Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries

Bryan R. Gorman; Georgios Voloudakis; Robert P. Igo Jr.; Tyler Kinzy; Christopher W. Halladay; Tim B. Bigdeli; Biao Zeng; Sanan Venkatesh; Jessica N. Cooke Bailey; Dana C. Crawford; Kyriacos Markianos; Frederick Dong; Patrick A. Schreiner; Wen Zhang; VA Million Veteran Program; International AMD Genomics Consortium (IAMDGC); Tamer Hadi; Matthew D. Anger; Amy Stockwell; Ronald B. Melles; Jie Yin; Hélène Choquet; Rebecca Kaye; Karina Patasova; Praveen J. Patel; Brian L. Yaspan; Eric Jorgenson; Pirro G. Hysi; Andrew J. Lotery; J. Michael Gaziano; Philip S. Tsao; Steven J. Fliesler; Jack M. Sullivan; Paul B. Greenberg; Wen-Chih Wu; Themistocles L. Assimes; Saiju Pyarajan; Panos Roussos; Neal S. Peachey; Sudha K. Iyengar

doi:10.1038/s41588-024-01764-0

Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries

Bryan R. Gorman, Georgios Voloudakis, Robert P. Igo Jr., Tyler Kinzy, Christopher W. Halladay, Tim B. Bigdeli, Biao Zeng, Sanan Venkatesh, Jessica N. Cooke Bailey, Dana C. Crawford, Kyriacos Markianos, Frederick Dong, Patrick A. Schreiner, Wen Zhang, VA Million Veteran Program, International AMD Genomics Consortium (IAMDGC), Tamer Hadi, Matthew D. Anger, Amy Stockwell, Ronald B. MellesJie Yin, Hélène Choquet, Rebecca Kaye, Karina Patasova, Praveen J. Patel, Brian L. Yaspan, Eric Jorgenson, Pirro G. Hysi, Andrew J. Lotery, J. Michael Gaziano, Philip S. Tsao, Steven J. Fliesler, Jack M. Sullivan, Paul B. Greenberg, Wen-Chih Wu, Themistocles L. Assimes, Saiju Pyarajan, Panos Roussos^*, Neal S. Peachey^*, Sudha K. Iyengar^*

^*Corresponding author for this work

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

2 Citations (Scopus)

Abstract

To effectively reduce vision loss due to age-related macular generation (AMD) on a global scale, knowledge of its genetic architecture in diverse populations is necessary. A critical element, AMD risk profiles in African and Hispanic/Latino ancestries, remains largely unknown. We combined data in the Million Veteran Program with five other cohorts to conduct the first multi-ancestry genome-wide association study of AMD and discovered 63 loci (30 novel). We observe marked cross-ancestry heterogeneity at major risk loci, especially in African-ancestry populations which demonstrate a primary signal in a major histocompatibility complex class II haplotype and reduced risk at the established CFH and ARMS2/HTRA1 loci. Dissecting local ancestry in admixed individuals, we find significantly smaller marginal effect sizes for CFH risk alleles in African ancestry haplotypes. Broadening efforts to include ancestrally distinct populations helped uncover genes and pathways that boost risk in an ancestry-dependent manner and are potential targets for corrective therapies.

Original language	English
Article number	1776
Pages (from-to)	2659-2671
Number of pages	28
Journal	Nature Genetics
Volume	56
Issue number	12
DOIs	https://doi.org/10.1038/s41588-024-01764-0
Publication status	Published - Dec 2024
Externally published	Yes

Access to Document

10.1038/s41588-024-01764-0

Cite this

Gorman, B. R., Voloudakis, G., Igo Jr., R. P., Kinzy, T., Halladay, C. W., Bigdeli, T. B., Zeng, B., Venkatesh, S., Cooke Bailey, J. N., Crawford, D. C., Markianos, K., Dong, F., Schreiner, P. A., Zhang, W., VA Million Veteran Program, International AMD Genomics Consortium (IAMDGC), Hadi, T., Anger, M. D., Stockwell, A., ... Iyengar, S. K. (2024). Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries. Nature Genetics, 56(12), 2659-2671. Article 1776. https://doi.org/10.1038/s41588-024-01764-0

@article{e8d34da23b0e40ad8438ac9b2149bbad,

title = "Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries",

abstract = "To effectively reduce vision loss due to age-related macular generation (AMD) on a global scale, knowledge of its genetic architecture in diverse populations is necessary. A critical element, AMD risk profiles in African and Hispanic/Latino ancestries, remains largely unknown. We combined data in the Million Veteran Program with five other cohorts to conduct the first multi-ancestry genome-wide association study of AMD and discovered 63 loci (30 novel). We observe marked cross-ancestry heterogeneity at major risk loci, especially in African-ancestry populations which demonstrate a primary signal in a major histocompatibility complex class II haplotype and reduced risk at the established CFH and ARMS2/HTRA1 loci. Dissecting local ancestry in admixed individuals, we find significantly smaller marginal effect sizes for CFH risk alleles in African ancestry haplotypes. Broadening efforts to include ancestrally distinct populations helped uncover genes and pathways that boost risk in an ancestry-dependent manner and are potential targets for corrective therapies.",

author = "Gorman, {Bryan R.} and Georgios Voloudakis and {Igo Jr.}, {Robert P.} and Tyler Kinzy and Halladay, {Christopher W.} and Bigdeli, {Tim B.} and Biao Zeng and Sanan Venkatesh and {Cooke Bailey}, {Jessica N.} and Crawford, {Dana C.} and Kyriacos Markianos and Frederick Dong and Schreiner, {Patrick A.} and Wen Zhang and {VA Million Veteran Program} and {International AMD Genomics Consortium (IAMDGC)} and Fritsche, {Lars G.} and Wilmar Igl and {Cooke Bailey}, {Jessica N.} and Felix Grassman and Sebanti Sengupta and Bragg-Gresham, {Jennifer L.} and Burdon, {Kathryn P.} and Hebring, {Scott J.} and Cindy Wen and Mathias Gorski 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 Terrie Kitchner and Zhenglin Yang and Zhiquang Su and Hongrong Luo and Daniel Chen and Ouyang Ouyang and Ken Flagg and Guanping Mao and Henry Ferreyra and Klaus Stark and Strachwitz, {Claudia Nvon} and Armin Wolf and Caroline Brandl and Guenther Rudolph and Matthias Olden and Morrison, {Margaux A.} and Morgan, {Deniste 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{\c c}ois} and Igo, {Robert P.} and Barbara Truitt 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 Daniel Lin and Gerald Liew and Tan, {Ava G.} and Bamini Gopinath and Tamer Hadi and Anger, {Matthew D.} and Amy Stockwell and Melles, {Ronald B.} and Jie Yin and H{\'e}l{\`e}ne Choquet and Rebecca Kaye and Karina Patasova and Patel, {Praveen J.} and Yaspan, {Brian L.} and Eric Jorgenson and Hysi, {Pirro G.} and Lotery, {Andrew J.} and Gaziano, {J. Michael} and Tsao, {Philip S.} and Fliesler, {Steven J.} and Sullivan, {Jack M.} and Greenberg, {Paul B.} and Wen-Chih Wu and Assimes, {Themistocles L.} and Saiju Pyarajan and Panos Roussos and Peachey, {Neal S.} and Iyengar, {Sudha K.}",

year = "2024",

month = dec,

doi = "10.1038/s41588-024-01764-0",

language = "English",

volume = "56",

pages = "2659--2671",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Springer, Springer Nature",

number = "12",

}

Gorman, BR, Voloudakis, G, Igo Jr., RP, Kinzy, T, Halladay, CW, Bigdeli, TB, Zeng, B, Venkatesh, S, Cooke Bailey, JN, Crawford, DC, Markianos, K, Dong, F, Schreiner, PA, Zhang, W, VA Million Veteran Program, International AMD Genomics Consortium (IAMDGC), Hadi, T, Anger, MD, Stockwell, A, Melles, RB, Yin, J, Choquet, H, Kaye, R, Patasova, K, Patel, PJ, Yaspan, BL, Jorgenson, E, Hysi, PG, Lotery, AJ, Gaziano, JM, Tsao, PS, Fliesler, SJ, Sullivan, JM, Greenberg, PB, Wu, W-C, Assimes, TL, Pyarajan, S, Roussos, P, Peachey, NS & Iyengar, SK 2024, 'Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries', Nature Genetics, vol. 56, no. 12, 1776, pp. 2659-2671. https://doi.org/10.1038/s41588-024-01764-0

TY - JOUR

T1 - Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries

AU - Gorman, Bryan R.

AU - Voloudakis, Georgios

AU - Igo Jr., Robert P.

AU - Kinzy, Tyler

AU - Halladay, Christopher W.

AU - Bigdeli, Tim B.

AU - Zeng, Biao

AU - Venkatesh, Sanan

AU - Cooke Bailey, Jessica N.

AU - Crawford, Dana C.

AU - Markianos, Kyriacos

AU - Dong, Frederick

AU - Schreiner, Patrick A.

AU - Zhang, Wen

AU - VA Million Veteran Program

AU - International AMD Genomics Consortium (IAMDGC)

AU - Fritsche, Lars G.

AU - Igl, Wilmar

AU - Cooke Bailey, Jessica N.

AU - Grassman, Felix

AU - Sengupta, Sebanti

AU - Bragg-Gresham, Jennifer L.

AU - Burdon, Kathryn P.

AU - Hebring, Scott J.

AU - Wen, Cindy

AU - Gorski, Mathias

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

AU - Yang, Zhenglin

AU - Su, Zhiquang

AU - Luo, Hongrong

AU - Chen, Daniel

AU - Ouyang, Ouyang

AU - Flagg, Ken

AU - Mao, Guanping

AU - Ferreyra, Henry

AU - Stark, Klaus

AU - Strachwitz, Claudia Nvon

AU - Wolf, Armin

AU - Brandl, Caroline

AU - Rudolph, Guenther

AU - Olden, Matthias

AU - Morrison, Margaux A.

AU - Morgan, Deniste 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 - 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 - Lin, Daniel

AU - Liew, Gerald

AU - Tan, Ava G.

AU - Gopinath, Bamini

AU - Hadi, Tamer

AU - Anger, Matthew D.

AU - Stockwell, Amy

AU - Melles, Ronald B.

AU - Yin, Jie

AU - Choquet, Hélène

AU - Kaye, Rebecca

AU - Patasova, Karina

AU - Patel, Praveen J.

AU - Yaspan, Brian L.

AU - Jorgenson, Eric

AU - Hysi, Pirro G.

AU - Lotery, Andrew J.

AU - Gaziano, J. Michael

AU - Tsao, Philip S.

AU - Fliesler, Steven J.

AU - Sullivan, Jack M.

AU - Greenberg, Paul B.

AU - Wu, Wen-Chih

AU - Assimes, Themistocles L.

AU - Pyarajan, Saiju

AU - Roussos, Panos

AU - Peachey, Neal S.

AU - Iyengar, Sudha K.

PY - 2024/12

Y1 - 2024/12

N2 - To effectively reduce vision loss due to age-related macular generation (AMD) on a global scale, knowledge of its genetic architecture in diverse populations is necessary. A critical element, AMD risk profiles in African and Hispanic/Latino ancestries, remains largely unknown. We combined data in the Million Veteran Program with five other cohorts to conduct the first multi-ancestry genome-wide association study of AMD and discovered 63 loci (30 novel). We observe marked cross-ancestry heterogeneity at major risk loci, especially in African-ancestry populations which demonstrate a primary signal in a major histocompatibility complex class II haplotype and reduced risk at the established CFH and ARMS2/HTRA1 loci. Dissecting local ancestry in admixed individuals, we find significantly smaller marginal effect sizes for CFH risk alleles in African ancestry haplotypes. Broadening efforts to include ancestrally distinct populations helped uncover genes and pathways that boost risk in an ancestry-dependent manner and are potential targets for corrective therapies.

AB - To effectively reduce vision loss due to age-related macular generation (AMD) on a global scale, knowledge of its genetic architecture in diverse populations is necessary. A critical element, AMD risk profiles in African and Hispanic/Latino ancestries, remains largely unknown. We combined data in the Million Veteran Program with five other cohorts to conduct the first multi-ancestry genome-wide association study of AMD and discovered 63 loci (30 novel). We observe marked cross-ancestry heterogeneity at major risk loci, especially in African-ancestry populations which demonstrate a primary signal in a major histocompatibility complex class II haplotype and reduced risk at the established CFH and ARMS2/HTRA1 loci. Dissecting local ancestry in admixed individuals, we find significantly smaller marginal effect sizes for CFH risk alleles in African ancestry haplotypes. Broadening efforts to include ancestrally distinct populations helped uncover genes and pathways that boost risk in an ancestry-dependent manner and are potential targets for corrective therapies.

UR - http://www.scopus.com/inward/record.url?scp=85211641427&partnerID=8YFLogxK

U2 - 10.1038/s41588-024-01764-0

DO - 10.1038/s41588-024-01764-0

M3 - Article

C2 - 39623103

AN - SCOPUS:85211641427

SN - 1061-4036

VL - 56

SP - 2659

EP - 2671

JO - Nature Genetics

JF - Nature Genetics

IS - 12

M1 - 1776

ER -

Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries

Abstract

Access to Document

Other files and links

Cite this