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

Felix Grassmann; Christina Kiel; Martina Zimmermann; Mathias Gorski; Veronika Grassmann; Klaus Stark; International AMD Genomics Consortium (IAMDGC); Iris Heid; Bernhard Weber

doi:10.1186/s13073-017-0418-0

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

Felix Grassmann, Christina Kiel, Martina Zimmermann, Mathias Gorski, Veronika Grassmann, Klaus Stark, International AMD Genomics Consortium (IAMDGC), Iris Heid, Bernhard Weber

College of Medicine and Public Health

Research output: Contribution to journal › Article › peer-review

43 Citations (Scopus)

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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 language	English
Article number	29
Number of pages	13
Journal	Genome Medicine: medicine in the post-genomic era
Volume	9
Issue number	1
DOIs	https://doi.org/10.1186/s13073-017-0418-0
Publication status	Published - 27 Mar 2017

Bibliographical note

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.

Keywords

Age-related macular degeneration
AMD
Complex traits
Genetic association studies
Genetic risk scores
GRS
Shared genetics

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@article{d4441f3caa244057abe9564fcd011e31,

title = "Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits",

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. ",

keywords = "Age-related macular degeneration, AMD, Complex traits, Genetic association studies, Genetic risk scores, GRS, Shared genetics",

author = "Felix Grassmann and Christina Kiel and Martina Zimmermann and Mathias Gorski and Veronika Grassmann and Klaus Stark and {International AMD Genomics Consortium (IAMDGC)} and Lars Fritsche and Wilmar Igl and {Cooke Bailey}, J and S Sengupta and Jennifer Bragg-Gresham and Kathryn Burdon and Scott Hebbring and Cindy Wen and Ivana Kim and David Cho and Donald Zack and Eric Souied and Hendrik Scholl and Elisa Bala and Kristine Lee and David Hunter and Rebecca Sardell and Paul Mitchell and Joanna Merriam and Valentina Cipriani and Joshua Hoffman and Tina Schick and Yara Lechanteur and Robyn Guymer and Matthew Johnson and Yingda Jiang and Chloe Stanton and G Buitendijk and Xiaowei Zhan and Alan Kwong and Alexis Boleda and Matthew Brooks and Linn Gieser and Rinki Ratnapriya and Kari Branham and Johanna Foerster and John Heckenlively and Mohammad Othman and Brendan Vote and Helena Liang and Emmanuelle Souzeau and Ian McAllister and Timothy Isaacs and Janette Hall and Stewart Lake and David Mackey and Ian Constable and Jamie Craig and Terrie Kitchner and Zhenglin Yang and Zhiguang Su and Hongrong Luo and Daniel Chen and Hong Ouyang and Ken Flagg and Danni Lin and Guanping Mao and Henry Ferreyra and {von Strachwitz}, Claudia and Armin Wolf and Caroline Brandl and Guenther Rudolph and Matthias Olden and Margaux Morrison and Denise Morgan and Matthew Schu and Jeeyun Ahn and Giuliana Silvestri and Evangelia Tsironi and Kyu Park and Lindsay Farrer and Anton Orlin and Alexander Brucker and Mingyao Li and Christine Curcio and Saddek Mohand-Sa{\"i}d and Jos{\'e}-Alain Sahel and Isabelle Audo and Mustapha Benchaboune and Angela Cree and Christina Rennie and Srinivas Goverdhan and Michelle Grunin and Shira Hagbi-Levi and P Campochiaro and Nicholas Katsanis and Frank Holz and Fr{\'e}d{\'e}ric Blond and H{\'e}l{\`e}ne Blanch{\'e} and Jean-Fran{\c c}ois Deleuze and Robert Igo and Barbara Truitt and Neal Peachey and Stacy Meuer and Chelsea Myers and Emily Moore and Ronald Klein and Michael Hauser and Eric Postel and Monique Courtenay and Stephen Schwartz and Jaclyn Kovach and William Scott and Gerald Liew and Ava Tan and Bamini Gopinath and John Merriam and R Smith and Jane Khan and Humma Shahid and Anthony Moore and J McGrath and Renee Laux and Milam Brantley and Anita Agarwal and Lebriz Ersoy and Albert Caramoy and Thomas Langmann and Nicole Saksens and {de Jong}, Eiko and Carel Hoyng and Melinda Cain and Andrea Richardson and Tammy Martin and John Blangero and Daniel Weeks and Bal Dhillon and {van Duijn}, Cornelia and Kimberly Doheny and Jane Romm and Caroline Klaver and Caroline Hayward and Michael Gorin and Michael Klein and Paul Baird and {den Hollander}, Anneke and Sascha Fauser and John Yates and Rando Allikmets and Jie Wang and Debra Schaumberg and Barbara Klein and Stephanie Hagstrom and Itay Chowers and Andrew Lotery and Kang Zhang and Thierry L{\'e}veillard and Murray Brilliant and Alex Hewitt and Emily Chew and Anand Swaroop and Margaret Pericak-Vance and Margaret Deangelis and Dwight Stambolian and Jonathan Haines and Sudha Iyengar and Abecasis, {G. R.} and Iris Heid and Bernhard Weber",

note = "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.",

year = "2017",

month = mar,

day = "27",

doi = "10.1186/s13073-017-0418-0",

language = "English",

volume = "9",

journal = "Genome Medicine: medicine in the post-genomic era",

issn = "1756-994X",

number = "1",

}

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 -

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

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Keywords

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