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

International AMD Genomics Consortium (IAMDGC)

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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

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Genetic Pleiotropy
Macular Degeneration
Autoimmune Diseases
Lipid Metabolism Disorders
Genome
Skin Neoplasms
Nervous System Diseases
Bone Density

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International AMD Genomics Consortium (IAMDGC). / Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits. In: Genome Medicine. 2017 ; Vol. 9, No. 1.
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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 = "{International AMD Genomics Consortium (IAMDGC)} and Felix Grassmann and Christina Kiel and Zimmermann, {Martina E.} and Mathias Gorski and Veronika Grassmann and Klaus Stark and Heid, {Iris M.} and Weber, {Bernhard H.F.} and Fritsche, {Lars G.} and Wilmar Igl and Bailey, {Jessica N.Cooke} and Sebanti Sengupta and Bragg-Gresham, {Jennifer L.} and Burdon, {Kathryn P.} and Hebbring, {Scott J.} and Cindy Wen and Kim, {Ivana K.} and David Cho and Donald Zack and Eric Souied and Scholl, {Hendrik P.N.} and Elisa Bala and Lee, {Kristine E.} and Hunter, {David J.} and Sardell, {Rebecca J.} and Paul Mitchell and Merriam, {Joanna E.} and Valentina Cipriani and Hoffman, {Joshua D.} and Tina Schick and Lechanteur, {Yara T.E.} and Guymer, {Robyn H.} and Johnson, {Matthew P.} and Yingda Jiang and Stanton, {Chloe M.} and Buitendijk, {Gabri{\"e}lle H.S.} and Xiaowei Zhan and Kwong, {Alan M.} and Alexis Boleda and Matthew Brooks and Linn Gieser and Rinki Ratnapriya and Branham, {Kari E.} and Foerster, {Johanna R.} and Heckenlively, {John R.} and Othman, {Mohammad I.} and Vote, {Brendan J.} and Liang, {Helena Hai} and Emmanuelle Souzeau and McAllister, {Ian L.} and Timothy Isaacs and Janette Hall and Stewart Lake and Mackey, {David A.} and Constable, {Ian J.} and Craig, {Jamie E.} and Kitchner, {Terrie E.} 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 N.} and Armin Wolf and Caroline Brandl and Guenther Rudolph and Matthias Olden and Morrison, {Margaux A.} and Morgan, {Denise J.} and Matthew Schu and Jeeyun Ahn and Giuliana Silvestri and Tsironi, {Evangelia E.} and Park, {Kyu Hyung} and Farrer, {Lindsay A.} and Anton Orlin and Alexander Brucker and Mingyao Li and Curcio, {Christine A.} and Saddek Mohand-Sa{\"i}d and Sahel, {Jos{\'e} Alain} and Isabelle Audo and Mustapha Benchaboune and Cree, {Angela J.} and Rennie, {Christina A.} and Goverdhan, {Srinivas V.} and Michelle Grunin and Shira Hagbi-Levi and Peter Campochiaro and Nicholas Katsanis and Holz, {Frank G.} and Fr{\'e}d{\'e}ric Blond and H{\'e}l{\`e}ne Blanch{\'e} and Deleuze, {Jean Fran{\cc}ois} and Igo, {Robert P.} and Barbara Truitt and Peachey, {Neal S.} and Meuer, {Stacy M.} and Myers, {Chelsea E.} and Moore, {Emily L.} and Ronald Klein and Hauser, {Michael A.} and Postel, {Eric A.} and Courtenay, {Monique D.} and Schwartz, {Stephen G.} and Kovach, {Jaclyn L.} and Scott, {William K.} and Gerald Liew and Tan, {Ava G.} and Bamini Gopinath and Merriam, {John C.} and Smith, {R. Theodore} and Khan, {Jane C.} and Humma Shahid and Moore, {Anthony T.} and McGrath, {J. Allie} and Rene{\'e} Laux and Brantley, {Milam A.} and Anita Agarwal and Lebriz Ersoy and Albert Caramoy and Thomas Langmann and Saksens, {Nicole T.M.} and {de Jong}, {Eiko K.} and Hoyng, {Carel B.} and Cain, {Melinda S.} and Richardson, {Andrea J.} and Martin, {Tammy M.} and John Blangero and Weeks, {Daniel E.} and Bal Dhillon and {van Duijn}, {Cornelia M.} and Doheny, {Kimberly F.} and Jane Romm and Klaver, {Caroline C.W.} and Caroline Hayward and Gorin, {Michael B.} and Klein, {Michael L.} and Baird, {Paul N.} and {den Hollander}, {Anneke I.} and Sascha Fauser and Yates, {John R.W.} and Rando Allikmets and Wang, {Jie Jin} and Schaumberg, {Debra A.} and Klein, {Barbara E.K.} and Hagstrom, {Stephanie A.} and Itay Chowers and Lotery, {Andrew J.} and Thierry L{\'e}veillard and Kang Zhang and Brilliant, {Murray H.} and Hewitt, {Alex W.} and Anand Swaroop and Chew, {Emily Y.} and Pericak-Vance, {Margaret A.} and Margaret DeAngelis and Dwight Stambolian and Haines, {Jonathan L.} and Iyengar, {Sudha K.} and Abecasis, {Gon{\cc}alo R.}",
year = "2017",
month = "3",
day = "27",
doi = "10.1186/s13073-017-0418-0",
language = "English",
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journal = "Genome Medicine",
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}

Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits. / International AMD Genomics Consortium (IAMDGC).

In: Genome Medicine, Vol. 9, No. 1, 29, 27.03.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits

AU - International AMD Genomics Consortium (IAMDGC)

AU - Grassmann, Felix

AU - Kiel, Christina

AU - Zimmermann, Martina E.

AU - Gorski, Mathias

AU - Grassmann, Veronika

AU - Stark, Klaus

AU - Heid, Iris M.

AU - Weber, Bernhard H.F.

AU - Fritsche, Lars G.

AU - Igl, Wilmar

AU - Bailey, Jessica N.Cooke

AU - Sengupta, Sebanti

AU - Bragg-Gresham, Jennifer L.

AU - Burdon, Kathryn P.

AU - Hebbring, Scott J.

AU - Wen, Cindy

AU - Kim, Ivana K.

AU - Cho, David

AU - Zack, Donald

AU - Souied, Eric

AU - Scholl, Hendrik P.N.

AU - Bala, Elisa

AU - Lee, Kristine E.

AU - Hunter, David J.

AU - Sardell, Rebecca J.

AU - Mitchell, Paul

AU - Merriam, Joanna E.

AU - Cipriani, Valentina

AU - Hoffman, Joshua D.

AU - Schick, Tina

AU - Lechanteur, Yara T.E.

AU - Guymer, Robyn H.

AU - Johnson, Matthew P.

AU - Jiang, Yingda

AU - Stanton, Chloe M.

AU - Buitendijk, Gabriëlle H.S.

AU - Zhan, Xiaowei

AU - Kwong, Alan M.

AU - Boleda, Alexis

AU - Brooks, Matthew

AU - Gieser, Linn

AU - Ratnapriya, Rinki

AU - Branham, Kari E.

AU - Foerster, Johanna R.

AU - Heckenlively, John R.

AU - Othman, Mohammad I.

AU - Vote, Brendan J.

AU - Liang, Helena Hai

AU - Souzeau, Emmanuelle

AU - McAllister, Ian L.

AU - Isaacs, Timothy

AU - Hall, Janette

AU - Lake, Stewart

AU - Mackey, David A.

AU - Constable, Ian J.

AU - Craig, Jamie E.

AU - Kitchner, Terrie E.

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 N.

AU - Wolf, Armin

AU - Brandl, Caroline

AU - Rudolph, Guenther

AU - Olden, Matthias

AU - Morrison, Margaux A.

AU - Morgan, Denise J.

AU - Schu, Matthew

AU - Ahn, Jeeyun

AU - Silvestri, Giuliana

AU - Tsironi, Evangelia E.

AU - Park, Kyu Hyung

AU - Farrer, Lindsay A.

AU - Orlin, Anton

AU - Brucker, Alexander

AU - Li, Mingyao

AU - Curcio, Christine A.

AU - Mohand-Saïd, Saddek

AU - Sahel, José Alain

AU - Audo, Isabelle

AU - Benchaboune, Mustapha

AU - Cree, Angela J.

AU - Rennie, Christina A.

AU - Goverdhan, Srinivas V.

AU - Grunin, Michelle

AU - Hagbi-Levi, Shira

AU - Campochiaro, Peter

AU - Katsanis, Nicholas

AU - Holz, Frank G.

AU - Blond, Frédéric

AU - Blanché, Hélène

AU - Deleuze, Jean François

AU - Igo, Robert P.

AU - Truitt, Barbara

AU - Peachey, Neal S.

AU - Meuer, Stacy M.

AU - Myers, Chelsea E.

AU - Moore, Emily L.

AU - Klein, Ronald

AU - Hauser, Michael A.

AU - Postel, Eric A.

AU - Courtenay, Monique D.

AU - Schwartz, Stephen G.

AU - Kovach, Jaclyn L.

AU - Scott, William K.

AU - Liew, Gerald

AU - Tan, Ava G.

AU - Gopinath, Bamini

AU - Merriam, John C.

AU - Smith, R. Theodore

AU - Khan, Jane C.

AU - Shahid, Humma

AU - Moore, Anthony T.

AU - McGrath, J. Allie

AU - Laux, Reneé

AU - Brantley, Milam A.

AU - Agarwal, Anita

AU - Ersoy, Lebriz

AU - Caramoy, Albert

AU - Langmann, Thomas

AU - Saksens, Nicole T.M.

AU - de Jong, Eiko K.

AU - Hoyng, Carel B.

AU - Cain, Melinda S.

AU - Richardson, Andrea J.

AU - Martin, Tammy M.

AU - Blangero, John

AU - Weeks, Daniel E.

AU - Dhillon, Bal

AU - van Duijn, Cornelia M.

AU - Doheny, Kimberly F.

AU - Romm, Jane

AU - Klaver, Caroline C.W.

AU - Hayward, Caroline

AU - Gorin, Michael B.

AU - Klein, Michael L.

AU - Baird, Paul N.

AU - den Hollander, Anneke I.

AU - Fauser, Sascha

AU - Yates, John R.W.

AU - Allikmets, Rando

AU - Wang, Jie Jin

AU - Schaumberg, Debra A.

AU - Klein, Barbara E.K.

AU - Hagstrom, Stephanie A.

AU - Chowers, Itay

AU - Lotery, Andrew J.

AU - Léveillard, Thierry

AU - Zhang, Kang

AU - Brilliant, Murray H.

AU - Hewitt, Alex W.

AU - Swaroop, Anand

AU - Chew, Emily Y.

AU - Pericak-Vance, Margaret A.

AU - DeAngelis, Margaret

AU - Stambolian, Dwight

AU - Haines, Jonathan L.

AU - Iyengar, Sudha K.

AU - Abecasis, Gonçalo R.

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

JF - Genome Medicine

SN - 1756-994X

IS - 1

M1 - 29

ER -