S, Mitchell, P, Wong, T-Y, Wang, JJ, Hammond, CJ, Barathi, VA, Cheng, C-Y, Yamashiro, K, Young, TL, Klaver, CCW, Saw, S-M, and Consortium of Refractive Error, Myopia (CREAM)

Abstract

[This corrects the article DOI: 10.1371/journal.pone.0220143.].

Published
2019

19. IMI - Myopia Genetics Report

Author

Tedja, MS, Haarman, AEG, Meester-Smoor, MA, Kaprio, J, Mackey, DA, Guggenheim, JA, Hammond, CJ, Verhoeven, VJM, Klaver, CCW, Bailey-Wilson, JE, Baird, PN, Veluchamy, AB, Biino, G, Burdon, KP, Campbell, H, Chen, LJ, Cheng, C-Y, Chew, EY, Craig, JE, Cumberland, PM, Deangelis, MM, Delcourt, C, Ding, X, van Duijn, CM, Evans, DM, Fan, Q, Fossarello, M, Foster, PJ, Gharahkhani, P, Iglesias, AI, Guol, X, Haller, T, Han, X, Hayward, C, He, M, Hewitt, AW, Hoang, Q, Hysi, PG, Igo, RP, Iyengar, SK, Jonas, JB, Kahonen, M, Khawaja, AP, Klein, BE, Klein, R, Lass, JH, Lee, K, Lehtimaki, T, Lewis, D, Li, Q, Li, S-M, Lyytikainen, L-P, MacGregor, S, Martin, NG, Meguro, A, Metspalu, A, Middlebrooks, C, Miyake, M, Mizuki, N, Musolf, A, Nickels, S, Oexle, K, Pang, CP, Parssinen, O, Paterson, AD, Pfeiffer, N, Polasek, O, Rahi, JS, Raitakari, O, Rudan, I, Sahebjada, S, Saw, S-M, Stambolian, D, Simpson, CL, Tai, E-S, Tideman, JWL, Tsujikawa, A, Vitart, V, Wang, N, Wedenoja, J, Wei, WB, Williams, C, Williams, KM, Wilson, JF, Wojciechowski, R, Wang, YX, Yamashiro, K, Yam, JCS, Yap, MKH, Yazar, S, Yip, SP, Young, TL, Zhou, X, Tedja, MS, Haarman, AEG, Meester-Smoor, MA, Kaprio, J, Mackey, DA, Guggenheim, JA, Hammond, CJ, Verhoeven, VJM, Klaver, CCW, Bailey-Wilson, JE, Baird, PN, Veluchamy, AB, Biino, G, Burdon, KP, Campbell, H, Chen, LJ, Cheng, C-Y, Chew, EY, Craig, JE, Cumberland, PM, Deangelis, MM, Delcourt, C, Ding, X, van Duijn, CM, Evans, DM, Fan, Q, Fossarello, M, Foster, PJ, Gharahkhani, P, Iglesias, AI, Guol, X, Haller, T, Han, X, Hayward, C, He, M, Hewitt, AW, Hoang, Q, Hysi, PG, Igo, RP, Iyengar, SK, Jonas, JB, Kahonen, M, Khawaja, AP, Klein, BE, Klein, R, Lass, JH, Lee, K, Lehtimaki, T, Lewis, D, Li, Q, Li, S-M, Lyytikainen, L-P, MacGregor, S, Martin, NG, Meguro, A, Metspalu, A, Middlebrooks, C, Miyake, M, Mizuki, N, Musolf, A, Nickels, S, Oexle, K, Pang, CP, Parssinen, O, Paterson, AD, Pfeiffer, N, Polasek, O, Rahi, JS, Raitakari, O, Rudan, I, Sahebjada, S, Saw, S-M, Stambolian, D, Simpson, CL, Tai, E-S, Tideman, JWL, Tsujikawa, A, Vitart, V, Wang, N, Wedenoja, J, Wei, WB, Williams, C, Williams, KM, Wilson, JF, Wojciechowski, R, Wang, YX, Yamashiro, K, Yam, JCS, Yap, MKH, Yazar, S, Yip, SP, Young, TL, and Zhou, X

Abstract

The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth.

Published
2019

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

Author

Bonnemaijer, PWM, van Leeuwen, EM, Iglesias, AI, Gharahkhani, P, Vitart, V, Khawaja, AP, Simcoe, M, Hoehn, R, Cree, AJ, Igo, RP, Burdon, KP, Craig, JE, Hewitt, AW, Jonas, J, Khor, C-C, Pasutto, F, Mackey, DA, Mitchell, P, Mishra, A, Pang, C, Pasquale, LR, Springelkamp, H, Thorleifsson, G, Thorsteinsdottir, U, Viswanathan, AC, Wojciechowski, R, Wong, T, Young, TL, Zeller, T, Atan, D, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway, DF, Gibson, J, Gore, D, Guggenheim, JA, Hardcastle, A, Harding, SP, Hogg, RE, Keane, PA, Khaw, PT, Lascaratos, G, Macgillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, Mckay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vernon, SA, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Allingham, R, Budenz, D, Bailey, JC, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, JL, Hark, L, Hauser, M, Kang, JH, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pericak, M, Realini, A, Rhee, D, Richards, JR, Ritch, R, Scott, WK, Singh, K, Sit, A, Vollrath, D, Weinreb, R, Wollstein, G, Wilmer, DZ, Gerhold-Ay, A, Nickels, S, Wilson, JF, Hayward, C, Boutin, TS, Polasek, O, Aung, T, Khor, CC, Amin, N, Lotery, AJ, Wiggs, JL, Cheng, C-Y, Hysi, PG, Hammond, CJ, Thiadens, AAHJ, MacGregor, S, Klaver, CCW, van Duijn, CM, Bonnemaijer, PWM, van Leeuwen, EM, Iglesias, AI, Gharahkhani, P, Vitart, V, Khawaja, AP, Simcoe, M, Hoehn, R, Cree, AJ, Igo, RP, Burdon, KP, Craig, JE, Hewitt, AW, Jonas, J, Khor, C-C, Pasutto, F, Mackey, DA, Mitchell, P, Mishra, A, Pang, C, Pasquale, LR, Springelkamp, H, Thorleifsson, G, Thorsteinsdottir, U, Viswanathan, AC, Wojciechowski, R, Wong, T, Young, TL, Zeller, T, Atan, D, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway, DF, Gibson, J, Gore, D, Guggenheim, JA, Hardcastle, A, Harding, SP, Hogg, RE, Keane, PA, Khaw, PT, Lascaratos, G, Macgillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, Mckay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vernon, SA, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Allingham, R, Budenz, D, Bailey, JC, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, JL, Hark, L, Hauser, M, Kang, JH, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pericak, M, Realini, A, Rhee, D, Richards, JR, Ritch, R, Scott, WK, Singh, K, Sit, A, Vollrath, D, Weinreb, R, Wollstein, G, Wilmer, DZ, Gerhold-Ay, A, Nickels, S, Wilson, JF, Hayward, C, Boutin, TS, Polasek, O, Aung, T, Khor, CC, Amin, N, Lotery, AJ, Wiggs, JL, Cheng, C-Y, Hysi, PG, Hammond, CJ, Thiadens, AAHJ, MacGregor, S, Klaver, CCW, and van Duijn, CM

Abstract

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.

Published
2019

21. Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium

Author

Wong, YL, Hysi, P, Cheung, G, Tedja, Milly, Hoang, QV, Tompson, SW, Whisenhunt, KN, Verhoeven, Virginie, Zhao, WT, Hess, M, Wong, CW, Kifley, A, Hosoda, Y, Haarman, Annet, Hopf, S, Laspas, P, Sensaki, S, Sim, X, Miyake, M, Tsujikawa, A, Lamoureux, E, Ohno-Matsui, K, Nickels, S, Mitchell, P, Wong, TY, Wang, JJ, Hammond, CJ, Barathi, VA, Cheng, CY (Ching-Yu), Yamashiro, K, Young, TL, Klaver, Caroline, Saw, SM, Wong, YL, Hysi, P, Cheung, G, Tedja, Milly, Hoang, QV, Tompson, SW, Whisenhunt, KN, Verhoeven, Virginie, Zhao, WT, Hess, M, Wong, CW, Kifley, A, Hosoda, Y, Haarman, Annet, Hopf, S, Laspas, P, Sensaki, S, Sim, X, Miyake, M, Tsujikawa, A, Lamoureux, E, Ohno-Matsui, K, Nickels, S, Mitchell, P, Wong, TY, Wang, JJ, Hammond, CJ, Barathi, VA, Cheng, CY (Ching-Yu), Yamashiro, K, Young, TL, Klaver, Caroline, and Saw, SM

Published
2019

22. Augenerkrankungen in Deutschland und deren Versorgung – Die Gutenberg-Gesundheitsstudie

Author

Schuster, AK, Nickels, S, and Pfeiffer, N

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Hintergrund: Augenerkrankungen sind Volkskrankheiten, insbesondere im höheren Alter treten diese häufig auf. Im Rahmen dieses Vortrags sollen Erkenntnisse zu Häufigkeiten von Augenerkrankungen wie altersassoziierter Makuladegeneration, Glaukom und diabetischer Retinopathie vorgestellt[zum vollständigen Text gelangen Sie über die oben angegebene URL], 91. Versammlung des Vereins Rhein-Mainischer Augenärzte

Published
2018
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23. Die altersassoziierte Makuladegeneration (AMD): Kumulative 5-Jahres-Inzidenz und -Progression in der bevölkerungsbasierten Gutenberg-Gesundheitsstudie (GHS)

Author

Korb, C, El-Baz, H, Schuster, A, Nickels, S, Ponto, K, Schulz, A, Wild, P, Münzel, T, Beutel, M, Schmidtmann, I, Lackner, K, Peto, T, and Pfeiffer, N

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Hintergrund: Die altersassoziierte Makuladegeneration (AMD) ist häufig, aber wir kennen kaum Daten zum Neuauftreten und dem Krankheitsverlauf der Frühstadien der AMD in Europa, Grundlage für die Einschätzung von Veränderung und gesundheitspolitischer Diskussionen. Methoden:[zum vollständigen Text gelangen Sie über die oben angegebene URL], 91. Versammlung des Vereins Rhein-Mainischer Augenärzte

Published
2018
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24. Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration: Evidence from the EYE-RISK and European Eye Epidemiology Consortia

Author

Colijn, J. M., Verzijden, T., Meester-Smoor, M. A., Klaver, C. C. W., Demirkan, A., Ahmad, S., van Duijn, C. M., den Hollander, A. I., Kersten, E., Hoyng, C. B., Cougnard-Gregoire, A., Merle, B. M. J., Korobelnik, J. -F., Delcourt, C., Papageorgiou, G., Mulder, M. T., Costa, M. A., Silva, R., Benlian, P., Bertelsen, G., Bron, A. M., Creuzot-Garcher, C., Claes, B., Hense, H. -W., Erke, M. G., Fauser, S., Foster, P. J., Khawaja, A. P., Hammond, C. J., Williams, K. M., Piermarocchi, S., Segato, T., Souied, E. H., Acar, N., Altay, L., Anastosopoulos, E., Azuara-Blanco, A., Berendschot, T., Bergen, A., Binquet, C., Bird, A., Bobak, M., Larsen, M. B., Boon, C., Bourne, R., Bretillon, L., Broe, R., Bron, A., Buitendijk, G., Cachulo, M. L., Capuano, V., Carriere, I., Chakravarthy, U., Chan, M., Chang, P., Colijn, J., Cree, A., Cumberland, P., Cunha-Vaz, J., Daien, V., De Jong, E., Deak, G., Delyfer, M. -N., Hollander, A. D., Dietzel, M., Faria, P., Farinha, C., Finger, R., Fletcher, A., Foster, P., Founti, P., Gorgels, T., Grauslund, J., Grus, F., Hammond, C., Heesterbeek, T., Hermann, M., Hoehn, R., Hogg, R., Holz, F., Hoyng, C., Jansonius, N., Janssen, S., de Jong, E., Khawaja, A., Klaver, C., Lamparter, J., Le Goff, M., Lehtimaki, T., Leung, I., Lotery, A., Mauschitz, M., Meester, M., Merle, B., Meyer zu Westrup, V., Midena, E., Miotto, S., Mirshahi, A., Mohan-Said, S., Mueller, M., Muldrew, A., Murta, J., Nickels, S., Nunes, S., Owen, C., Peto, T., Pfeiffer, N., Prokofyeva, E., Rahi, J., Raitakari, O., Rauscher, F., Ribeiro, L., Rougier, M. -B., Rudnicka, A., Randjvar, Sahel, Salonikiou, A., Sanchez, C., Schick, T., Schmitz-Valckenberg, S., Schuster, A., Schweitzer, C., Shehata, J., Silvestri, G., Simader, C., Souied, E., Speckauskas, M., Springelkamp, H., Tapp, R., Topouzis, F., van Leeuwen, E., Verhoeven, V., Vingerling, H., Von Hanno, T., Williams, K., Wolfram, C., Yip, J., Zerbib, J., Ajana, S., Arango-Gonzalez, B., Arndt, V., Bhatia, V., Bhattacharya, S. S., Biarnes, M., Borrell, A., Buhren, S., Calado, S. M., Dammeier, S., de Jong, E. K., De la Cerda, B., Diaz-Corrales, F. J., Diether, S., Emri, E., Endermann, T., Ferraro, L. L., Garcia, M., Heesterbeek, T. J., Honisch, S., Kilger, E., Langen, H., Lengyel, I., Luthert, P., Maugeais, C., Meester-Smoor, M., Merle Inserm, B. M. J., Mones, J., Nogoceke, E., Pool, F. M., Rodriguez, E., Ueffing, M., Ulrich Bartz-Schmidt, K. U., van Leeuwen, E. M., and Zumbansen, M.

Subjects
Male, Magnetic Resonance Spectroscopy, HDL, genetic structures, European Continental Ancestry Group, Polymorphism, Single Nucleotide, White People, LDL, Macular Degeneration, Risk Factors, 80 and over, Odds Ratio, Humans, Metabolomics, European Union, Polymorphism, Triglycerides, Aged, Aged, 80 and over, Cholesterol, HDL, Single Nucleotide, Cholesterol, LDL, Middle Aged, Lipid Metabolism, eye diseases, Cholesterol Ester Transfer Proteins, Cholesterol, Cross-Sectional Studies, lipids (amino acids, peptides, and proteins), Female, sense organs
Abstract

Purpose Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset. Design Pooled analysis of cross-sectional data. Participants Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data. Methods AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations. Main Outcome Measures AMD features and stage; lipid measurements. Results HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14–1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91–0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10–1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 × 10–7), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 × 10–6 and P = 1.6 × 10–4). Conclusions Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered.

Published
2018

25. A genome-wide association study for corneal astigmatism: The CREAM Consortium

Author

Shah, Rupal, Li, Q, Zhao, W, Tedja, MS, Tideman, WL, Khawaja, A, Fan, Q, Yazar, S, Williams, KM, Verhoeven, VJM, Xie, J, Wang, YX, Hess, M, Nickels, S, Lackner, KJ, Pärssinen, O, Wedenoja, J, Biino, G, Concas, MP, Uitterlinden, A, Rivadeneira, F, Jaddoe, VWV, Hysi, PG, Sim, X, Tan, N, Tham, Y, Sensaki, S, Hofman, A, Vingerling, JR, Jonas, JB, Mitchell, P, Hammond, CJ, Höhn, R, Baird, PN, Wong, TY, Cheng, C, Teo, YY, Mackey, DA, Williams, C, Saw, S, Klaver, CCW, Guggenheim, Jeremy, Bailey-Wilson, JE, and The CREAM Consortium

Abstract

Purpose: To identify genes and genetic markers associated with corneal astigmatism.\ud Methods: A meta-analysis was performed of genome-wide association studies (GWAS) of corneal astigmatism undertaken for 14 European ancestry (N = 22,250) and 8 Asian ancestry (N = 9,120) cohorts by the CREAM Consortium. Cases were defined as having >0.75 D of corneal astigmatism. For the meta-analysed results of European ancestry cohorts, subsequent gene-based and gene-set analyses were performed using VEGAS2 and MAGMA software. Additionally, estimates of SNP-based heritability for corneal and refractive astigmatism and spherical equivalent were calculated for Europeans using LD score regression.\ud Results: Meta-analysis of all cohorts identified a genome-wide significant locus near the gene PDGFRA (platelet derived growth factor receptor alpha): top SNP: rs7673984, odds ratio = 1.12 (95% CI: 1.08-1.16), P = 5.55 x 10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified 3 novel candidate genes for corneal astigmatism in Europeans: CLDN7 (claudin-7), ACP2 (acid phosphatase 2, lysosomal) and TNFAIP8L3 (TNF alpha induced protein 8 like 3).\ud Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified 3 novel candidate genes CLDN7, ACP2 and TNFAIP8L3 that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors to the development of astigmatism.

Published
2018

26. Zusammenhang von Geburtsgewicht mit Hornhautbrechkraft in der Jugend: Ergebnisse des National Health and Nutrition Examination Survey (NHANES) von 1999-2008

Author

Fieß, A., Schuster, A. K., Pfeiffer, N., and Nickels, S.

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Ziel: Das Ziel dieser Studie ist es den Einfluss von Geburtsgewicht auf die Augenmorphologie, die Refraktion und auf die Sehschärfe bei Jugendlichen im Alter von 12 bis 15 Jahren zu untersuchen. Material und Methoden: Hierfür führten wir eine Analyse der öffentlich zugänglichen[zum vollständigen Text gelangen Sie über die oben angegebene URL], 90. Versammlung des Vereins Rhein-Mainischer Augenärzte

Published
2017
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27. Niedriges Geburtsgewicht ist assoziiert mit reduzierter Sehschärfe und Refraktionsveränderungen im Erwachsenenalter – Ergebnisse der Gutenberg-Gesundheitsstudie

Author

Fieß, A, Schuster, AK, Nickels, S, Elflein, H, Schulz, A, Beutel, ME, Blettner, M, and Pfeiffer, N

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Ziel: In verschiedenen Studien wurde gezeigt, dass niedriges Geburtsgewicht mit veränderter Organentwicklung in der Kindheit assoziiert ist, was insbesondere für die Augenmorphologie und Funktion bei Kindern bereits nachgewiesen wurde. Das Ziel der vorliegenden Studie war es deshalb, den Einfluss[zum vollständigen Text gelangen Sie über die oben angegebene URL], 90. Versammlung des Vereins Rhein-Mainischer Augenärzte

Published
2017
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28. A genome-wide association study of corneal astigmatism: The CREAM Consortium

Author

Shah, R.L., Li, Q., Zhao, W., Tedja, M.S., Tideman, J.W., Khawaja, A.P., Fan, Q., Yazar, S., Williams, K.M., Verhoeven, V.J., Xie, J., Wang, Y.X., Hess, M., Nickels, S., Lackner, K.J., Parssinen, O., Wedenoja, J., Biino, G., Concas, M.P., Uitterlinden, A., Rivadeneira, F., Jaddoe, V.W., Hysi, P.G., Sim, X., Tan, N., Tham, Y.C., Sensaki, S., Hofman, A., Vingerling, J.R., Jonas, J.B., Mitchell, P., Hammond, C.J., Hohn, R., Baird, P.N., Wong, T.Y., Cheng, C.Y., Teo, Y.Y., Mackey, D.A., Williams, C., Saw, S.M., Klaver, C.C.W., Guggenheim, J.A., Bailey-Wilson, J.E., Shah, R.L., Li, Q., Zhao, W., Tedja, M.S., Tideman, J.W., Khawaja, A.P., Fan, Q., Yazar, S., Williams, K.M., Verhoeven, V.J., Xie, J., Wang, Y.X., Hess, M., Nickels, S., Lackner, K.J., Parssinen, O., Wedenoja, J., Biino, G., Concas, M.P., Uitterlinden, A., Rivadeneira, F., Jaddoe, V.W., Hysi, P.G., Sim, X., Tan, N., Tham, Y.C., Sensaki, S., Hofman, A., Vingerling, J.R., Jonas, J.B., Mitchell, P., Hammond, C.J., Hohn, R., Baird, P.N., Wong, T.Y., Cheng, C.Y., Teo, Y.Y., Mackey, D.A., Williams, C., Saw, S.M., Klaver, C.C.W., Guggenheim, J.A., and Bailey-Wilson, J.E.

Abstract

Contains fulltext : 191261.pdf (publisher's version ) (Open Access), Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55x10(-9). No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

Published
2018

29. A genome-wide association study of corneal astigmatism: The CREAM Consortium

Author

Shah, RL, Li, Q, Zhao, W, Tedja, MS, Tideman, JWL, Khawaja, AP, Fan, Q, Yazar, S, Williams, KM, Verhoeven, VJM, Xie, J, Wang, YX, Hess, M, Nickels, S, Lackner, KJ, Parssinen, O, Wedenoja, J, Biino, G, Concas, MP, Uitterlinden, A, Rivadeneira, F, Jaddoe, VWV, Hysi, PG, Sim, X, Tan, N, Tham, Y-C, Sensaki, S, Hofman, A, Vingerling, JR, Jonas, JB, Mitchell, P, Hammond, CJ, Hoehn, R, Baird, PN, Wong, T-Y, Cheng, C-Y, Teo, YY, Mackey, DA, Williams, C, Saw, S-M, Klaver, CCW, Guggenheim, JA, Bailey-Wilson, JE, Shah, RL, Li, Q, Zhao, W, Tedja, MS, Tideman, JWL, Khawaja, AP, Fan, Q, Yazar, S, Williams, KM, Verhoeven, VJM, Xie, J, Wang, YX, Hess, M, Nickels, S, Lackner, KJ, Parssinen, O, Wedenoja, J, Biino, G, Concas, MP, Uitterlinden, A, Rivadeneira, F, Jaddoe, VWV, Hysi, PG, Sim, X, Tan, N, Tham, Y-C, Sensaki, S, Hofman, A, Vingerling, JR, Jonas, JB, Mitchell, P, Hammond, CJ, Hoehn, R, Baird, PN, Wong, T-Y, Cheng, C-Y, Teo, YY, Mackey, DA, Williams, C, Saw, S-M, Klaver, CCW, Guggenheim, JA, and Bailey-Wilson, JE

Abstract

PURPOSE: To identify genes and genetic markers associated with corneal astigmatism. METHODS: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. RESULTS: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). CONCLUSIONS: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

Published
2018

30. 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

31. 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
Full Text
View/download PDF

32. 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
Full Text
View/download PDF

33. 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

35. 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

36. 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

37. PALB2, CHEK2 and ATM rare variants and cancer risk:data from COGS

Author

Southey, M. C. (Melissa C.), Goldgar, D. E. (David E.), Winqvist, R. (Robert), Pylkäs, K. (Katri), Couch, F. (Fergus), Tischkowitz, M. (Marc), Foulkes, W. D. (William D.), Dennis, J. (Joe), Michailidou, K. (Kyriaki), van Rensburg, E. J. (Elizabeth J.), Heikkinen, T. (Tuomas), Nevanlinna, H. (Heli), Hopper, J. L. (John L.), Doerk, T. (Thilo), Claes, K. B. (Kathleen B. M.), Reis-Filho, J. (Jorge), Teo, Z. L. (Zhi Ling), Radice, P. (Paolo), Catucci, I. (Irene), Peterlongo, P. (Paolo), Tsimiklis, H. (Helen), Odefrey, F. A. (Fabrice A.), Dowty, J. G. (James G.), Schmidt, M. K. (Marjanka K.), Broeks, A. (Annegien), Hogervorst, F. B. (Frans B.), Verhoef, S. (Senno), Carpenter, J. (Jane), Clarke, C. (Christine), Scott, R. J. (Rodney J.), Fasching, P. A. (Peter A.), Haeberle, L. (Lothar), Ekici, A. B. (Arif B.), Beckmann, M. W. (Matthias W.), Peto, J. (Julian), dos-Santos-Silva, I. (Isabel), Fletcher, O. (Olivia), Johnson, N. (Nichola), Bolla, M. K. (Manjeet K.), Sawyer, E. J. (Elinor J.), Tomlinson, I. (Ian), Kerin, M. J. (Michael J.), Miller, N. (Nicola), Marme, F. (Federik), Burwinkel, B. (Barbara), Yang, R. (Rongxi), Guenel, P. (Pascal), Menegaux, F. (Florence), Sanchez, M. (Marie), Bojesen, S. (Stig), Nielsen, S. F. (Sune F.), Flyger, H. (Henrik), Benitez, J. (Javier), Pilar Zamora, M. (M.), Arias Perez, J. I. (Jose Ignacio), Menendez, P. (Primitiva), Anton-Culver, H. (Hoda), Neuhausen, S. (Susan), Ziogas, A. (Argyrios), Clarke, C. A. (Christina A.), Brenner, H. (Hermann), Arndt, V. (Volker), Stegmaier, C. (Christa), Brauch, H. (Hiltrud), Bruening, T. (Thomas), Ko, Y.-D. (Yon-Dschun), Muranen, T. A. (Taru A.), Aittomaki, K. (Kristiina), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia V.), Antonenkova, N. N. (Natalia N.), Lindblom, A. (Annika), Margolin, S. (Sara), Mannermaa, A. (Arto), Kataja, V. (Vesa), Kosma, V.-M. (Veli-Matti), Hartikainen, J. M. (Jaana M.), Spurdle, A. B. (Amanda B.), Wauters, E. (Els), Smeets, D. (Dominiek), Beuselinck, B. (Benoit), Floris, G. (Giuseppe), Chang-Claude, J. (Jenny), Rudolph, A. (Anja), Seibold, P. (Petra), Flesch-Janys, D. (Dieter), Olson, J. E. (Janet E.), Vachon, C. (Celine), Pankratz, V. S. (Vernon S.), McLean, C. (Catriona), Haiman, C. A. (Christopher A.), Henderson, B. E. (Brian E.), Schumacher, F. (Fredrick), Le Marchand, L. (Loic), Kristensen, V. (Vessela), Alnaes, G. G. (Grethe Grenaker), Zheng, W. (Wei), Hunter, D. J. (David J.), Lindstrom, S. (Sara), Hankinson, S. E. (Susan E.), Kraft, P. (Peter), Andrulis, I. (Irene), Knight, J. A. (Julia A.), Glendon, G. (Gord), Mulligan, A. M. (Anna Marie), Jukkola-Vuorinen, A. (Arja), Grip, M. (Mervi), Kauppila, S. (Saila), Devilee, P. (Peter), Tollenaar, R. A. (Robert A. E. M.), Seynaeve, C. (Caroline), Hollestelle, A. (Antoinette), Garcia-Closas, M. (Montserrat), Figueroa, J. (Jonine), Chanock, S. J. (Stephen J.), Lissowska, J. (Jolanta), Czene, K. (Kamila), Darabi, H. (Hatef), Eriksson, M. (Mikael), Eccles, D. M. (Diana M.), Rafiq, S. (Sajjad), Tapper, W. J. (William J.), Gerty, S. M. (Sue M.), Hooning, M. J. (Maartje J.), Martens, J. W. (John W. M.), Collee, J. M. (J. Margriet), Tilanus-Linthorst, M. (Madeleine), Hall, P. (Per), Li, J. (Jingmei), Brand, J. S. (Judith S.), Humphreys, K. (Keith), Cox, A. (Angela), Reed, M. W. (Malcolm W. R.), Luccarini, C. (Craig), Baynes, C. (Caroline), Dunning, A. M. (Alison M.), Hamann, U. (Ute), Torres, D. (Diana), Ulmer, H. U. (Hans Ulrich), Ruediger, T. (Thomas), Jakubowska, A. (Anna), Lubinski, J. (Jan), Jaworska, K. (Katarzyna), Durda, K. (Katarzyna), Slager, S. (Susan), Toland, A. E. (Amanda E.), Ambrosone, C. B. (Christine B.), Yannoukakos, D. (Drakoulis), Swerdlow, A. (Anthony), Ashworth, A. (Alan), Orr, N. (Nick), Jones, M. (Michael), Gonzalez-Neira, A. (Anna), Pita, G. (Guillermo), Rosario Alonso, M. (M.), Alvarez, N. (Nuria), Herrero, D. (Daniel), Tessier, D. C. (Daniel C.), Vincent, D. (Daniel), Bacot, F. (Francois), Simard, J. (Jacques), Dumont, M. (Martine), Soucy, P. (Penny), Eeles, R. (Rosalind), Muir, K. (Kenneth), Wiklund, F. (Fredrik), Gronberg, H. (Henrik), Schleutker, J. (Johanna), Nordestgaard, B. G. (Borge G.), Weischer, M. (Maren), Travis, R. C. (Ruth C.), Neal, D. (David), Donovan, J. L. (Jenny L.), Hamdy, F. C. (Freddie C.), Khaw, K.-T. (Kay-Tee), Stanford, J. L. (Janet L.), Blot, W. J. (William J.), Thibodeau, S. (Stephen), Schaid, D. J. (Daniel J.), Kelley, J. L. (Joseph L.), Maier, C. (Christiane), Kibel, A. S. (Adam S.), Cybulski, C. (Cezary), Cannon-Albright, L. (Lisa), Butterbach, K. (Katja), Park, J. (Jong), Kaneva, R. (Radka), Batra, J. (Jyotsna), Teixeira, M. R. (Manuel R.), Kote-Jarai, Z. (Zsofia), Al Olama, A. A. (Ali Amin), Benlloch, S. (Sara), Renner, S. P. (Stefan P.), Hartmann, A. (Arndt), Hein, A. (Alexander), Ruebner, M. (Matthias), Lambrechts, D. (Diether), Van Nieuwenhuysen, E. (Els), Vergote, I. (Ignace), Lambretchs, S. (Sandrina), Doherty, J. A. (Jennifer A.), Rossing, M. A. (Mary Anne), Nickels, S. (Stefan), Eilber, U. (Ursula), Wang-Gohrke, S. (Shan), Odunsi, K. (Kunle), Sucheston-Campbell, L. E. (Lara E.), Friel, G. (Grace), Lurie, G. (Galina), Killeen, J. L. (Jeffrey L.), Wilkens, L. R. (Lynne R.), Goodman, M. T. (Marc T.), Runnebaum, I. (Ingo), Hillemanns, P. A. (Peter A.), Pelttari, L. M. (Liisa M.), Butzow, R. (Ralf), Modugno, F. (Francesmary), Edwards, R. P. (Robert P.), Ness, R. B. (Roberta B.), Moysich, K. B. (Kirsten B.), du Bois, A. (Andreas), Heitz, F. (Florian), Harter, P. (Philipp), Kommoss, S. (Stefan), Karlan, B. Y. (Beth Y.), Walsh, C. (Christine), Lester, J. (Jenny), Jensen, A. (Allan), Kjaer, S. K. (Susanne Kruger), Hogdall, E. (Estrid), Peissel, B. (Bernard), Bonanni, B. (Bernardo), Bernard, L. (Loris), Goode, E. L. (Ellen L.), Fridley, B. L. (Brooke L.), Vierkant, R. A. (Robert A.), Cunningham, J. M. (Julie M.), Larson, M. C. (Melissa C.), Fogarty, Z. C. (Zachary C.), Kalli, K. R. (Kimberly R.), Liang, D. (Dong), Lu, K. H. (Karen H.), Hildebrandt, M. A. (Michelle A. T.), Wu, X. (Xifeng), Levine, D. A. (Douglas A.), Dao, F. (Fanny), Bisogna, M. (Maria), Berchuck, A. (Andrew), Iversen, E. S. (Edwin S.), Marks, J. R. (Jeffrey R.), Akushevich, L. (Lucy), Cramer, D. W. (Daniel W.), Schildkraut, J. (Joellen), Terry, K. L. (Kathryn L.), Poole, E. M. (Elizabeth M.), Stampfer, M. (Meir), Tworoger, S. S. (Shelley S.), Bandera, E. V. (Elisa V.), Orlow, I. (Irene), Olson, S. H. (Sara H.), Bjorge, L. (Line), Salvesen, H. B. (Helga B.), van Altena, A. M. (Anne M.), Aben, K. K. (Katja K. H.), Kiemeney, L. A. (Lambertus A.), Massuger, L. F. (Leon F. A. G.), Pejovic, T. (Tanja), Bean, Y. (Yukie), Brooks-Wilson, A. (Angela), Kelemen, L. E. (Linda E.), Cook, L. S. (Linda S.), Le, N. D. (Nhu D.), Grski, B. (Bohdan), Gronwald, J. (Jacek), Menkiszak, J. (Janusz), Hogdall, C. K. (Claus K.), Lundvall, L. (Lene), Nedergaard, L. (Lotte), Engelholm, S. A. (Svend Aage), Dicks, E. (Ed), Tyrer, J. (Jonathan), Campbell, I. (Ian), McNeish, I. (Iain), Paul, J. (James), Siddiqui, N. (Nadeem), Glasspool, R. (Rosalind), Whittemore, A. S. (Alice S.), Rothstein, J. H. (Joseph H.), McGuire, V. (Valerie), Sieh, W. (Weiva), Cai, H. (Hui), Shu, X.-O. (Xiao-Ou), Teten, R. T. (Rachel T.), Sutphen, R. (Rebecca), McLaughlin, J. R. (John R.), Narod, S. A. (Steven A.), Phelan, C. M. (Catherine M.), Monteiro, A. N. (Alvaro N.), Fenstermacher, D. (David), Lin, H.-Y. (Hui-Yi), Permuth, J. B. (Jennifer B.), Sellers, T. A. (Thomas A.), Chen, Y. A. (Y. Ann), Tsai, Y.-Y. (Ya-Yu), Chen, Z. (Zhihua), Gentry-Maharaj, A. (Aleksandra), Gayther, S. A. (Simon A.), Ramus, S. J. (Susan J.), Menon, U. (Usha), Wu, A. H. (Anna H.), Pearce, C. L. (Celeste L.), Van den Berg, D. (David), Pike, M. C. (Malcolm C.), Dansonka-Mieszkowska, A. (Agnieszka), Plisiecka-Halasa, J. (Joanna), Moes-Sosnowska, J. (Joanna), Kupryjanczyk, J. (Jolanta), Pharoah, P. D. (Paul D. P.), Song, H. (Honglin), Winship, I. (Ingrid), Chenevix-Trench, G. (Georgia), Giles, G. G. (Graham G.), Tavtigian, S. V. (Sean V.), Easton, D. F. (Doug F.), and Milne, R. L. (Roger L.)

Subjects
skin and connective tissue diseases
Abstract

Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p = 7.1 × 10⁻⁵), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p = 6.9 × 10⁻⁸) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p = 0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p ≤ 0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p = 0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p = 0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Published
2016

39. Associations of fatigue to work-related stress, mental and physical health in an employed community sample

Author

Rose, D. M., primary, Seidler, A., additional, Nübling, M., additional, Latza, U., additional, Brähler, E., additional, Klein, E. M., additional, Wiltink, J., additional, Michal, M., additional, Nickels, S., additional, Wild, P. S., additional, König, J., additional, Claus, M., additional, Letzel, S., additional, and Beutel, M. E., additional

Published
2017
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40. The Canadian Consortium for Arctic Data Interoperability: An Emerging Polar Information Network.

Author

CHRISTOFFERSEN, SHANNON, MURRAY, M., ARTHURS, D., BARNARD, C., CARPENDALE, S., CHU, B., DUGUAY, C., FOREST, A., HAYES, A., LEDREW, E., LIANG, S., NICKELS, S., PAPAKYRIAKOU, T., PARROTT, J., PULSIFER, P., REIS, C., SCASSA, T., SOKOL, J., TAYLOR, F., and VINCENT, W.

Subjects
DATA management, INTERNETWORKING, INFORMATION sharing, METADATA
Abstract

Established in 2015, the Canadian Consortium for Arctic Data Interoperability (CCADI) is an emerging initiative to develop an integrated Canadian arctic data management system that will facilitate information discovery, establish metadata and data sharing standards, enable interoperability among existing data infrastructures, and that will be accessible to a broad audience of users. Key to the CCADI vision are: standards and mechanisms for metadata interoperability and semantic interoperability; a distributed data exchange platform; streamlined data services with common entry, access, search, match, analysis, visualization and output tools; an intellectual property and sensitive data service; and data stewardship capacity. This will be a particularly challenging set of tasks given that the data planned for inclusion is multidisciplinary, in multiple types that range from sensor data to material artifacts, and, in some cases, confidential. [ABSTRACT FROM AUTHOR]

Published
2018

41. When do myopia genes have their effect? Comparison of genetic risks between children and adults

Author

Tideman, J.W., Fan, Q., Polling, J.R., Guo, X., Yazar, S., Khawaja, A., Hohn, R., Lu, Y., Jaddoe, V.W., Yamashiro, K., Yoshikawa, M., Gerhold-Ay, A., Nickels, S., Zeller, T., He, M., Boutin, T., Bencic, G., Vitart, V., Mackey, D.A., Foster, P.J., MacGregor, S., Williams, C., Saw, S.M., Guggenheim, J.A., Klaver, C.C.W., Tideman, J.W., Fan, Q., Polling, J.R., Guo, X., Yazar, S., Khawaja, A., Hohn, R., Lu, Y., Jaddoe, V.W., Yamashiro, K., Yoshikawa, M., Gerhold-Ay, A., Nickels, S., Zeller, T., He, M., Boutin, T., Bencic, G., Vitart, V., Mackey, D.A., Foster, P.J., MacGregor, S., Williams, C., Saw, S.M., Guggenheim, J.A., and Klaver, C.C.W.

Abstract

Item does not contain fulltext, Previous studies have identified many genetic loci for refractive error and myopia. We aimed to investigate the effect of these loci on ocular biometry as a function of age in children, adolescents, and adults. The study population consisted of three age groups identified from the international CREAM consortium: 5,490 individuals aged <10 years; 5,000 aged 10-25 years; and 16,274 aged >25 years. All participants had undergone standard ophthalmic examination including measurements of axial length (AL) and corneal radius (CR). We examined the lead SNP at all 39 currently known genetic loci for refractive error identified from genome-wide association studies (GWAS), as well as a combined genetic risk score (GRS). The beta coefficient for association between SNP genotype or GRS versus AL/CR was compared across the three age groups, adjusting for age, sex, and principal components. Analyses were Bonferroni-corrected. In the age group <10 years, three loci (GJD2, CHRNG, ZIC2) were associated with AL/CR. In the age group 10-25 years, four loci (BMP2, KCNQ5, A2BP1, CACNA1D) were associated; and in adults 20 loci were associated. Association with GRS increased with age; beta = 0.0016 per risk allele (P = 2 x 10-8 ) in <10 years, 0.0033 (P = 5 x 10-15 ) in 10- to 25-year-olds, and 0.0048 (P = 1 x 10-72 ) in adults. Genes with strongest effects (LAMA2, GJD2) had an early effect that increased with age. Our results provide insights on the age span during which myopia genes exert their effect. These insights form the basis for understanding the mechanisms underlying high and pathological myopia.

Published
2016

42. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author

Hampras, SS, Sucheston-Campbell, LE, Cannioto, R, Chang-Claude, J, Modugno, F, Doerk, T, Hillemanns, P, Preus, L, Knutson, KL, Wallace, PK, Hong, C-C, Friel, G, Davis, W, Nesline, M, Pearce, CL, Kelemen, LE, Goodman, MT, Bandera, EV, Terry, KL, Schoof, N, Eng, KH, Clay, A, Singh, PK, Joseph, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Despierre, E, Dicks, E, Doherty, JA, du Bois, A, Duerst, M, Easton, D, Eccles, D, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hogdall, C, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Klapdor, R, Kolomeyevskaya, N, Krakstad, C, Kjaer, SK, Kruszka, B, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Liu, S, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Moes-Sosnowska, J, Narod, SA, Nedergaard, L, Nevanlinna, H, Nickels, S, Olson, SH, Orlow, I, Weber, RP, Paul, J, Pejovic, T, Pelttari, LM, Perkins, B, Permuth-Wey, J, Pike, MC, Plisiecka-Halasa, J, Poole, EM, Risch, HA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schmitt, K, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Tangen, IL, Teo, S-H, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Tyrer, J, van Altena, AM, Vergote, I, Vierkant, RA, Walsh, C, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Gayther, SA, Ramus, SJ, Sellers, TA, Schildkraut, JM, Phelan, CM, Berchuck, A, Chenevix-Trench, G, Cunningham, JM, Pharoah, PP, Ness, RB, Odunsi, K, Goode, EL, Moysich, KB, Hampras, SS, Sucheston-Campbell, LE, Cannioto, R, Chang-Claude, J, Modugno, F, Doerk, T, Hillemanns, P, Preus, L, Knutson, KL, Wallace, PK, Hong, C-C, Friel, G, Davis, W, Nesline, M, Pearce, CL, Kelemen, LE, Goodman, MT, Bandera, EV, Terry, KL, Schoof, N, Eng, KH, Clay, A, Singh, PK, Joseph, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Despierre, E, Dicks, E, Doherty, JA, du Bois, A, Duerst, M, Easton, D, Eccles, D, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hogdall, C, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Klapdor, R, Kolomeyevskaya, N, Krakstad, C, Kjaer, SK, Kruszka, B, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Liu, S, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Moes-Sosnowska, J, Narod, SA, Nedergaard, L, Nevanlinna, H, Nickels, S, Olson, SH, Orlow, I, Weber, RP, Paul, J, Pejovic, T, Pelttari, LM, Perkins, B, Permuth-Wey, J, Pike, MC, Plisiecka-Halasa, J, Poole, EM, Risch, HA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schmitt, K, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Tangen, IL, Teo, S-H, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Tyrer, J, van Altena, AM, Vergote, I, Vierkant, RA, Walsh, C, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Gayther, SA, Ramus, SJ, Sellers, TA, Schildkraut, JM, Phelan, CM, Berchuck, A, Chenevix-Trench, G, Cunningham, JM, Pharoah, PP, Ness, RB, Odunsi, K, Goode, EL, and Moysich, KB

Abstract

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Published
2016

43. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Author

Southey, MC, Goldgar, DE, Winqvist, R, Pylkas, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Doerk, T, Claes, KBM, Reis-Filho, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK, Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Burwinkel, B, Yang, R, Guenel, P, Therese, T, Menegaux, F, Sanchez, M, Bojesen, S, Nielsen, SF, Flyger, H, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Anton-Culver, H, Neuhausen, S, Ziogas, A, Clarke, CA, Brenner, H, Arndt, V, Stegmaier, C, Brauch, H, Bruening, T, Ko, Y-D, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Spurdle, AB, Wauters, E, Smeets, D, Beuselinck, B, Floris, G, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Olson, JE, Vachon, C, Pankratz, VS, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GG, Zheng, W, Hunter, DJ, Lindstrom, S, Hankinson, SE, Kraft, P, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Jukkola-Vuorinen, A, Grip, M, Kauppila, S, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Hollestelle, A, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, M, Eccles, DM, Rafiq, S, Tapper, WJ, Gerty, SM, Hooning, MJ, Martens, JWM, Collee, JM, Tilanus-Linthorst, M, Hall, P, Li, J, Brand, JS, Humphreys, K, Cox, A, Reed, MWR, Luccarini, C, Baynes, C, Dunning, AM, Hamann, U, Torres, D, Ulmer, HU, Ruediger, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Simard, J, Dumont, M, Soucy, P, Eeles, R, Muir, K, Wiklund, F, Gronberg, H, Schleutker, J, Nordestgaard, BG, Weischer, M, Travis, RC, Neal, D, Donovan, JL, Hamdy, FC, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Schaid, DJ, Kelley, JL, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Butterbach, K, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Renner, SP, Hartmann, A, Hein, A, Ruebner, M, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambretchs, S, Doherty, JA, Rossing, MA, Nickels, S, Eilber, U, Wang-Gohrke, S, Odunsi, K, Sucheston-Campbell, LE, Friel, G, Lurie, G, Killeen, JL, Wilkens, LR, Goodman, MT, Runnebaum, I, Hillemanns, PA, Pelttari, LM, Butzow, R, Modugno, F, Edwards, RP, Ness, RB, Moysich, KB, du Bois, A, Heitz, F, Harter, P, Kommoss, S, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, E, Peissel, B, Bonanni, B, Bernard, L, Goode, EL, Fridley, BL, Vierkant, RA, Cunningham, JM, Larson, MC, Fogarty, ZC, Kalli, KR, Liang, D, Lu, KH, Hildebrandt, MAT, Wu, X, Levine, DA, Dao, F, Bisogna, M, Berchuck, A, Iversen, ES, Marks, JR, Akushevich, L, Cramer, DW, Schildkraut, J, Terry, KL, Poole, EM, Stampfer, M, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Bjorge, L, Salvesen, HB, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, Y, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Grski, B, Gronwald, J, Menkiszak, J, Hogdall, CK, Lundvall, L, Nedergaard, L, Engelholm, SA, Dicks, E, Tyrer, J, Campbell, I, McNeish, I, Paul, J, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Cai, H, Shu, X-O, Teten, RT, Sutphen, R, McLaughlin, JR, Narod, SA, Phelan, CM, Monteiro, AN, Fenstermacher, D, Lin, H-Y, Permuth, JB, Sellers, TA, Chen, YA, Tsai, Y-Y, Chen, Z, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Menon, U, Wu, AH, Pearce, CL, Van den Berg, D, Pike, MC, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Moes-Sosnowska, J, Kupryjanczyk, J, Pharoah, PDP, Song, H, Winship, I, Chenevix-Trench, G, Giles, GG, Tavtigian, SV, Easton, DF, Milne, RL, Southey, MC, Goldgar, DE, Winqvist, R, Pylkas, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Doerk, T, Claes, KBM, Reis-Filho, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK, Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Burwinkel, B, Yang, R, Guenel, P, Therese, T, Menegaux, F, Sanchez, M, Bojesen, S, Nielsen, SF, Flyger, H, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Anton-Culver, H, Neuhausen, S, Ziogas, A, Clarke, CA, Brenner, H, Arndt, V, Stegmaier, C, Brauch, H, Bruening, T, Ko, Y-D, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Spurdle, AB, Wauters, E, Smeets, D, Beuselinck, B, Floris, G, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Olson, JE, Vachon, C, Pankratz, VS, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GG, Zheng, W, Hunter, DJ, Lindstrom, S, Hankinson, SE, Kraft, P, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Jukkola-Vuorinen, A, Grip, M, Kauppila, S, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Hollestelle, A, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, M, Eccles, DM, Rafiq, S, Tapper, WJ, Gerty, SM, Hooning, MJ, Martens, JWM, Collee, JM, Tilanus-Linthorst, M, Hall, P, Li, J, Brand, JS, Humphreys, K, Cox, A, Reed, MWR, Luccarini, C, Baynes, C, Dunning, AM, Hamann, U, Torres, D, Ulmer, HU, Ruediger, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Simard, J, Dumont, M, Soucy, P, Eeles, R, Muir, K, Wiklund, F, Gronberg, H, Schleutker, J, Nordestgaard, BG, Weischer, M, Travis, RC, Neal, D, Donovan, JL, Hamdy, FC, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Schaid, DJ, Kelley, JL, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Butterbach, K, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Renner, SP, Hartmann, A, Hein, A, Ruebner, M, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambretchs, S, Doherty, JA, Rossing, MA, Nickels, S, Eilber, U, Wang-Gohrke, S, Odunsi, K, Sucheston-Campbell, LE, Friel, G, Lurie, G, Killeen, JL, Wilkens, LR, Goodman, MT, Runnebaum, I, Hillemanns, PA, Pelttari, LM, Butzow, R, Modugno, F, Edwards, RP, Ness, RB, Moysich, KB, du Bois, A, Heitz, F, Harter, P, Kommoss, S, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, E, Peissel, B, Bonanni, B, Bernard, L, Goode, EL, Fridley, BL, Vierkant, RA, Cunningham, JM, Larson, MC, Fogarty, ZC, Kalli, KR, Liang, D, Lu, KH, Hildebrandt, MAT, Wu, X, Levine, DA, Dao, F, Bisogna, M, Berchuck, A, Iversen, ES, Marks, JR, Akushevich, L, Cramer, DW, Schildkraut, J, Terry, KL, Poole, EM, Stampfer, M, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Bjorge, L, Salvesen, HB, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, Y, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Grski, B, Gronwald, J, Menkiszak, J, Hogdall, CK, Lundvall, L, Nedergaard, L, Engelholm, SA, Dicks, E, Tyrer, J, Campbell, I, McNeish, I, Paul, J, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Cai, H, Shu, X-O, Teten, RT, Sutphen, R, McLaughlin, JR, Narod, SA, Phelan, CM, Monteiro, AN, Fenstermacher, D, Lin, H-Y, Permuth, JB, Sellers, TA, Chen, YA, Tsai, Y-Y, Chen, Z, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Menon, U, Wu, AH, Pearce, CL, Van den Berg, D, Pike, MC, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Moes-Sosnowska, J, Kupryjanczyk, J, Pharoah, PDP, Song, H, Winship, I, Chenevix-Trench, G, Giles, GG, Tavtigian, SV, Easton, DF, and Milne, RL

Abstract

BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Published
2016

44. Fine-scale mapping of the 4q24 locus identifies & pr two Independent loci associated with breast cancer risk

Author

Guo, X. (Xingyi), Long, J. (Jirong), Zeng, C. (Chenjie), Michailidou, K. (Kyriaki), Ghoussaini, M. (Maya), Bolla, M.K. (Manjeet), Wang, Q. (Qing), Milne, R.L. (Roger L.), Shu, X.-O. (Xiao-Ou), Cai, Q. (Qiuyin), Beesley, J. (Jonathan), Kar, S. (Siddhartha), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Beckmann, M.W. (Matthias), Beeghly-Fadiel, A. (Alicia), Benítez, J. (Javier), Blot, W.J. (William), Bogdanova, N.V. (Natalia), Bojesen, S.E. (Stig), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brinton, L.A. (Louise), Broekss, A. (Annegien), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Cai, H. (Hui), Canisius, S. (Sander), Chang-Claude, J. (Jenny), Choi, J.-Y. (J.), Couch, F.J. (Fergus), Cox, A. (Angela), Cross, S.S. (Simon), Czene, K. (Kamila), Darabi, H. (Hatef), Devilee, P. (Peter), Droit, A. (Arnaud), Dörk, T. (Thilo), Fasching, P.A. (Peter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fostira, F. (Florentia), Gaborieau, V. (Valerie), García-Closas, M. (Montserrat), Giles, G.G. (Graham G.), Grip, M. (Mervi), Guénel, P. (Pascal), Haiman, C.A. (Christopher A.), Hamann, U. (Ute), Hartman, J.M. (Joost), Hollestelle, A. (Antoinette), Hopper, J.L. (John L.), Hsiung, C.-N. (Chia-Ni), Ito, H. (Hidemi), Jakubowska, A. (Anna), Johnson, N. (Nichola), Kabisch, M. (Maria), Kang, D. (Daehee), Khan, S. (Sofia), Knight, J.A. (Julia), Kosma, V-M. (Veli-Matti), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Li, J. (Jingmei), Lindblom, A. (Annika), Lophatananon, A. (Artitaya), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Marme, F. (Federick), Matsuo, K. (Keitaro), McLean, C.A. (Catriona Ann), Meindl, A. (Alfons), Muir, K. (Kenneth), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Nord, S. (Silje), Olson, J.E. (Janet), Orr, N. (Nick), Peterlongo, P. (Paolo), Putti, T.C. (Thomas Choudary), Rudolph, A. (Anja), Sangrajrang, S. (Suleeporn), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Shen, C-Y. (Chen-Yang), Shi, J. (Jiajun), Shrubsole, M. (Martha), Southey, M.C. (Melissa), Swerdlow, A.J. (Anthony ), Teo, S.H. (Soo Hwang), Thienpont, B. (Bernard), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Tomlinson, I. (Ian), Truong, T. (Thérèse), Tseng, C.-C. (Chiu-chen), Ouweland, A.M.W. (Ans) van den, Wen, W. (Wanqing), Winqvist, R. (Robert), Wu, A. (Anna), Yip, C.H. (Cheng Har), Zamora, M.P. (Pilar), Zheng, Y. (Ying), Hall, P. (Per), Pharoah, P.D.P. (Paul), Simard, J. (Jacques), Chenevix-Trench, G. (Georgia), Dunning, A.M. (Alison), Easton, D.F. (Douglas F.), Zheng, W. (Wei), Eeles, R. (Rosalind), Al Olama, A.A. (Ali Amin), Kote-Jarai, Z., Benlloch, S. (Sara), Antoniou, A.C. (Antonis), McGuffog, L. (Lesley), Offit, K. (Kenneth), Lee, A. (Andrew), Dicks, E. (Ed), Luccarini, C. (Craig), Tessier, D.C. (Daniel C.), Bacot, F. (Francois), Vincent, D. (Daniel), La Boissière, S. (Sylvie), Robidoux, F. (Frederic), Nielsen, S.F. (Sune), Cunningham, J.M. (Julie), Windebank, S.A. (Sharon A.), Hilker, C.A. (Christopher A.), Meyer, J. (Jeffrey), Angelakos, M. (Maggie), Maskiell, J. (Judi), Rutgers, E.J. (Emiel J.), Verhoef, S., Hogervorst, F.B.L. (Frans), Boonyawongviroj, P. (Prat), Siriwanarungsan, P. (Pornthep), Schrauder, A. (André), Rübner, M. (Matthias), Oeser, S. (Sonja), Landrith, S. (Silke), Williams, E. (Eileen), Ryder-Mills, E. (Elaine), Sargus, K. (Kara), McInerney, N. (Niall), Colleran, G. (Gabrielle), Rowan, A. (Andrew), Jones, A. (Angela), Sohn, C. (Christof), Schneeweiß, A. (Andeas), Bugert, P. (Peter), Álvarez, N. (Nuria), Bernstein, L. (Leslie), Lacey, J. (James), Wang, S. (Sophia), Ma, H. (Huiyan), Lu, Y. (Yani), Clague De Hart, J. (Jessica), Deapen, D. (Dennis), Pinder, R. (Rich), Lee, E. (Eunjung), Schumacher, F.R. (Fredrick), Horn-Ross, P. (Pam), Reynolds, P. (Peggy), Nelson, D. (David), Park, H. (Hannah), Ziegler, H. (Hartwig), Wolf, S. (Sonja), Hermann, V. (Volker), Lo, W.-Y. (Wing-Yee), Justenhoven, C. (Christina), Ko, Y.-D. (Yon-Dschun), Baisch, C. (Christian), Fischer, H.-P. (Hans-Peter), Pesch, B. (Beate), Rabstein, S. (Sylvia), Lotz, A. (Anne), Harth, V. (Volker), Heikkinen, T. (Tuomas), Erkkilä, I. (Irja), Aaltonen, K. (Kirsimari), Smitten, K. (Karl) von, Antonenkova, N.N. (Natalia), Hillemanns, P. (Peter), Christiansen, H. (Hans), Myöhänen, E. (Eija), Kemiläinen, H. (Helena), Thorne, H. (Heather), Niedermayr, E. (Eveline), Bowtell, D., De Fazio, A. (Anna), Gertig, D., Green, A., Webb, P. (Penny), Parsons, P., Hayward, N., Webb, P.M. (P.), Whiteman, D., Fung, A. (Annie), Yashiki, J. (June), Peuteman, G. (Gilian), Smeets, D. (Dominiek), Van Brussel, T. (Thomas), Corthouts, K. (Kathleen), Obi, N. (Nadia), Heinz, J. (Judith), Behrens, T.W. (Timothy), Eilber, U. (Ursula), Celik, M. (Muhabbet), Olchers, T. (Til), Peissel, B. (Bernard), Scuvera, G. (Giulietta), Zaffaroni, D. (Daniela), Bonnani, B. (Bernardo), Feroce, I. (Irene), Maniscalco, A. (Angela), Rossi, A. (Alessandra), Bernard, L. (Loris), Tranchant, M. (Martine), Valois, M.-F. (Marie-France), Turgeon, A. (Annie), Heguy, L. (Lea), Yee, P.S. (Phuah Sze), Kang, P. (Peter), Nee, K.I. (Kang In), Mariapun, S. (Shivaani), Sook-Yee, Y. (Yoon), Lee, D.S.C. (Daphne S.C.), Ching, T.Y. (Teh Yew), Taib, N.A.M. (Nur Aishah Mohd), Otsukka, M. (Meeri), Mononen, K. (Kari), Selander, T. (Teresa), Weerasooriya, N. (Nayana), Krol-Warmerdam, E.M.M. (Elly), Molenaar, J., Blom, J., Szeszenia-Dabrowska, N. (Neonilia), Peplonska, B. (Beata), Zatonski, W. (Witold), Chao, P. (Pei), Stagner, M. (Michael), Bos, P. (Petra), Blom, J. (Jannet), Crepin, E. (Ellen), Nieuwlaat, A. (Anja), Heemskerk, A. (Annette), Higham, S. (Sue), Cramp, H.E. (Helen), Connley, D. (Daniel), Balasubramanian, S. (Sabapathy), Brock, I.W. (Ian), Kerin, M. (Michael), Miller, N. (Nicola), Kerbrat, P. (Pierre), Arveux, P. (Patrick), Le Scodan, R. (Romuald), Raoul, Y. (Yves), Laurent-Puig, P. (Pierre), Mulot, C. (Claire), Stegmaier, C. (Christa), Butterbach, K. (Katja), Karstens, J.H. (Johann), Flesch-Janys, D. (Dieter), Seibold, P. (Petra), Vrieling, A. (Alina), Nickels, S. (Stefan), Radice, P. (Paolo), Pykäs, K. (Katri), Jukkola-Vuorinen, A. (Arja), Kauppila, S. (Saila), Conroy, D. (Don), Baynes, C. (Caroline), Chua, K. (Kimberley), Pilarski, R. (Robert), Guo, X. (Xingyi), Long, J. (Jirong), Zeng, C. (Chenjie), Michailidou, K. (Kyriaki), Ghoussaini, M. (Maya), Bolla, M.K. (Manjeet), Wang, Q. (Qing), Milne, R.L. (Roger L.), Shu, X.-O. (Xiao-Ou), Cai, Q. (Qiuyin), Beesley, J. (Jonathan), Kar, S. (Siddhartha), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Beckmann, M.W. (Matthias), Beeghly-Fadiel, A. (Alicia), Benítez, J. (Javier), Blot, W.J. (William), Bogdanova, N.V. (Natalia), Bojesen, S.E. (Stig), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brinton, L.A. (Louise), Broekss, A. (Annegien), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Cai, H. (Hui), Canisius, S. (Sander), Chang-Claude, J. (Jenny), Choi, J.-Y. (J.), Couch, F.J. (Fergus), Cox, A. (Angela), Cross, S.S. (Simon), Czene, K. (Kamila), Darabi, H. (Hatef), Devilee, P. (Peter), Droit, A. (Arnaud), Dörk, T. (Thilo), Fasching, P.A. (Peter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fostira, F. (Florentia), Gaborieau, V. (Valerie), García-Closas, M. (Montserrat), Giles, G.G. (Graham G.), Grip, M. (Mervi), Guénel, P. (Pascal), Haiman, C.A. (Christopher A.), Hamann, U. (Ute), Hartman, J.M. (Joost), Hollestelle, A. (Antoinette), Hopper, J.L. (John L.), Hsiung, C.-N. (Chia-Ni), Ito, H. (Hidemi), Jakubowska, A. (Anna), Johnson, N. (Nichola), Kabisch, M. (Maria), Kang, D. (Daehee), Khan, S. (Sofia), Knight, J.A. (Julia), Kosma, V-M. (Veli-Matti), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Li, J. (Jingmei), Lindblom, A. (Annika), Lophatananon, A. (Artitaya), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Marme, F. (Federick), Matsuo, K. (Keitaro), McLean, C.A. (Catriona Ann), Meindl, A. (Alfons), Muir, K. (Kenneth), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Nord, S. (Silje), Olson, J.E. (Janet), Orr, N. (Nick), Peterlongo, P. (Paolo), Putti, T.C. (Thomas Choudary), Rudolph, A. (Anja), Sangrajrang, S. (Suleeporn), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Shen, C-Y. (Chen-Yang), Shi, J. (Jiajun), Shrubsole, M. (Martha), Southey, M.C. (Melissa), Swerdlow, A.J. (Anthony ), Teo, S.H. (Soo Hwang), Thienpont, B. (Bernard), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Tomlinson, I. (Ian), Truong, T. (Thérèse), Tseng, C.-C. (Chiu-chen), Ouweland, A.M.W. (Ans) van den, Wen, W. (Wanqing), Winqvist, R. (Robert), Wu, A. (Anna), Yip, C.H. (Cheng Har), Zamora, M.P. (Pilar), Zheng, Y. (Ying), Hall, P. (Per), Pharoah, P.D.P. (Paul), Simard, J. (Jacques), Chenevix-Trench, G. (Georgia), Dunning, A.M. (Alison), Easton, D.F. (Douglas F.), Zheng, W. (Wei), Eeles, R. (Rosalind), Al Olama, A.A. (Ali Amin), Kote-Jarai, Z., Benlloch, S. (Sara), Antoniou, A.C. (Antonis), McGuffog, L. (Lesley), Offit, K. (Kenneth), Lee, A. (Andrew), Dicks, E. (Ed), Luccarini, C. (Craig), Tessier, D.C. (Daniel C.), Bacot, F. (Francois), Vincent, D. (Daniel), La Boissière, S. (Sylvie), Robidoux, F. (Frederic), Nielsen, S.F. (Sune), Cunningham, J.M. (Julie), Windebank, S.A. (Sharon A.), Hilker, C.A. (Christopher A.), Meyer, J. (Jeffrey), Angelakos, M. (Maggie), Maskiell, J. (Judi), Rutgers, E.J. (Emiel J.), Verhoef, S., Hogervorst, F.B.L. (Frans), Boonyawongviroj, P. (Prat), Siriwanarungsan, P. (Pornthep), Schrauder, A. (André), Rübner, M. (Matthias), Oeser, S. (Sonja), Landrith, S. (Silke), Williams, E. (Eileen), Ryder-Mills, E. (Elaine), Sargus, K. (Kara), McInerney, N. (Niall), Colleran, G. (Gabrielle), Rowan, A. (Andrew), Jones, A. (Angela), Sohn, C. (Christof), Schneeweiß, A. (Andeas), Bugert, P. (Peter), Álvarez, N. (Nuria), Bernstein, L. (Leslie), Lacey, J. (James), Wang, S. (Sophia), Ma, H. (Huiyan), Lu, Y. (Yani), Clague De Hart, J. (Jessica), Deapen, D. (Dennis), Pinder, R. (Rich), Lee, E. (Eunjung), Schumacher, F.R. (Fredrick), Horn-Ross, P. (Pam), Reynolds, P. (Peggy), Nelson, D. (David), Park, H. (Hannah), Ziegler, H. (Hartwig), Wolf, S. (Sonja), Hermann, V. (Volker), Lo, W.-Y. (Wing-Yee), Justenhoven, C. (Christina), Ko, Y.-D. (Yon-Dschun), Baisch, C. (Christian), Fischer, H.-P. (Hans-Peter), Pesch, B. (Beate), Rabstein, S. (Sylvia), Lotz, A. (Anne), Harth, V. (Volker), Heikkinen, T. (Tuomas), Erkkilä, I. (Irja), Aaltonen, K. (Kirsimari), Smitten, K. (Karl) von, Antonenkova, N.N. (Natalia), Hillemanns, P. (Peter), Christiansen, H. (Hans), Myöhänen, E. (Eija), Kemiläinen, H. (Helena), Thorne, H. (Heather), Niedermayr, E. (Eveline), Bowtell, D., De Fazio, A. (Anna), Gertig, D., Green, A., Webb, P. (Penny), Parsons, P., Hayward, N., Webb, P.M. (P.), Whiteman, D., Fung, A. (Annie), Yashiki, J. (June), Peuteman, G. (Gilian), Smeets, D. (Dominiek), Van Brussel, T. (Thomas), Corthouts, K. (Kathleen), Obi, N. (Nadia), Heinz, J. (Judith), Behrens, T.W. (Timothy), Eilber, U. (Ursula), Celik, M. (Muhabbet), Olchers, T. (Til), Peissel, B. (Bernard), Scuvera, G. (Giulietta), Zaffaroni, D. (Daniela), Bonnani, B. (Bernardo), Feroce, I. (Irene), Maniscalco, A. (Angela), Rossi, A. (Alessandra), Bernard, L. (Loris), Tranchant, M. (Martine), Valois, M.-F. (Marie-France), Turgeon, A. (Annie), Heguy, L. (Lea), Yee, P.S. (Phuah Sze), Kang, P. (Peter), Nee, K.I. (Kang In), Mariapun, S. (Shivaani), Sook-Yee, Y. (Yoon), Lee, D.S.C. (Daphne S.C.), Ching, T.Y. (Teh Yew), Taib, N.A.M. (Nur Aishah Mohd), Otsukka, M. (Meeri), Mononen, K. (Kari), Selander, T. (Teresa), Weerasooriya, N. (Nayana), Krol-Warmerdam, E.M.M. (Elly), Molenaar, J., Blom, J., Szeszenia-Dabrowska, N. (Neonilia), Peplonska, B. (Beata), Zatonski, W. (Witold), Chao, P. (Pei), Stagner, M. (Michael), Bos, P. (Petra), Blom, J. (Jannet), Crepin, E. (Ellen), Nieuwlaat, A. (Anja), Heemskerk, A. (Annette), Higham, S. (Sue), Cramp, H.E. (Helen), Connley, D. (Daniel), Balasubramanian, S. (Sabapathy), Brock, I.W. (Ian), Kerin, M. (Michael), Miller, N. (Nicola), Kerbrat, P. (Pierre), Arveux, P. (Patrick), Le Scodan, R. (Romuald), Raoul, Y. (Yves), Laurent-Puig, P. (Pierre), Mulot, C. (Claire), Stegmaier, C. (Christa), Butterbach, K. (Katja), Karstens, J.H. (Johann), Flesch-Janys, D. (Dieter), Seibold, P. (Petra), Vrieling, A. (Alina), Nickels, S. (Stefan), Radice, P. (Paolo), Pykäs, K. (Katri), Jukkola-Vuorinen, A. (Arja), Kauppila, S. (Saila), Conroy, D. (Don), Baynes, C. (Caroline), Chua, K. (Kimberley), and Pilarski, R. (Robert)

Abstract

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P=2.51 × 10-4; OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P=1.86 × 10-4; OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.

Published
2015
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45. TOWARDS AN INTERNATIONAL POLAR DATA COORDINATION NETWORK.

Author

Pulsifer, P. L., Yarmey, L., Nickels, S., Tweedie, C., Larsen, J. R., Huck, J., Godøy, Ø., Friddell, J., Parsons, M., Vincent, W. F., de Bruin, T., Manley, W., Gaylord, A., and Hayes, A.

Subjects
DATA management, POLAR research, INTERNETWORKING, COMPUTER networks, COMPUTER file sharing
Abstract

Data management is integral to sound polar science. Through analysis of documents reporting on meetings of the Arctic data management community, a set of priorities and strategies are identified. These include the need to improve data sharing, make use of existing resources, and better engage stakeholders. Network theory is applied to a preliminary inventory of polar and global data management actors to improve understanding of the emerging community of practice. Under the name the Arctic Data Coordination Network, we propose a model network that can support the community in achieving their goals through improving connectivity between existing actors. [ABSTRACT FROM AUTHOR]

Published
2014
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46. Neural and behavioral markers of inhibitory control predict symptom improvement during internet-delivered cognitive behavioral therapy for depression.

Author

Thai M, Olson EA, Nickels S, Dillon DG, Webb CA, Ren B, Killgore WDS, Rauch SL, Rosso IM, and Pizzagalli DA

Subjects
Humans, Male, Female, Adult, Middle Aged, Emotional Regulation physiology, Treatment Outcome, Gyrus Cinguli physiopathology, Gyrus Cinguli diagnostic imaging, Young Adult, Internet, Internet-Based Intervention, Insular Cortex diagnostic imaging, Insular Cortex physiopathology, Cognitive Behavioral Therapy methods, Depressive Disorder, Major therapy, Depressive Disorder, Major physiopathology, Magnetic Resonance Imaging, Inhibition, Psychological
Abstract

Poor inhibitory control contributes to deficits in emotion regulation, which are often targeted by treatments for major depressive disorder (MDD), including cognitive behavioral therapy (CBT). Brain regions that contribute to inhibitory control and emotion regulation overlap; thus, inhibitory control might relate to response to CBT. In this study, we examined whether baseline inhibitory control and resting state functional connectivity (rsFC) within overlapping emotion regulation-inhibitory control regions predicted treatment response to internet-based CBT (iCBT). Participants with MDD were randomly assigned to iCBT (N = 30) or a monitored attention control (MAC) condition (N = 30). Elastic net regression was used to predict post-treatment Patient Health Questionnaire-9 (PHQ-9) scores from baseline variables, including demographic variables, PHQ-9 scores, Flanker effects (interference, sequential dependency, post-error slowing), and rsFC between the dorsal anterior cingulate cortex, bilateral anterior insula (AI), and right temporoparietal junction (TPJ). Essential prognostic predictor variables retained in the elastic net regression included treatment group, gender, Flanker interference response time (RT), right AI-TPJ rsFC, and left AI-right AI rsFC. Prescriptive predictor variables retained included interactions between treatment group and baseline PHQ-9 scores, age, gender, Flanker RT, sequential dependency effects on accuracy, post-error accuracy, right AI-TPJ rsFC, and left AI-right AI rsFC. Inhibitory control and rsFC within inhibitory control-emotion regulation regions predicted reduced symptom severity following iCBT, and these effects were stronger in the iCBT group than in the MAC group. These findings contribute to a growing literature indicating that stronger inhibitory control at baseline predicts better outcomes to psychotherapy, including iCBT., (© 2024. The Author(s).)

Published
2024
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47. Identifying a stable and generalizable factor structure of major depressive disorder across three large longitudinal cohorts.

Author

Tseng VWS, Tharp JA, Reiter JE, Ferrer W, Hong DS, Doraiswamy PM, and Nickels S

Subjects
Humans, Surveys and Questionnaires, Patient Health Questionnaire, Anhedonia, Suicidal Ideation, Depression psychology, Depressive Disorder, Major diagnosis, Depressive Disorder, Major psychology
Abstract

The Patient Health Questionnaire 9 (PHQ-9) is the current standard outpatient screening tool for measuring and tracking the nine symptoms of major depressive disorder (MDD). While the PHQ-9 was originally conceptualized as a unidimensional measure, it has become clear that MDD is not a monolithic construct, as evidenced by high comorbidities with other theoretically distinct diagnoses and common symptom overlap between depression and other diagnoses. Therefore, identifying reliable and temporally stable subfactors of depressive symptoms could allow research and care to be tailored to different depression phenotypes. This study improved on previous factor analysis studies of the PHQ-9 by leveraging samples that were clinical (participants with depression only), large (N = 1483 depressed individuals in total), longitudinal (up to 5 years), and from three diverse (matching racial distribution of the United States) datasets. By refraining from assuming the number of factors or item loadings a priori, and thus utilizing a solely data-driven approach, we identified a ranked list of best-fitting models, with the parsimonious one achieving good model fit across studies at most timepoints (average TLI >= 0.90). This model categorizes the PHQ-9 items into four factors: (1) Affective (Anhedonia + Depressed Mood), (2) Somatic (Sleep + Fatigue + Appetite), (3) Internalizing (Worth/Guilt + Suicidality), (4) Sensorimotor (Concentration + Psychomotor), which may be used to further precision psychiatry by testing factor-specific interventions in research and clinical settings., Competing Interests: Declaration of competing interest Financial support for this analysis was provided by Verily. Employees of Verily (VWST, JAT, JER, WF, SN) have participated in the conception, analysis, and dissemination of results from this study. PMD has received grants, advisory or board fees and/or stock from several health/biotechnology companies. PMD is an investigator on the PBHS research group and was previously a paid advisor to Verily. PMD is a co-inventor on several patents unrelated to the current manuscript., (Copyright © 2023. Published by Elsevier B.V.)

Published
2024
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48. Impaired neuron differentiation in GBA-associated Parkinson's disease is linked to cell cycle defects in organoids.

Author

Rosety I, Zagare A, Saraiva C, Nickels S, Antony P, Almeida C, Glaab E, Halder R, Velychko S, Rauen T, Schöler HR, Bolognin S, Sauter T, Jarazo J, Krüger R, and Schwamborn JC

Abstract

The mechanisms underlying Parkinson's disease (PD) etiology are only partially understood despite intensive research conducted in the field. Recent evidence suggests that early neurodevelopmental defects might play a role in cellular susceptibility to neurodegeneration. To study the early developmental contribution of GBA mutations in PD we used patient-derived iPSCs carrying a heterozygous N370S mutation in the GBA gene. Patient-specific midbrain organoids displayed GBA-PD relevant phenotypes such as reduction of GCase activity, autophagy impairment, and mitochondrial dysfunction. Genome-scale metabolic (GEM) modeling predicted changes in lipid metabolism which were validated with lipidomics analysis, showing significant differences in the lipidome of GBA-PD. In addition, patient-specific midbrain organoids exhibited a decrease in the number and complexity of dopaminergic neurons. This was accompanied by an increase in the neural progenitor population showing signs of oxidative stress-induced damage and premature cellular senescence. These results provide insights into how GBA mutations may lead to neurodevelopmental defects thereby predisposing to PD pathology., (© 2023. The Author(s).)

Published
2023
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49. Association of autoantibody levels with different stages of age-related macular degeneration (AMD): Results from the population-based Gutenberg Health Study (GHS).

Author

Korb CA, Lackner KJ, Wolters D, Schuster AK, Nickels S, Beutgen VM, Münzel T, Wild PS, Beutel ME, Schmidtmann I, Pfeiffer N, and Grus FH

Subjects
Humans, Adult, Middle Aged, Aged, Retina, Fundus Oculi, Autoantibodies, Macular Degeneration diagnosis, Retinal Drusen
Abstract

Purpose: Anti-retinal autoantibodies are assumed to be associated with age-related macular degeneration (AMD). To our knowledge, this is the first evaluation of autoantibodies in human sera of participants with different stages of AMD in a large population-based, observational cohort study in Germany., Methods: The Gutenberg Health Study (GHS) is a population-based, observational cohort study in Germany, including 15,010 participants aged between 35 and 74. Amongst others, non-mydriatic fundus photography (Visucam PRO NM™, Carl Zeiss Meditec AG, Jena, Germany) was performed. Fundus images of the first 5000 participants were graded based on the Rotterdam Eye Study classification. Sera of participants with AMD (n=541) and sera of age-matched participants without AMD (n=490) were analyzed by antigen-microarrays. Besides descriptive statistics, autoantibody-levels were compared by Mann-Whitney-U test and the associations of level of autoantibodies with AMD were calculated by logistic regression analysis. Likewise, possible associations of the autoantibodies and both clinical and laboratory parameters on AMD subjects were analyzed., Results: Autoantibodies against transferrin (p<0.001) were significantly downregulated in participants with early AMD and soft, distinct drusen (≥63 μm) or pigmentary abnormalities only compared to Controls. Mitogen-activated protein kinase 3 (p=0.041), glutathione peroxidase 4 (p=0.048), clusterin (p=0.045), lysozyme (p=0.19), protein kinase C substrate 80K-H (p=0.02), heat shock 70 kDa protein 1A (p=0.04) and insulin (p=0.018) show a trend between Control and participants with early AMD and soft, distinct drusen (≥63 μm) or pigmentary abnormalities only., Conclusions: This study contributes to a growing knowledge of autoantibodies in association with different AMD stages compared to controls in the context of a large population-based study in Germany. Especially autoantibodies against inflammatory proteins were downregulated in participants with early AMD and soft, distinct drusen (≥63 μm) or pigmentary abnormalities only., (© 2023. The Author(s).)

Published
2023
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50. A generalizable deep learning regression model for automated glaucoma screening from fundus images.

Author

Hemelings R, Elen B, Schuster AK, Blaschko MB, Barbosa-Breda J, Hujanen P, Junglas A, Nickels S, White A, Pfeiffer N, Mitchell P, De Boever P, Tuulonen A, and Stalmans I

Abstract

A plethora of classification models for the detection of glaucoma from fundus images have been proposed in recent years. Often trained with data from a single glaucoma clinic, they report impressive performance on internal test sets, but tend to struggle in generalizing to external sets. This performance drop can be attributed to data shifts in glaucoma prevalence, fundus camera, and the definition of glaucoma ground truth. In this study, we confirm that a previously described regression network for glaucoma referral (G-RISK) obtains excellent results in a variety of challenging settings. Thirteen different data sources of labeled fundus images were utilized. The data sources include two large population cohorts (Australian Blue Mountains Eye Study, BMES and German Gutenberg Health Study, GHS) and 11 publicly available datasets (AIROGS, ORIGA, REFUGE1, LAG, ODIR, REFUGE2, GAMMA, RIM-ONEr3, RIM-ONE DL, ACRIMA, PAPILA). To minimize data shifts in input data, a standardized image processing strategy was developed to obtain 30° disc-centered images from the original data. A total of 149,455 images were included for model testing. Area under the receiver operating characteristic curve (AUC) for BMES and GHS population cohorts were at 0.976 [95% CI: 0.967-0.986] and 0.984 [95% CI: 0.980-0.991] on participant level, respectively. At a fixed specificity of 95%, sensitivities were at 87.3% and 90.3%, respectively, surpassing the minimum criteria of 85% sensitivity recommended by Prevent Blindness America. AUC values on the eleven publicly available data sets ranged from 0.854 to 0.988. These results confirm the excellent generalizability of a glaucoma risk regression model trained with homogeneous data from a single tertiary referral center. Further validation using prospective cohort studies is warranted., (© 2023. The Author(s).)

Published
2023
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