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

International AMD Genomics Consortium (IAMDGC)

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 (US)
Article number29
JournalGenome Medicine
Volume9
Issue number1
DOIs
StatePublished - Mar 27 2017

Fingerprint

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

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

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

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 Tammy Martin and Michael Klein",
year = "2017",
month = "3",
day = "27",
doi = "10.1186/s13073-017-0418-0",
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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 - Martin, Tammy

AU - Klein, Michael

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

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