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

Author

Fan, Qiao, Pozarickij, Alfred, Tan, Nicholas Y. Q., Guo, Xiaobo, Verhoeven, Virginie J. M., Vitart, Veronique, Guggenheim, Jeremy A., Miyake, Masahiro, Tideman, J. Willem L., Khawaja, Anthony P., Zhang, Liang, MacGregor, Stuart, Höhn, René, Chen, Peng, Biino, Ginevra, Wedenoja, Juho, Saffari, Seyed Ehsan, Tedja, Milly S., Xie, Jing, Lanca, Carla, Wang, Ya Xing, Sahebjada, Srujana, Mazur, Johanna, Mirshahi, Alireza, Martin, Nicholas G., Yazar, Seyhan, Pennell, Craig E., Yap, Maurice, Haarman, Annechien E. G., Enthoven, Clair A., Polling, JanRoelof, Hewitt, Alex W., Jaddoe, Vincent W. V., Van Duijn, Cornelia M., Hayward, Caroline, Polasek, Ozren, Tai, E-Shyong, Yoshikatsu, Hosoda, Hysi, Pirro G., Young, Terri L., Tsujikawa, Akitaka, Wang, Jie Jing, Mitchell, Paul, Pfeiffer, Norbert, Pärssinen, Olavi, Foster, Paul J., Fossarello, Maurizio, Yip, Shea Ping, Williams, Cathy, Hammond, Christopher J., Jonas, Jost B., He, Mingguang, Mackey, David A., Wong, Tien-Yin, Klaver, Caroline C. W., Saw, Seang-Mei, Baird, Paul N., Cheng, Ching-Yu, Bailey-Wilson, Joan E., Veluchamy, Amutha Barathi, Burdon, Kathryn P., Campbell, Harry, Chen, Li Jia, Chew, Emily Y., Craig, Jamie E., Cumberland, Phillippa M., Deangelis, Margaret M., Delcourt, Cécile, Ding, Xiaohu, Evans, David M., Gharahkhani, Puya, Iglesias, Adriana I., Haller, Toomas, Han, Xikun, Hoang, Quan, Igo, Robert P., Iyengar, Sudha K., Kähönen, Mika, Kaprio, Jaakko, Klein, Barbara E., Klein, Ronald, Lass, Jonathan H., Lee, Kris, Lehtimäki, Terho, Lewis, Deyana D., Li, Qing, Li, Shi-Ming, Lyytikäinen, Leo-Pekka, Meguro, Akira, Metspalu, Andres, Middlebrooks, Candace D., Mizuki, Nobuhisa, Musolf, Anthony M., Nickels, Stefan, Oexle, Konrad, Pang, Chi Pui, Paterson, Andrew D., Rahi, Jugnoo S., Raitakari, Olli, Rudan, Igor, Stambolian, Dwight, Simpson, Claire L., Wang, Ningli, Bin Wei, Wen, Williams, Katie M., Wilson, James F., Wojciechowski, Robert, Yamashiro, Kenji, Yam, Jason C. S., Zhou, Xiangtian, Aslam, Tariq, Barman, Sarah A., Barrett, Jenny H., Bishop, Paul, Blows, Peter, Bunce, Catey, Carare, Roxana O., Chakravarthy, Usha, Chan, Michelle, Chua, Sharon Y. L., Crabb, David P., Cumberland, Philippa M., Day, Alexander, Desai, Parul, Dhillon, Bal, Dick, Andrew D., Egan, Cathy, Ennis, Sarah, Fruttiger, Marcus, Gallacher, John E. J., Garway-Heath, David F., Gibson, Jane, Gore, Dan, Hardcastle, Alison, Harding, Simon P., Hogg, Ruth E., Keane, Pearse A., Khaw, Sir Peng T., Lascaratos, Gerassimos, Lotery, Andrew J., Macgillivray, Tom, Mackie, Sarah, Martin, Keith, McGaughey, Michelle, McGuinness, Bernadette, McKay, Gareth J., McKibbin, Martin, Mitry, Danny, Moore, Tony, Morgan, James E., Muthy, Zaynah A., O’Sullivan, Eoin, Owen, Chris G., Patel, Praveen, Paterson, Euan, Peto, Tunde, Petzold, Axel, Rudnikca, Alicja R., Self, Jay, Sivaprasad, Sobha, Steel, David, Stratton, Irene, Strouthidis, Nicholas, Sudlow, Cathie, Thomas, Dhanes, Trucco, Emanuele, Tufail, Adnan, Vernon, Stephen A., Viswanathan, Ananth C., Williams, Katie, Woodside, Jayne V., Yates, Max M., Yip, Jennifer, Zheng, Yalin, Verhoeven, Virginie J. M. [0000-0001-7359-7862], Vitart, Veronique [0000-0002-4991-3797], Guggenheim, Jeremy A. [0000-0001-5164-340X], Khawaja, Anthony P. [0000-0001-6802-8585], Zhang, Liang [0000-0001-9264-170X], MacGregor, Stuart [0000-0001-6731-8142], Wedenoja, Juho [0000-0002-6155-0378], Saffari, Seyed Ehsan [0000-0002-6473-4375], Tedja, Milly S. [0000-0003-0356-9684], Lanca, Carla [0000-0001-9918-787X], Wang, Ya Xing [0000-0003-2749-7793], Martin, Nicholas G. [0000-0003-4069-8020], Yap, Maurice [0000-0003-4687-4101], Hewitt, Alex W. [0000-0002-5123-5999], Jaddoe, Vincent W. V. [0000-0003-2939-0041], Hayward, Caroline [0000-0002-9405-9550], Hysi, Pirro G. [0000-0001-5752-2510], Young, Terri L. [0000-0001-6994-9941], Wang, Jie Jing [0000-0001-9491-4898], Pfeiffer, Norbert [0000-0002-5766-2617], Foster, Paul J. [0000-0002-4755-177X], Hammond, Christopher J. [0000-0002-3227-2620], Jonas, Jost B. [0000-0003-2972-5227], Klaver, Caroline C. W. [0000-0002-2355-5258], Baird, Paul N. [0000-0002-1305-3502], and Apollo - University of Cambridge Repository

Subjects
genetic structures, 45, 692/699/3161/3163, 631/208/727/2000, 631/208/205/2138, 45/43, article, sense organs, eye diseases
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
2021
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2. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium

Author

Fan, Qiao, Guo, Xiaobo, Tideman, J Willem L, Williams, Katie M, Yazar, Seyhan, Hosseini, S Mohsen, Howe, Laura D, Pourcain, Beaté St, Evans, David M, Timpson, Nicholas J, McMahon, George, Hysi, Pirro G, Krapohl, Eva, Wang, Ya Xing, Jonas, Jost B, Baird, Paul Nigel, Wang, Jie Jin, Cheng, Ching-Yu, Teo, Yik-Ying, Wong, Tien-Yin, Ding, Xiaohu, Wojciechowski, Robert, Young, Terri L, Pärssinen, Olavi, Oexle, Konrad, Pfeiffer, Norbert, Bailey-Wilson, Joan E, Paterson, Andrew D, Klaver, Caroline CW, Plomin, Robert, Hammond, Christopher J, Mackey, David A, He, Mingguang, Saw, Seang-Mei, Williams, Cathy, Guggenheim, Jeremy A, CREAM Consortium, Hosseini, S Mohsen [0000-0003-3626-9928], and Apollo - University of Cambridge Repository

Subjects
Male, Adolescent, Refractive Errors, Polymorphism, Single Nucleotide, Article, White People, Asian People, Myopia, Humans, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Longitudinal Studies, Age of Onset, Child, Genome-Wide Association Study
Abstract

Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).

Published
2016

3. Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians

Author

Chen, Peng, Takeuchi, Fumihiko, Lee, Jong-Young, Li, Huaixing, Wu, Jer-Yuarn, Liang, Jun, Long, Jirong, Tabara, Yasuharu, Goodarzi, Mark O, Pereira, Mark A, Kim, Young Jin, Go, Min Jin, Stram, Daniel O, Vithana, Eranga, Khor, Chiea-Chuen, Liu, Jianjun, Liao, Jiemin, Ye, Xingwang, Wang, Yiqin, Lu, Ling, Young, Terri L, Lee, Jeannette, Thai, Ah Chuan, Cheng, Ching-Yu, van Dam, Rob M, Friedlander, Yechiel, Heng, Chew-Kiat, Koh, Woon-Puay, Chen, Chien-Hsiun, Chang, Li-Ching, Pan, Wen-Harn, Qi, Qibin, Isono, Masato, Zheng, Wei, Cai, Qiuyin, Gao, Yutang, Yamamoto, Ken, Ohnaka, Keizo, Takayanagi, Ryoichi, Kita, Yoshikuni, Ueshima, Hirotsugu, Hsiung, Chao A, Cui, Jinrui, Sheu, Wayne H-H, Rotter, Jerome I, Chen, Yii-Der I, Hsu, Chris, Okada, Yukinori, Kubo, Michiaki, Takahashi, Atsushi, Tanaka, Toshihiro, van Rooij, Frank JA, Ganesh, Santhi K, Huang, Jinyan, Huang, Tao, Yuan, Jianmin, Hwang, Joo-Yeon, CHARGE Hematology Working Group, Gross, Myron D, Assimes, Themistocles L, Miki, Tetsuro, Shu, Xiao-Ou, Qi, Lu, Chen, Yuan-Tson, Lin, Xu, Aung, Tin, Wong, Tien-Yin, Teo, Yik-Ying, Kim, Bong-Jo, Kato, Norihiro, and Tai, E-Shyong

Subjects
Asian Continental Ancestry Group, Blood Glucose, Adult, Male, Glycated Hemoglobin A, Asia, Far East, Glycosylated, Eastern, Medical and Health Sciences, Cohort Studies, Genetic Heterogeneity, Endocrinology & Metabolism, Asian People, Genetics, Humans, 2.1 Biological and endogenous factors, Polymorphism, Aetiology, Metabolic and endocrine, Aged, Glycated Hemoglobin, CHARGE Hematology Working Group, Prevention, Diabetes, Human Genome, Hemoglobin A, Single Nucleotide, Middle Aged, Genetic Loci, Female, Genome-Wide Association Study
Abstract

Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10(-23)], HBS1L/MYB [8.5 × 10(-15)], MYO9B [9.0 × 10(-12)], and CYBA [1.1 × 10(-8)] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (

Published
2014

4. Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error

Author

Cheng, Ching-Yu, Schache, Maria, Ikram, M Kamran, Young, Terri L, Guggenheim, Jeremy A, Vitart, Veronique, MacGregor, Stuart, Verhoeven, Virginie JM, Barathi, Veluchamy A, Liao, Jiemin, Hysi, Pirro G, Bailey-Wilson, Joan E, St Pourcain, Beate, Kemp, John P, McMahon, George, Timpson, Nicholas J, Evans, David M, Montgomery, Grant W, Mishra, Aniket, Wang, Ya Xing, Wang, Jie Jin, Rochtchina, Elena, Polasek, Ozren, Wright, Alan F, Amin, Najaf, van Leeuwen, Elisabeth M, Wilson, James F, Pennell, Craig E, van Duijn, Cornelia M, de Jong, Paulus TVM, Vingerling, Johannes R, Zhou, Xin, Chen, Peng, Li, Ruoying, Tay, Wan-Ting, Zheng, Yingfeng, Chew, Merwyn, Consortium for Refractive Error and Myopia, Burdon, Kathryn P, Craig, Jamie E, Iyengar, Sudha K, Igo, Robert P, Lass, Jonathan H, Fuchs' Genetics Multi-Center Study Group, Chew, Emily Y, Haller, Toomas, Mihailov, Evelin, Metspalu, Andres, Wedenoja, Juho, Simpson, Claire L, Wojciechowski, Robert, Höhn, René, Mirshahi, Alireza, Zeller, Tanja, Pfeiffer, Norbert, Lackner, Karl J, Wellcome Trust Case Control Consortium 2, Bettecken, Thomas, Meitinger, Thomas, Oexle, Konrad, Pirastu, Mario, Portas, Laura, Nag, Abhishek, Williams, Katie M, Yonova-Doing, Ekaterina, Klein, Ronald, Klein, Barbara E, Hosseini, S Mohsen, Paterson, Andrew D, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions, and Complications Research Group, Makela, Kari-Matti, Lehtimaki, Terho, Kahonen, Mika, Raitakari, Olli, Yoshimura, Nagahisa, Matsuda, Fumihiko, Chen, Li Jia, Pang, Chi Pui, Yip, Shea Ping, Yap, Maurice KH, Meguro, Akira, Mizuki, Nobuhisa, Inoko, Hidetoshi, Foster, Paul J, Zhao, Jing Hua, Vithana, Eranga, Tai, E-Shyong, Fan, Qiao, Xu, Liang, Campbell, Harry, Fleck, Brian, Rudan, Igor, Aung, Tin, Hofman, Albert, Uitterlinden, André G, Bencic, Goran, Khor, Chiea-Chuen, Forward, Hannah, Pärssinen, Olavi, and Mitchell, Paul

Subjects
Adult, Male, Adolescent, Gene Expression, Eye, Medical and Health Sciences, White People, Asian People, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Axial Length, Polymorphism, Aetiology, Eye Proteins, Eye Disease and Disorders of Vision, Aged, Genetics & Heredity, Consortium for Refractive Error and Myopia, Wellcome Trust Case Control Consortium 2, Human Genome, Single Nucleotide, Middle Aged, Biological Sciences, and Complications Research Group, Refractive Errors, Fuchs' Genetics Multi-Center Study Group, Genetic Loci, Female, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions, Signal Transduction, Genome-Wide Association Study
Abstract

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Published
2013

5. Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations

Author

Okada, Yukinori, Sim, Xueling, Go, Min Jin, Wu, Jer-Yuarn, Gu, Dongfeng, Takeuchi, Fumihiko, Takahashi, Atsushi, Maeda, Shiro, Tsunoda, Tatsuhiko, Chen, Peng, Lim, Su-Chi, Wong, Tien-Yin, Liu, Jianjun, Young, Terri L, Aung, Tin, Seielstad, Mark, Teo, Yik-Ying, Kim, Young Jin, Lee, Jong-Young, Han, Bok-Ghee, Kang, Daehee, Chen, Chien-Hsiun, Tsai, Fuu-Jen, Chang, Li-Ching, Fann, S-J Cathy, Mei, Hao, Rao, Dabeeru C, Hixson, James E, Chen, Shufeng, Katsuya, Tomohiro, Isono, Masato, Ogihara, Toshio, Chambers, John C, Zhang, Weihua, Kooner, Jaspal S, KidneyGen Consortium, CKDGen Consortium, Albrecht, Eva, GUGC consortium, Yamamoto, Kazuhiko, Kubo, Michiaki, Nakamura, Yusuke, Kamatani, Naoyuki, Kato, Norihiro, He, Jiang, Chen, Yuan-Tsong, Cho, Yoon Shin, Tai, E-Shyong, and Tanaka, Toshihiro

Subjects
Kidney Disease, CKDGen Consortium, Human Genome, Renal and urogenital, KidneyGen Consortium, Single Nucleotide, Biological Sciences, Kidney, Medical and Health Sciences, GUGC consortium, Uric Acid, Blood Urea Nitrogen, Cohort Studies, Asian People, Creatinine, Genetics, Humans, Genetic Predisposition to Disease, Renal Insufficiency, Polymorphism, Chronic, Glomerular Filtration Rate, Genome-Wide Association Study, Developmental Biology
Abstract

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

Published
2012

6. Emerging trends in breastfeeding practices in Singaporean Chinese women: findings from a population-based study

Author

Hornbeak, Dana M., Dirani, Mohamed, Sham, Wai Kit, Li, Jialiang, Young, Terri L., Tien Y Wong, Chong, Yap Seng, and Saw, Seang Mei

Subjects
Male, China, Singapore, Breast Feeding, Child, Preschool, Surveys and Questionnaires, Educational Status, Humans, Infant, Mothers, Female, General Medicine, Child
Abstract

Introduction: This study records the prevalence and patterns of breastfeeding in Singaporean Chinese mothers who gave birth between 2000 and 2008. Materials and Methods: The Strabismus, Amblyopia and Refractive Error in Singaporean Children (STARS) study is a population-based survey conducted in South-Western Singapore. Disproportionate random sampling by 6-month age groups of Chinese children born from 2000 to 2008 was performed. The mothers (n = 3009) completed a standard questionnaire which recorded the initiation, content, method and duration of breastfeeding. World Health Organization (WHO) definitions for feeding content were used: Replacement (exclusive commercial formula or any liquid or solid/semi-solid food, excluding breast milk), Complementary (breast milk, solid/semi-solid foods, and any non-human liquid), and Exclusive (breast milk only, without additional food, drink or water). STARS-specific definitions for feeding method were used: Expressed (breast milk only fed via bottle, with no additional food or non-human liquid), Combination (breast milk and non-breast milk, fed via bottle and breast), and Direct (breast milk only fed via breast). Results: Breastfeeding initiation (overall prevalence 77.0%) and duration increased over time, and were independently associated with higher maternal education: in 2000 and 2001, 68.6% of mothers initiated breastfeeding and 12.9% breast fed for ≤6 months, versus 82.0% and 26.7%, respectively, from 2006 to 2008; 47.4% of primary-school-educated women initiated breastfeeding, and 11.1% fed for ≥6 months, vs 90.9% and 35.3%, respectively, of university-educated women (P

Published
2010

7. Genetic Loci for Retinal Arteriolar Microcirculation

Author

Xueling, Sim, Jensen, Richard A., Kamran Ikram, M., Mary Frances Cotch, Xiaohui, Li, Stuart, Macgregor, Jing, Xie, Albert Vernon Smith, Eric, Boerwinkle, Paul, Mitchell, Ronald, Klein, Klein, Barbara E. K., Glazer, Nicole L., Thomas, Lumley, Barbara, Mcknight, Psaty, Bruce M., de Jong, Paulus T. V. M., Albert, Hofman, Fernando, Rivadeneira, Uitterlinden, Andre G., van Duijn, Cornelia M., Thor, Aspelund, Gudny, Eiriksdottir, Harris, Tamara B., Fridbert, Jonasson, Launer, Lenore J., John, Attia, Baird, Paul N., Stephen, Harrap, Holliday, Elizabeth G., Michael, Inouye, Elena, Rochtchina, Scott, Rodney J., Ananth, Viswanathan, Guo, Li, Smith, Nicholas L., Wiggins, Kerri L., Kuo, Jane Z., Taylor, Kent D., Hewitt, Alex W., Martin, Nicholas G., Montgomery, Grant W., Cong, Sun, Young, Terri L., Mackey, David A., van Zuydam, Natalie R., Doney, Alex S. F., Palmer, Colin N. A., Morris, Andrew D., Rotter, Jerome I., Shyong Tai, E., Vilmundur, Gudnason, Vingerling, Johannes R., Siscovick, David S., Jie Jin Wang, Wong, Tien Y., Donnelly, P, Barroso, I, Blackwell, Jm, Bramon, E, Brown, Ma, Casas, Jp, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, Hs, Mathew, Cg, Palmer, Cn, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cc, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, Se, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Mathew, C, Mccarthy, Mi, Newton Cheh, C, Johnson, T, Gateva, V, Tobin, Md, Bochud, M, Coin, L, Najjar, Ss, Zhao, Jh, Heath, Sc, Eyheramendy, S, Papadakis, K, Voight, Bf, Scott, Lj, Zhang, F, Farrall, M, Tanaka, T, Wallace, C, Chambers, Jc, Khaw, Kt, Nilsson, P, van der Harst, P, Polidoro, Silvia, Grobbee, De, Onland Moret NC, Bots, Ml, Wain, Lv, Elliott, Ks, Teumer, A, Luan, J, Lucas, G, Kuusisto, J, Burton, Pr, Hadley, D, Mcardle, Wl, Brown, M, Dominiczak, A, Newhouse, Sj, Samani, Nj, Webster, J, Zeggini, E, Beckmann, Js, Bergmann, S, Lim, N, Song, K, Vollenweider, P, Waeber, G, Waterworth, Dm, Yuan, X, Groop, L, Orho Melander, M, Allione, A, Di Gregorio, A, Guarrera, Simonetta, Panico, S, Ricceri, Fulvio, Romanazzi, V, Sacerdote, Carlotta, Vineis, Paolo, Sandhu, Ms, Luben, Rn, Crawford, Gj, Jousilahti, P, Perola, M, Boehnke, M, Bonnycastle, Ll, Collins, Fs, Jackson, Au, Mohlke, Kl, Stringham, Hm, Valle, Tt, Willer, Cj, Bergman, Rn, Morken, Ma, Döring, A, Gieger, C, Illig, T, Meitinger, T, Org, E, Pfeufer, A, Wichmann, He, Kathiresan, S, Marrugat, J, O'Donnell, Cj, Schwartz, Sm, Siscovick, Ds, Subirana, I, Freimer, Nb, Hartikainen, Al, O'Reilly, Pf, Peltonen, L, Pouta, A, de Jong PE, Snieder, H, van Gilst WH, Clarke, R, Goel, A, Hamsten, A, Peden, Jf, Seedorf, U, Syvänen, Ac, Tognoni, G, Lakatta, Eg, Sanna, S, Scheet, P, Schlessinger, D, Scuteri, A, Dörr, M, Ernst, F, Felix, Sb, Homuth, G, Lorbeer, R, Reffelmann, T, Rettig, R, Völker, U, Galan, P, Gut, Ig, Hercberg, S, Lathrop, Gm, Zeleneka, D, Soranzo, N, Williams, Fm, Zhai, G, Salomaa, V, Laakso, M, Elosua, R, Forouhi, Ng, Völzke, H, Uiterwaal, Cs, van der Schouw YT, Numans, Me, Matullo, Giuseppe, Navis, G, Berglund, G, Bingham, Sa, Kooner, Js, Connell, Jm, Bandinelli, S, Ferrucci, L, Watkins, H, Spector, Td, Tuomilehto, J, Altshuler, D, Strachan, Dp, Laan, M, Meneton, P, Wareham, Nj, Uda, M, Jarvelin, Mr, Mooser, V, Melander, O, Loos, Rj, Elliott, P, Abecasis, Gr, Caulfield, M, Munroe, P. B., Inouye, Michael [0000-0001-9413-6520], Apollo - University of Cambridge Repository, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Wellcome Trust Case Control Consortium 2, Global BPGen Consortium, Donnelly, P., Barroso, I., Blackwell, J.M., Bramon, E., Brown, M.A., Casas, J.P., Corvin, A., Deloukas, P., Duncanson, A., Jankowski, J., Markus, H.S., Mathew, C.G., Palmer, C.N., Plomin, R., Rautanen, A., Sawcer, S.J., Trembath, R.C., Viswanathan, A.C., Wood, N.W., Spencer, C.C., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Giannoulatou, E., Pirinen, M., Pearson, R., Strange, A., Su, Z., Vukcevic, D., Langford, C., Hunt, S.E., Edkins, S., Gwilliam, R., Blackburn, H., Bumpstead, S.J., Dronov, S., Gillman, M., Gray, E., Hammond, N., Jayakumar, A., McCann, O.T., Liddle, J., Potter, S.C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Mathew, C., McCarthy, M.I., Newton-Cheh, C., Johnson, T., Gateva, V., Tobin, M.D., Bochud, M., Coin, L., Najjar, S.S., Zhao, J.H., Heath, S.C., Eyheramendy, S., Papadakis, K., Voight, B.F., Scott, L.J., Zhang, F., Farrall, M., Tanaka, T., Wallace, C., Chambers, J.C., Khaw, K.T., Nilsson, P., van der Harst, P., Polidoro, S., Grobbee, D.E., Onland-Moret, N.C., Bots, M.L., Wain, L.V., Elliott, K.S., Teumer, A., Luan, J.J., Lucas, G., Kuusisto, J., Burton, P.R., Hadley, D., McArdle, W.L., Brown, M., Dominiczak, A., Newhouse, S.J., Samani, N.J., Webster, J., Zeggini, E., Beckmann, J.S., Bergmann, S., Lim, N., Song, K., Vollenweider, P., Waeber, G., Waterworth, D.M., Yuan, X., Groop, L., Orho-Melander, M., Allione, A., Di Gregorio, A., Guarrera, S., Panico, S., Ricceri, F., Romanazzi, V., Sacerdote, C., Vineis, P., Sandhu, M.S., Luben, R.N., Crawford, G.J., Jousilahti, P., Perola, M., Boehnke, M., Bonnycastle, L.L., Collins, F.S., Jackson, A.U., Mohlke, K.L., Stringham, H.M., Valle, T.T., Willer, C.J., Bergman, R.N., Morken, M.A., Döring, A., Gieger, C., Illig, T., Meitinger, T., Org, E., Pfeufer, A., Wichmann, H.E., Kathiresan, S., Marrugat, J., O'Donnell, C.J., Schwartz, S.M., Siscovick, D.S., Subirana, I., Freimer, N.B., Hartikainen, A.L., O'Reilly, P.F., Peltonen, L., Pouta, A., de Jong, P.E., Snieder, H., van Gilst, W.H., Clarke, R., Goel, A., Hamsten, A., Peden, J.F., Seedorf, U., Syvänen, A.C., Tognoni, G., Lakatta, E.G., Sanna, S., Scheet, P., Schlessinger, D., Scuteri, A., Dörr, M., Ernst, F., Felix, S.B., Homuth, G., Lorbeer, R., Reffelmann, T., Rettig, R., Völker, U., Galan, P., Gut, I.G., Hercberg, S., Lathrop, G.M., Zeleneka, D., Soranzo, N., Williams, F.M., Zhai, G., Salomaa, V., Laakso, M., Elosua, R., Forouhi, N.G., Völzke, H., Uiterwaal, C.S., van der Schouw, Y.T., Numans, M.E., Matullo, G., Navis, G., Berglund, G., Bingham, S.A., Kooner, J.S., Connell, J.M., Bandinelli, S., Ferrucci, L., Watkins, H., Spector, T.D., Tuomilehto, J., Altshuler, D., Strachan, D.P., Laan, M., Meneton, P., Wareham, N.J., Uda, M., Jarvelin, M.R., Mooser, V., Melander, O., Loos, R.J., Elliott, P., Abecasis, G.R., Caulfield, M., Munroe, P.B., Ophthalmology, Epidemiology, Internal Medicine, Erasmus School of Social and Behavioural Sciences, and Obstetrics & Gynecology

Subjects
Male, Pathology, BLUE MOUNTAINS EYE, VESSEL DIAMETERS, lcsh:Medicine, MICROVASCULAR ABNORMALITIES, Genome-wide association study, Cardiovascular, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, genome-wide association, Microcirculation, Retinal Arteriolar Microcirculation, Myocardial infarction, lcsh:Science, Aged, 80 and over, Medicine(all), 0303 health sciences, Multidisciplinary, Agricultural and Biological Sciences(all), MEF2 Transcription Factors, Genomics, Middle Aged, 3. Good health, Arterioles, medicine.anatomical_structure, Medicine, Chromosomes, Human, Pair 5, Female, INCIDENT SEVERE HYPERTENSION, Research Article, medicine.medical_specialty, Genotype, Clinical Research Design, ANTIHYPERTENSIVE DRUG THERAPIES, Single-nucleotide polymorphism, White People, 03 medical and health sciences, Genome Analysis Tools, Vascular Biology, BEAVER DAM EYE, Genetics, Genome-Wide Association Studies, medicine, Humans, CORONARY-HEART-DISEASE, GENOME-WIDE ASSOCIATION, Biology, Aged, 030304 developmental biology, Retina, Models, Genetic, Biochemistry, Genetics and Molecular Biology(all), Vascular disease, business.industry, lcsh:R, Computational Biology, Retinal Vessels, Human Genetics, Retinal, medicine.disease, Ophthalmology, chemistry, Genetic Loci, VASCULAR CALIBER, 030221 ophthalmology & optometry, lcsh:Q, Meta-Analyses, GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK, business, Genome-Wide Association Study
Abstract

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value -8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10-12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

Published
2013

8. Genetic loci for retinal arteriolar microcirculation

Author

Sim, Xueling, Jensen, Richard A, Ikram, M Kamran, Cotch, Mary Frances, Li, Xiaohui, MacGregor, Stuart, Xie, Jing, Smith, Albert Vernon, Boerwinkle, Eric, Mitchell, Paul, Klein, Ronald, Klein, Barbara EK, Glazer, Nicole L, Lumley, Thomas, McKnight, Barbara, Psaty, Bruce M, De Jong, Paulus TVM, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G, Van Duijn, Cornelia M, Aspelund, Thor, Eiriksdottir, Gudny, Harris, Tamara B, Jonasson, Fridbert, Launer, Lenore J, Wellcome Trust Case Control Consortium 2, Attia, John, Baird, Paul N, Harrap, Stephen, Holliday, Elizabeth G, Inouye, Michael, Rochtchina, Elena, Scott, Rodney J, Viswanathan, Ananth, Global BPGen Consortium, Li, Guo, Smith, Nicholas L, Wiggins, Kerri L, Kuo, Jane Z, Taylor, Kent D, Hewitt, Alex W, Martin, Nicholas G, Montgomery, Grant W, Sun, Cong, Young, Terri L, Mackey, David A, Van Zuydam, Natalie R, Doney, Alex SF, Palmer, Colin NA, Morris, Andrew D, Rotter, Jerome I, Tai, E Shyong, Gudnason, Vilmundur, Vingerling, Johannes R, Siscovick, David S, Wang, Jie Jin, and Wong, Tien Y

Subjects
Aged, 80 and over, Male, Genotype, Models, Genetic, MEF2 Transcription Factors, Microcirculation, Retinal Vessels, Middle Aged, White People, 3. Good health, Arterioles, Genetic Loci, Chromosomes, Human, Pair 5, Humans, Female, Aged, Genome-Wide Association Study
Abstract

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value

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

Author

Gharahkhani, Puya, Jorgenson, Eric, Hysi, Pirro, Khawaja, Anthony P, Pendergrass, Sarah, Han, Xikun, Ong, Jue Sheng, Hewitt, Alex W, Segrè, Ayellet V, Rouhana, John M, Hamel, Andrew R, Igo, Robert P, Choquet, Helene, Qassim, Ayub, Josyula, Navya S, Cooke Bailey, Jessica N, Bonnemaijer, Pieter WM, Iglesias, Adriana, Siggs, Owen M, Young, Terri L, Vitart, Veronique, Thiadens, Alberta AHJ, Karjalainen, Juha, Uebe, Steffen, Melles, Ronald B, Nair, K Saidas, Luben, Robert, Simcoe, Mark, Amersinghe, Nishani, Cree, Angela J, Hohn, Rene, Poplawski, Alicia, Chen, Li Jia, Rong, Shi-Song, Aung, Tin, Vithana, Eranga Nishanthie, NEIGHBORHOOD Consortium, ANZRAG Consortium, Biobank Japan Project, FinnGen Study, UK Biobank Eye And Vision Consortium, GIGA Study Group, 23 And Me Research Team, Tamiya, Gen, Shiga, Yukihiro, Yamamoto, Masayuki, Nakazawa, Toru, Currant, Hannah, Birney, Ewan, Wang, Xin, Auton, Adam, Lupton, Michelle K, Martin, Nicholas G, Ashaye, Adeyinka, Olawoye, Olusola, Williams, Susan E, Akafo, Stephen, Ramsay, Michele, Hashimoto, Kazuki, Kamatani, Yoichiro, Akiyama, Masato, Momozawa, Yukihide, Foster, Paul J, Khaw, Peng T, Morgan, James E, Strouthidis, Nicholas G, Kraft, Peter, Kang, Jae H, Pang, Chi Pui, Pasutto, Francesca, Mitchell, Paul, Lotery, Andrew J, Palotie, Aarno, Van Duijn, Cornelia, Haines, Jonathan L, Hammond, Chris, Pasquale, Louis R, Klaver, Caroline CW, Hauser, Michael, Khor, Chiea Chuen, Mackey, David A, Kubo, Michiaki, Cheng, Ching-Yu, Craig, Jamie E, MacGregor, Stuart, and Wiggs, Janey L

Subjects
genetic structures, Asian People, Genotype, Genetic Loci, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, eye diseases, Glaucoma, Open-Angle, White People, 3. Good health, Genome-Wide Association Study
Abstract

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

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

Author

Fan, Qiao, Pozarickij, Alfred, Tan, Nicholas YQ, Guo, Xiaobo, Verhoeven, Virginie JM, Vitart, Veronique, Guggenheim, Jeremy A, Miyake, Masahiro, Tideman, J Willem L, Khawaja, Anthony P, Zhang, Liang, MacGregor, Stuart, Höhn, René, Chen, Peng, Biino, Ginevra, Wedenoja, Juho, Saffari, Seyed Ehsan, Tedja, Milly S, Xie, Jing, Lanca, Carla, Wang, Ya Xing, Sahebjada, Srujana, Mazur, Johanna, Mirshahi, Alireza, Martin, Nicholas G, Yazar, Seyhan, Pennell, Craig E, Yap, Maurice, Haarman, Annechien EG, Enthoven, Clair A, Polling, JanRoelof, Consortium For Refractive Error And Myopia (CREAM), UK Biobank Eye And Vision Consortium, Hewitt, Alex W, Jaddoe, Vincent WV, Van Duijn, Cornelia M, Hayward, Caroline, Polasek, Ozren, Tai, E-Shyong, Yoshikatsu, Hosoda, Hysi, Pirro G, Young, Terri L, Tsujikawa, Akitaka, Wang, Jie Jing, Mitchell, Paul, Pfeiffer, Norbert, Pärssinen, Olavi, Foster, Paul J, Fossarello, Maurizio, Yip, Shea Ping, Williams, Cathy, Hammond, Christopher J, Jonas, Jost B, He, Mingguang, Mackey, David A, Wong, Tien-Yin, Klaver, Caroline CW, Saw, Seang-Mei, Baird, Paul N, and Cheng, Ching-Yu

Subjects
genetic structures, Corneal Topography, Polymorphism, Single Nucleotide, Risk Assessment, eye diseases, White People, 3. Good health, Cornea, Axial Length, Eye, Refractometry, Phenotype, Asian People, Genetic Loci, Risk Factors, Databases, Genetic, Myopia, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, sense organs, 10. No inequality, Genome-Wide Association Study
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.

11. Interrogation of the platelet-derived growth factor receptor alpha locus and corneal astigmatism in Australians of Northern European ancestry: Results of a genome-wide association study

Author

Yazar, Seyhan, Mishra, Aniket, Ang, Wei, Kearns, Lisa S., Mountain, Jenny A., Pennell, Craig, Montgomery, Grant W., Young, Terri L., Hammond, Christopher J., Stuart MacGregor, Mackey, David A., and Hewitt, Alex W.

Subjects
Male, Receptor, Platelet-Derived Growth Factor alpha, Australia, Astigmatism, Polymorphism, Single Nucleotide, White People, Cohort Studies, Cornea, Young Adult, Phenotype, Meta-Analysis as Topic, Genetic Loci, Humans, Twin Studies as Topic, Female, Genetic Predisposition to Disease, Research Article, Demography, Genealogy and Heraldry, Genome-Wide Association Study, Signal Transduction
Abstract

Purpose Corneal astigmatism is a common eye disorder characterized by irregularities in corneal curvature. Recently, the rs7677751 single nucleotide polymorphism (SNP) at the platelet-derived growth factor receptor alpha (PDGFRA) locus was found to be associated with corneal astigmatism in people of Asian ancestry. In the present study, we sought to replicate this finding and identify other genetic markers of corneal astigmatism in an Australian population of Northern European ancestry. Methods Data from two cohorts were included in this study. The first cohort consisted of 1,013 individuals who were part of the Western Australian Pregnancy Cohort (Raine) Study: 20-year follow-up Eye Study. The second cohort comprised 1,788 individuals of 857 twin families who were recruited through the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study. Corneal astigmatism was calculated as the absolute difference between the keratometry readings in two meridians, and genotype data were extracted from genome-wide arrays. Initially, each cohort was analyzed separately, before being combined for meta- and subsequent genome-wide pathway analysis. Results Following meta-analysis, SNP rs7677751 at the PDGFRA locus had a combined p=0.32. No variant was found to be statistically significantly associated with corneal astigmatism at the genome-wide level (p

12. Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations

Author

Okada, Y, Sim, X, Go, Mj, Wu, Jy, Gu, D, Takeuchi, F, Takahashi, A, Maeda, S, Tsunoda, T, Chen, P, Lim, Sc, Wong, Ty, Liu, J, Young, Tl, Aung, T, Seielstad, M, Teo, Yy, Kim, Yj, Lee, Jy, Han, Bg, Kang, D, Chen, Ch, Tsai, Fj, Chang, Lc, Fann, Sj, Mei, H, Rao, Dc, Hixson, Je, Chen, S, Katsuya, T, Isono, M, Ogihara, T, Chambers, Jc, Zhang, W, Kooner, Js, Kidneygen, Consortium, Ckdgen, Consortium, Albrecht, E, Gugc, Consortium, Yamamoto, K, Kubo, M, Nakamura, Y, Kamatani, N, Kato, N, He, J, Chen, Yt, Cho, Ys, Tai, Es, Tanaka, T., Lord, Gm, van der Harst, P, Lawlor, Da, Sehmi, Js, Gale, Dp, Wass, Mn, Ahmadi, Kr, Bakker, Sj, Beckmann, J, Bilo, Hj, Bochud, M, Brown, Mj, Caulfield, Mj, Connell, Jm, Cook, Ht, Cotlarciuc, I, Smith, Gd, de Silva, R, Deng, G, Devuyst, O, Dikkeschei, Ld, Dimkovic, N, Dockrell, M, Dominiczak, A, Ebrahim, S, Eggermann, T, Farrall, M, Ferrucci, L, Floege, J, Forouhi, Ng, Gansevoort, Rt, Han, X, Hedblad, B, van der Heide JJ, Hepkema, Bg, Hernandez Fuentes, M, Hypponen, E, Johnson, T, de Jong PE, Kleefstra, N, Lagou, V, Lapsley, M, Li, Y, Loos, Rj, Luan, J, Luttropp, K, Maréchal, C, Melander, O, Munroe, Pb, Nordfors, L, Parsa, A, Peltonen, L, Penninx, Bw, Perucha, E, Pouta, A, Prokopenko, I, Roderick, Pj, Ruokonen, A, Samani, Nj, Sanna, S, Schalling, M, Schlessinger, D, Schlieper, G, Seelen, Ma, Shuldiner, Ar, Sjögren, M, Smit, Jh, Snieder, H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Tanaka, T, Ubink Veltmaat LJ, Uda, M, Vollenweider, P, Wallace, C, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Mooser, V, Abecasis, Gr, Lightstone, L, Scott, J, Navis, G, Elliott, P, Köttgen, A, Pattaro, C, Böger, Ca, Fuchsberger, C, Olden, M, Glazer, Nl, Gao, X, Yang, Q, Smith, Av, O'Connell, Jr, Li, M, Schmidt, H, Isaacs, A, Ketkar, S, Hwang, Sj, Johnson, Ad, Dehghan, A, Teumer, A, Paré, G, Atkinson, Ej, Zeller, T, Lohman, K, Cornelis, Mc, Probst Hensch NM, Kronenberg, F, Tönjes, A, Hayward, C, Aspelund, T, Eiriksdottir, G, Launer, Lj, Harris, Tb, Rampersaud, E, Mitchell, Bd, Arking, De, Boerwinkle, E, Struchalin, M, Cavalieri, M, Singleton, A, Giallauria, F, Metter, J, de Boer IH, Haritunians, T, Lumley, T, Siscovick, D, Psaty, Bm, Zillikens, Mc, Oostra, Ba, Feitosa, M, Province, M, de Andrade, M, Turner, St, Schillert, A, Ziegler, A, Wild, Ps, Schnabel, Rb, Wilde, S, Munzel, Tf, Leak, Ts, Illig, T, Klopp, N, Meisinger, C, Wichmann, He, Koenig, W, Zgaga, L, Zemunik, T, Kolcic, I, Minelli, C, Hu, Fb, Johansson, Å, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Schreiber, S, Aulchenko, Ys, Felix, Jf, Rivadeneira, F, Uitterlinden, Ag, Hofman, A, Imboden, M, Nitsch, D, Brandstätter, A, Kollerits, B, Kedenko, L, Mägi, R, Stumvoll, M, Kovacs, P, Boban, M, Campbell, S, Endlich, K, Völzke, H, Kroemer, Hk, Nauck, M, Völker, U, Polasek, O, Vitart, V, Badola, S, Parker, An, Ridker, Pm, Kardia, Sl, Blankenberg, S, Liu, Y, Curhan, Gc, Franke, A, Rochat, T, 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Subjects
Asian Continental Ancestry Group, kidney, Population, Renal function, Genome-wide association study, Biology, Kidney, Polymorphism, Single Nucleotide, Article, Blood Urea Nitrogen, Cohort Studies, chemistry.chemical_compound, SDG 3 - Good Health and Well-being, Asian People, loci, Asian, medicine, Humans, genetics, Genetic Predisposition to Disease, Renal Insufficiency, Chronic, education, meta-analysis, Genome-Wide Association Study, Genetic association, Genetics, Creatinine, education.field_of_study, ta3121, medicine.disease, Uric Acid, Asian Continental Ancestry Group/genetics, Creatinine/blood, Glomerular Filtration Rate/genetics, Kidney/physiology, Renal Insufficiency, Chronic/genetics, Uric Acid/blood, medicine.anatomical_structure, chemistry, Genetic epidemiology, Cohort Studie, Human, Kidney disease, Glomerular Filtration Rate
Abstract

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genomewide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 x 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of similar to 110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

Published
2012

13. Convergence of Genetic Disease Association and Ocular Expression

Author

Hawthorne, Felicia Alessandra and Young, Terri L

Subjects
Association, Genetics, Myopia, Ocular Disease, Expression
Abstract

The visual system in humans provides the ability to interpret our surroundings from many distances. This complex system serves as a powerful sense which can drastically impact the quality of life when threatened or eliminated. While the mechanisms involved in visual interpretation are largely understood, many of the mechanisms of ocular diseases remain elusive. The most common ocular disorders are refractive errors, where failure of normal growth processes results in eye components with shape and sizes that are not matched to provide uncorrected sharp visual acuity without correction. Myopia, or nearsightedness, is a refractive error with prevalence rates of epidemic proportions in some urban Asian settings, and rising in other developed countries. Pathological, or high myopia, has an increased risk for potentially blinding ocular morbidities which can be irreversible and further negatively impact quality of life. Myopia, like other common ocular disorders, results from a combination of environmental and genetic factors. Over 20 candidate genomic regions have been identified as involved in myopic development progression. One such locus, MYP3, on chromosome 12q21-23 spans nearly 44 Mb with more than 200 protein-encoding genes mapped within. Sizable candidate disease genomic regions typically require refinement to identify genes or variants within them which may contribute to disease development. Without an understanding of the underlying mechanistic framework of a disease, as is the case with myopia, biological inferences are difficult to make in prioritizing candidates, which can make finding true disease causing variants seem like finding a needle in a haystack. A better understanding of human ocular growth, as it relates to refractive error, may lead to more knowledgeable approaches to identifying the cause(s) of myopic development and associated ocular diseases. To identify genes involved in ocular growth and development, whole genome expression patterns were assessed in human ocular tissues of fetal versus adult eyes, and adult posterior versus peripheral tissues. No database exists of fetal ocular tissue gene expression. In addition to providing insights into expression patterns during ocular development, these tissues were also compared as a surrogate to study rapid eye growth states such as in myopia. Only ocular tissue types with clinical phenotypes associated with myopic development were considered. Human retina/retinal pigment epithelium (RPE), choroid, sclera, cornea* and optic nerve* tissues were isolated from fetal (N=9; *N= 6) and adult (N=6) normal donor eyes. The Illumina® whole genome expression microarray platform was used to assess differential expression of genes. Fetal tissues were compared to their adult counterparts while adult posterior tissues were compared to their peripheral counterparts, and the differences in each were assessed using Ingenuity Pathway Analysis (IPA) for enriched functional groups and canonical pathways. Statistical significance for all tissue comparisons was determined using the Benjamin and Hochberg False Discovery Rate (FDR, 5%). Differentially expressed genes were compared to previously identified candidates for myopic development.Additionally, qualitative and quantitative association studies in a large family (N=82) based high myopia cohort by genotyping 768 single nucleotide polymorphisms (SNPs) in the peak linkage area was performed to fine map the MYP3 linkage peak. Qualitative testing for high myopia (≤ -5 diopter (D) affected, > -5 D unaffected) and quantitative testing on the average (avg) dioptric sphere (SPH) was performed. Five candidate SNPs were genotyped in a replicate high myopia cohort for independent validation. Additionally, the most significant SNPs were screened in a previously genotyped twin cohort as a second independent validation cohort.Ocular growth expression data were used to help prioritize the resulting association candidates as supporting evidence and was not used on its own to identify or exclude candidates. Candidate genes (within 100 kilobases (kb) of highly associated SNPs) identified through either qualitative or quantitative association testing were screened in the most disease relevant tissues (retina/ retinal pigment epithelium (RPE), choroid and sclera) for differential expression during ocular growth and by physical regions of the tissues within the eye. Genes that were identified by microarray studies as being differentially expressed in one or more tissue were validated using quantitative real time PCR (RT-qPCR). Significant gene expression changes with fold changes > 1.5 were found in adult versus fetal retina/RPE (N=1185), choroid (N=6446), sclera (N=1349), and cornea (N=3872), but not the optic nerve nor any of the central versus peripheral tissues. In all adult versus fetal tissues, differentially expressed genes belonging to cancer, development, and cell death/growth functional groups, as well as signaling canonical pathways were enriched. Seventeen genes previously associated with increased susceptibility for non-syndromic high myopia were in the most significant functional assignments for at least one adult versus fetal ocular tissue. In adult central versus peripheral tissues, there was considerably more variation by tissue in enriched functions and canonical pathways of differentially expressed genes. The only functional category shared by all three tissue types was development. MYP3 association testing yielded several genetic markers as nominally significant in association with high myopia in qualitative testing including rs3803036 (p=9.1X10-4), a missense mutation in PTPRR; and rs4764971 (p = 6.1X10-4), an intronic SNP in UHRF1BP1L. After correction for multiple testing, quantitative tests found statistically significant SNPs rs4764971 (p = 3.1x10-6), also found by qualitative testing; rs7134216 (p = 5.4X10-7), in the 31 UTR of DEPDC4; and rs17306116 (p < 9X10-4), intronic within PPFIA2. The intronic SNP in UHRF1BP1L, rs4764971, was validated for association with the quantitative trait of sphere (SPH) using an independently collected non-syndromic, high myopia cohort. SNPs within PTPRR (for quantitative association) and PPFIA2 (for qualitative and quantitative association) both approached significance in the independent high myopia cohort.As with screening genes previously implicated in myopic development, qualitative and quantitative association candidates were screened in the independent whole genome expression array analyses, comparing normal rapidly growing fetal to normal grown adult ocular tissues. PTPRR and PPFIA2, candidates from qualitative and quantitative association respectively, were both validated by RT-qPCR with differential expression in at least one disease relevant ocular tissue. PTPRR and PPFIA2 belong to the same gene family- that of protein tyrosine phosphatase (PTP) genes. This family of genes relays extracellular signals that regulate cell growth, division, maturation and function, and its differential expression is consistent with our myopia surrogate model. Many genes implicated in either syndromic or non-syndromic myopia were present in the most significantly enriched adult versus fetal functional and/or canonical pathways together. The adult versus fetal choroid and cornea tissue types had the most overlap with known non-syndromic myopic-associated genes in the most significantly enriched functional groups. Further exploration of the connections amongst these known genes may elucidate possible mechanistic roles for disease progression and/or reveal related novel candidate genes. Differentially expressed genes in central versus peripheral tissues yielded minimal overlap with genes implicated in myopia; however, in addition to broadening our understanding of the spatial variances in these tissues they may contain clues to the development and/or progression of other ocular diseases such as retinopathy of prematurity development.The overlap with previously identified myopia-associated genes supports the model of eye growth for studying myopic development in human tissues. This expression data can be used both in prioritizing candidate genes other proposed genomic myopia loci, and also in detailed pathway analyses to identify potential biological mechanisms for candidates within these loci. Our most strongly associated candidate gene both in the discovery and replicate cohort was UHRF1BP1L, which was not differentially expressed in our data; however, interacting genes regulate the expression of at least one differentially expressed gene, indicating a possibly pathway connection. It is possible that differential expression may have been missed by the microarray data, or it may not be differentially expressed and affects myopic development through alternative or indirect means. While the expression data is a useful tool in prioritizing and inferring mechanistic roles for candidates, it cannot be used to exclude candidates. Deeper study of the pathways of candidate genes for myopic development may reveal connections to genes involved in ocular growth. Despite these potential limitations, two of the three novel candidates, PTPRR and PPFIA2, were supported by genomic convergence with the expression data, in addition to our discovery genetic association data. The other novel candidate, UHRF1BP1L, was validated in an independent Caucasian high-grade myopia cohort. Further validation and refinement of these three novel MYP3 candidate genes is necessary to make further claims about their possible involvement in myopic progression.

Published
2012

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