Association of coding and UTR variants in the known regions with wet age-related macular degeneration in Han Chinese population


Age-related macular degeneration (AMD) is the leading cause worldwide of severe visual impairment among people older than 55 years of age. This study aimed to investigate the genetic association between coding and untranslated region (UTR) variants in previously reported loci and exudative age-related macular degeneration (wet AMD) in a Han Chinese population. Using our previously published whole exome sequencing dataset of 349 wet AMD patients and 1253 controls, we searched for associations between coding and UTR variants of the 72 genes located within the 47 reported wet AMD loci regions. From these, 25 variants in 18 of the 72 genes with P< 10 × 10−3 were selected for the first replication of Sequenom mass-array genotyping in 885 wet AMD subjects and 562 controls. Next, four SNPs were selected for further validation by SNaPshot genotyping in a third Chinese cohort with 456 wet AMD subjects and 211 controls. As a result, we identified two new potential coding and UTR variant SNPs (rs189132250 in BBX located in 3q12.1 and rs144351944 in FILIP1L located in 3q12.1) that showed weak associations with wet AMD in the Han Chinese population. These findings provide new information regarding the coding and UTR variants of the known wet AMD loci in the studied Chinese cohort.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Coleman HR, Chan CC, Ferris FL, 3rd & Chew EY. Age-related macular degeneration. Lancet. 2008;372:1835–1845.

  2. 2.

    Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY. et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. The Lancet. Global health. 2014;2:e106–116.

  3. 3.

    Bernstein PS. Nutritional Interventions against Age-Related Macular Degeneration. Acta horticulturae. 2009;841:103–112.

  4. 4.

    Chen Y, Zeng J, Zhao C, Wang K, Trood E, Buehler J. et al. Assessing susceptibility to age-related macular degeneration with genetic markers and environmental factors. Archives of ophthalmology. 2011;129:344–351.

  5. 5.

    Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419–421.

  6. 6.

    Edwards AO, Ritter R, 3rd, Abel KJ, Manning A, Panhuysen C. & Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421–424 .

  7. 7.

    Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C. et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385–389.

  8. 8.

    Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ. et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006;314:992–993.

  9. 9.

    Dewan A, Liu, M Hartman, S, Zhang SS, Liu D.T, Zhao C. et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science. 2006;314:989–992.

  10. 10.

    Yu Y, Bhangale TR, Fagerness J, Ripke S, Thorleifsson G, Tan P.L. et al. Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Human molecular genetics. 2011;20:3699–3709.

  11. 11.

    Yates J.R, Sepp T, Matharu BK, Khan J.C, Thurlby D.A, Shahid H. et al. Complement C3 variant and the risk of age-related macular degeneration. The New England journal of medicine. 2007;357:553–561.

  12. 12.

    Gold B, Merriam JE, Zernant J, Hancox LS, Taiber A.J, Gehrs K. et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nature genetics. 2006;38:458–462.

  13. 13.

    Cheng CY. & Yamashiro K. & Chen LJ. & Ahn J. & Huang L. & Huang L. et al. New loci and coding variants confer risk for age-related macular degeneration in East Asians. Nature communications. 2015;6:6063.

  14. 14.

    Huang L, Zhang H, Cheng CY, Wen F, Tam PO, Zhao P. et al. A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy. Nature genetics. 2016;48:640–647.

  15. 15.

    Skol AD, Scott LJ, Abecasis GR. & Boehnke M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nature genetics. 2006;38:209–213.

  16. 16.

    Neale BM, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S. et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proceedings of the National Academy of Sciences of the United States of America. 2010;107:7395–7400.

  17. 17.

    Chen W, Stambolian D, Edwards AO, Branham K.E, Othman M, Jakobsdottir, J. et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America. 2010;107:7401–7406.

  18. 18.

    Seddon JM, Cote J, Page WF, Aggen SH. & Neale MC. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Archives of ophthalmology. 2005;123:321–327.

  19. 19.

    Kanda A, Chen W, Othman M, Branham KE, Brooks, M, Khanna R. et al. A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America. 2007;104:16227–16232.

  20. 20.

    Ng TK, Chen LJ, Liu DT, Tam PO, Chan WM, Liu K. et al. Multiple gene polymorphisms in the complement factor h gene are associated with exudative age-related macular degeneration in chinese. Investigative ophthalmology & visual science. 2008;49:3312–3317.

  21. 21.

    Davila S, Wright VJ, Khor CC, Sim KS, Binder A, Breunis WB. et al. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nature genetics. 2010;42:772–776.

  22. 22.

    Mori K, Horie-Inoue K, Gehlbach P.L, Takita H, Kabasawa S, Kawasaki I. et al. Phenotype and genotype characteristics of age-related macular degeneration in a Japanese population. Ophthalmology. 2010;117:928–938.

  23. 23.

    Arakawa S, Takahashi A, Ashikawa K, Hosono N, Aoi T, Yasuda M. et al. Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population. Nature genetics. 2011;43:1001–1004.

  24. 24.

    Teper SJ, Nowinska A. & Wylegala E. A69S and R38X ARMS2 and Y402H CFH gene polymorphisms as risk factors for neovascular age-related macular degeneration in Poland - a brief report. Medical science monitor : international medical journal of experimental and clinical research. 2012;18:PR1-3.

  25. 25.

    Woo SJ, Ahn J, Morrison MA, Ahn SY, Lee J, Kim KW. et al. Analysis of Genetic and Environmental Risk Factors and Their Interactions in Korean Patients with Age-Related Macular Degeneration. PloS one. 2015;10:e0132771.

  26. 26.

    Ye Z, Mayer J, Ivacic L, Zhou Z, He M, Schrodi SJ. et al. Phenome-wide association studies (PheWASs) for functional variants. European journal of human genetics : EJHG. 2015;23:523–529.

  27. 27.

    Yu W, Dong S, Zhao C, Wang H, Dai F. & Yang J. Cumulative association between age-related macular degeneration and less studied genetic variants in PLEKHA1/ARMS2/HTRA1: a meta and gene-cluster analysis. Molecular biology reports. 2013;40:5551–5561.

  28. 28.

    Caporaso N, Gu F, Chatterjee N, Sheng-Chih J, Yu K, Yeager M. et al. Genome-wide and candidate gene association study of cigarette smoking behaviors. PloS one. 4, e4653 (2009).

  29. 29.

    Hughes AE, Orr N, Patterson C, Esfandiary H, Hogg R, McConnell, V. et al. Neovascular age-related macular degeneration risk based on CFH, LOC387715/HTRA1, and smoking. PLoS medicine. 2007;4:e355.

  30. 30.

    Xie C, Gou M.L, Yi T, Deng H, Li Z.Y, Liu P. et al. Efficient inhibition of ovarian cancer by truncation mutant of FILIP1L gene delivered by novel biodegradable cationic heparin-polyethyleneimine nanogels. Human gene therapy. 2011;22:1413–1422.

  31. 31.

    Dieterich LC, Mellberg S, Langenkamp E, Zhang L, Zieba A, Salomaki H. et al. Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFbeta2 in vascular abnormalization. The Journal of pathology. 2012;228:378–390.

  32. 32.

    Kwon M, Lee S.J, Reddy S, Rybak Y, Adem A. & Libutti S.K. Down-regulation of Filamin A interacting protein 1-like Is associated with promoter methylation and an invasive phenotype in breast, colon, lung and pancreatic cancers [corrected]. PloS one. 2013;8:e82620.

  33. 33.

    Notaridou M, Quaye L, Dafou D, Jones C, Song H, Hogdall E. et al. Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer. International journal of cancer. 2011;128:2063–2074.

  34. 34.

    Fritsche LG. & Igl W. & Bailey JN. & Grassmann F. & Sengupta S. & Bragg-Gresham JL. et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nature genetics. 2016;48:134–143.

Download references


We would like to thank all the AMD patients and their families for participating in this study. This research project was supported by: National key scientific research program (2016YFC0905200, ZY), the National Natural Science Foundation of China (81170883(ZY), 81430008 (ZY), 81470647(FW), 81300802 and 81670895 (LH), the Department of Science and Technology of Sichuan Province, China (2014SZ0169 (ZY), 2015SZ0052 (ZY), 2015JQO057 (LH), 2013JY0195 (LH), 2016HH0072(LH), and 2017JQ0024(LH).

Author contributions

ZY designed the study. FW, XZ, POST, HC and CP recruited the participants. LH and FH performed the genotyping. LH wrote the initial draft, with edits from ZY corrected the English spelling and grammar. All authors critically revised and gave final approval of this manuscript.

Author information

Correspondence to Fen Wen or Zhenglin Yang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic-database information

The URLs for data presented herein are as follows: 1000 Genomes Browser,; GWAS Integrator database (; UCSC hg19:; BWA:; SAMTOOLS:; Annovar:

Electronic supplementary material

supplementary figure 1

supplementary table 1

supplementary table 2

supplementary table 3

supplementary table 4

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark