TY - JOUR
T1 - Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits
AU - Grassmann, Felix
AU - Kiel, Christina
AU - Zimmermann, Martina
AU - Gorski, Mathias
AU - Grassmann, Veronika
AU - Stark, Klaus
AU - International AMD Genomics Consortium (IAMDGC)
AU - Fritsche, Lars
AU - Igl, Wilmar
AU - Cooke Bailey, J
AU - Sengupta, S
AU - Bragg-Gresham, Jennifer
AU - Burdon, Kathryn
AU - Hebbring, Scott
AU - Wen, Cindy
AU - Kim, Ivana
AU - Cho, David
AU - Zack, Donald
AU - Souied, Eric
AU - Scholl, Hendrik
AU - Bala, Elisa
AU - Lee, Kristine
AU - Hunter, David
AU - Sardell, Rebecca
AU - Mitchell, Paul
AU - Merriam, Joanna
AU - Cipriani, Valentina
AU - Hoffman, Joshua
AU - Schick, Tina
AU - Lechanteur, Yara
AU - Guymer, Robyn
AU - Johnson, Matthew
AU - Jiang, Yingda
AU - Stanton, Chloe
AU - Buitendijk, G
AU - Zhan, Xiaowei
AU - Kwong, Alan
AU - Boleda, Alexis
AU - Brooks, Matthew
AU - Gieser, Linn
AU - Ratnapriya, Rinki
AU - Branham, Kari
AU - Foerster, Johanna
AU - Heckenlively, John
AU - Othman, Mohammad
AU - Vote, Brendan
AU - Liang, Helena
AU - Souzeau, Emmanuelle
AU - McAllister, Ian
AU - Isaacs, Timothy
AU - Hall, Janette
AU - Lake, Stewart
AU - Mackey, David
AU - Constable, Ian
AU - Craig, Jamie
AU - Kitchner, Terrie
AU - Yang, Zhenglin
AU - Su, Zhiguang
AU - Luo, Hongrong
AU - Chen, Daniel
AU - Ouyang, Hong
AU - Flagg, Ken
AU - Lin, Danni
AU - Mao, Guanping
AU - Ferreyra, Henry
AU - von Strachwitz, Claudia
AU - Wolf, Armin
AU - Brandl, Caroline
AU - Rudolph, Guenther
AU - Olden, Matthias
AU - Morrison, Margaux
AU - Morgan, Denise
AU - Schu, Matthew
AU - Ahn, Jeeyun
AU - Silvestri, Giuliana
AU - Tsironi, Evangelia
AU - Park, Kyu
AU - Farrer, Lindsay
AU - Orlin, Anton
AU - Brucker, Alexander
AU - Li, Mingyao
AU - Curcio, Christine
AU - Mohand-Saïd, Saddek
AU - Sahel, José-Alain
AU - Audo, Isabelle
AU - Benchaboune, Mustapha
AU - Cree, Angela
AU - Rennie, Christina
AU - Goverdhan, Srinivas
AU - Grunin, Michelle
AU - Hagbi-Levi, Shira
AU - Campochiaro, P
AU - Katsanis, Nicholas
AU - Holz, Frank
AU - Blond, Frédéric
AU - Blanché, Hélène
AU - Deleuze, Jean-François
AU - Igo, Robert
AU - Truitt, Barbara
AU - Peachey, Neal
AU - Meuer, Stacy
AU - Myers, Chelsea
AU - Moore, Emily
AU - Klein, Ronald
AU - Hauser, Michael
AU - Postel, Eric
AU - Courtenay, Monique
AU - Schwartz, Stephen
AU - Kovach, Jaclyn
AU - Scott, William
AU - Liew, Gerald
AU - Tan, Ava
AU - Gopinath, Bamini
AU - Merriam, John
AU - Smith, R
AU - Khan, Jane
AU - Shahid, Humma
AU - Moore, Anthony
AU - McGrath, J
AU - Laux, Renee
AU - Brantley, Milam
AU - Agarwal, Anita
AU - Ersoy, Lebriz
AU - Caramoy, Albert
AU - Langmann, Thomas
AU - Saksens, Nicole
AU - de Jong, Eiko
AU - Hoyng, Carel
AU - Cain, Melinda
AU - Richardson, Andrea
AU - Martin, Tammy
AU - Blangero, John
AU - Weeks, Daniel
AU - Dhillon, Bal
AU - van Duijn, Cornelia
AU - Doheny, Kimberly
AU - Romm, Jane
AU - Klaver, Caroline
AU - Hayward, Caroline
AU - Gorin, Michael
AU - Klein, Michael
AU - Baird, Paul
AU - den Hollander, Anneke
AU - Fauser, Sascha
AU - Yates, John
AU - Allikmets, Rando
AU - Wang, Jie
AU - Schaumberg, Debra
AU - Klein, Barbara
AU - Hagstrom, Stephanie
AU - Chowers, Itay
AU - Lotery, Andrew
AU - Zhang, Kang
AU - Léveillard, Thierry
AU - Brilliant, Murray
AU - Hewitt, Alex
AU - Chew, Emily
AU - Swaroop, Anand
AU - Pericak-Vance, Margaret
AU - Deangelis, Margaret
AU - Stambolian, Dwight
AU - Haines, Jonathan
AU - Iyengar, Sudha
AU - Abecasis, G. R.
AU - Heid, Iris
AU - Weber, Bernhard
N1 - Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
PY - 2017/3/27
Y1 - 2017/3/27
N2 -
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.
AB -
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.
KW - Age-related macular degeneration
KW - AMD
KW - Complex traits
KW - Genetic association studies
KW - Genetic risk scores
KW - GRS
KW - Shared genetics
UR - http://www.scopus.com/inward/record.url?scp=85016152757&partnerID=8YFLogxK
U2 - 10.1186/s13073-017-0418-0
DO - 10.1186/s13073-017-0418-0
M3 - Article
VL - 9
JO - Genome Medicine: medicine in the post-genomic era
JF - Genome Medicine: medicine in the post-genomic era
SN - 1756-994X
IS - 1
M1 - 29
ER -