Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits

Felix Grassmann, Christina Kiel, International AMD Genomics Consortium (IAMDGC), Martina E. Zimmermann, Mathias Gorski, Veronika Grassmann, Klaus Stark, Iris M. Heid, Bernhard H.F. Weber*, Lars G. Fritsche, Wilmar Igl, Jessica N.Cooke Bailey, Sebanti Sengupta, Jennifer L. Bragg-Gresham, Kathryn P. Burdon, Scott J. Hebbring, Cindy Wen, Ivana K. Kim, David Cho, Donald ZackEric Souied, Hendrik P.N. Scholl, Elisa Bala, Kristine E. Lee, David J. Hunter, Rebecca J. Sardell, Paul Mitchell, Joanna E. Merriam, Valentina Cipriani, Joshua D. Hoffman, Tina Schick, Yara T.E. Lechanteur, Robyn H. Guymer, Matthew P. Johnson, Yingda Jiang, Chloe M. Stanton, Gabriëlle H.S. Buitendijk, Xiaowei Zhan, Alan M. Kwong, Alexis Boleda, Matthew Brooks, Linn Gieser, Rinki Ratnapriya, Kari E. Branham, Johanna R. Foerster, John R. Heckenlively, Eiko K. de Jong, Cornelia M. van Duijn, Caroline C.W. Klaver, Anneke I. den Hollander, Jie Jin Wang

*Corresponding author for this work

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Abstract

Background: Age-related macular degeneration (AMD) is a common condition of vision loss with disease development strongly influenced by environmental and genetic factors. Recently, 34 loci were associated with AMD at genome-wide significance. So far, little is known about a genetic overlap between AMD and other complex diseases or disease-relevant traits. Methods: For each of 60 complex diseases/traits with publicly available genome-wide significant association data, the lead genetic variant per independent locus was extracted and a genetic score was calculated for each disease/trait as the weighted sum of risk alleles. The association with AMD was estimated based on 16,144 AMD cases and 17,832 controls using logistic regression. Results: Of the respective disease/trait variance, the 60 genetic scores explained on average 4.8% (0.27-20.69%) and 16 of them were found to be significantly associated with AMD (Q-values < 0.01, p values from < 1.0 × 10-16 to 1.9 × 10-3). Notably, an increased risk for AMD was associated with reduced risk for cardiovascular diseases, increased risk for autoimmune diseases, higher HDL and lower LDL levels in serum, lower bone-mineral density as well as an increased risk for skin cancer. By restricting the analysis to 1824 variants initially used to compute the 60 genetic scores, we identified 28 novel AMD risk variants (Q-values < 0.01, p values from 1.1 × 10-7 to 3.0 × 10-4), known to be involved in cardiovascular disorders, lipid metabolism, autoimmune diseases, anthropomorphic traits, ocular disorders, and neurological diseases. The latter variants represent 20 novel AMD-associated, pleiotropic loci. Genes in the novel loci reinforce previous findings strongly implicating the complement system in AMD pathogenesis. Conclusions: We demonstrate a substantial overlap of the genetics of several complex diseases/traits with AMD and provide statistically significant evidence for an additional 20 loci associated with AMD. This highlights the possibility that so far unrelated pathologies may have disease pathways in common.

Original languageEnglish
Article number29
JournalGenome Medicine
Volume9
Issue number1
DOIs
Publication statusPublished - 27 Mar 2017

Bibliographical note

Funding Information:
This study was supported in parts by the Deutsche Forschungsgemeinschaft (WE 1259/19-1 and WE 1259/19-2 to BHFW), the Alcon Research Institute (to BHFW), and by grants from the German Federal Ministry of Education and Research (BMBF 01ER1206 and 01ER1507 to IMH). Genotyping was conducted as part of the IAMDGC exome-chip project supported by CIDR (contract number HHSN268201200008I) and funded by EY022310 (to Jonathan L. Haines, Case Western Reserve University, Cleveland) and 1X01HG006934-01 (to Gonçalo R. Abecasis, University of Michigan, Department of Biostatistics). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Publisher Copyright:
© 2017 The Author(s).

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