Recombinant haplotypes narrow the ARMS2/HTRA1 association signal for age-related macular degeneration

Felix Grassmann; Iris M. Heid; Bernhard H.F. Weber; International AMD Genomics Consortium (IAMDGC)

doi:10.1534/genetics.116.195966

Recombinant haplotypes narrow the ARMS2/HTRA1 association signal for age-related macular degeneration

Felix Grassmann, Iris M. Heid, Bernhard H.F. Weber, International AMD Genomics Consortium (IAMDGC)

College of Medicine and Public Health

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

62 Citations (Scopus)

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in ageing societies, triggered by both environmental and genetic factors. The strongest genetic signal for AMD with odds ratios of up to 2.8 per adverse allele was found previously over a chromosomal region in 10q26 harboring two genes, ARMS2 and HTRA1, although with little knowledge as to which gene or genetic variation is functionally relevant to AMD pathology. In this study, we analyzed rare recombinant haplotypes in 16,144 AMD cases and 17,832 controls from the International AMD Genomics Consortium and identified variants in ARMS2 but not HTRA1 to exclusively carry the AMD risk with P-values between 10 × 10^-773 and 6.7 × 10^-5. This now allows prioritization of the gene of interest for subsequent functional studies.

Original language	English
Pages (from-to)	919-924
Number of pages	6
Journal	Genetics
Volume	205
Issue number	2
DOIs	https://doi.org/10.1534/genetics.116.195966
Publication status	Published - Feb 2017

Keywords

Age-related macular degeneration
ARMS2/HTRA1 gene locus
Genetic association studies
Haplotypes
Linkage disequilibrium

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10.1534/genetics.116.195966

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@article{a31e6eaa50df4d2f9a93be9bb9926517,

title = "Recombinant haplotypes narrow the ARMS2/HTRA1 association signal for age-related macular degeneration",

abstract = "Age-related macular degeneration (AMD) is the leading cause of blindness in ageing societies, triggered by both environmental and genetic factors. The strongest genetic signal for AMD with odds ratios of up to 2.8 per adverse allele was found previously over a chromosomal region in 10q26 harboring two genes, ARMS2 and HTRA1, although with little knowledge as to which gene or genetic variation is functionally relevant to AMD pathology. In this study, we analyzed rare recombinant haplotypes in 16,144 AMD cases and 17,832 controls from the International AMD Genomics Consortium and identified variants in ARMS2 but not HTRA1 to exclusively carry the AMD risk with P-values between 10 × 10-773 and 6.7 × 10-5. This now allows prioritization of the gene of interest for subsequent functional studies.",

keywords = "Age-related macular degeneration, ARMS2/HTRA1 gene locus, Genetic association studies, Haplotypes, Linkage disequilibrium",

author = "Felix Grassmann and Heid, {Iris M.} and Weber, {Bernhard H.F.} and {International AMD Genomics Consortium (IAMDGC)} and Fritsche, {Lars G.} and Wilmar Igl and Cooke-Bailey, {Jessica N.} and F. Grassmann and Sebanti Sengupta and Bragg-Gresham, {Jennifer L.} and {Kathryn P. Burdon}, {Kathryn Penelope} and Hebbring, {Scott J.} and Wen, {Cindy H.} and Gorski, {Mathias M.} and Kim, {Ivana K.} and David Cho and Zack, {Donald J.} and Sou{\"i}ed, {{\'E}ric H.} and Scholl, {Hendrik P.N.} and Elisa Bala and Lee, {Kristine E.} and Hunter, {D. J.} and Sardell, {Rebecca J.} and Mitchell, {Paul G.} 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 Gieser, {Linn M.} and Rinki Ratnapriya and Branham, {Kari E.} and Foerster, {Johanna R.} and Heckenlively, {John R.} and Othman, {Mohammad I.} and Vote, {Brendan J.T.} and Liang, {Helena Hai} and Emmanuelle Souzeau and McAllister, {Ian L.} and Isaacs, {Timothy William} and Hall, {Janette Eve} and Lake, {Stewart R.} and Mackey, {David A.} and Constable, {Ian Jeffery} and Craig, {Jamie Evan} 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 Ferreyra, {Henry A.} and Stark, {Klaus J.} and {Von Strachwitz}, {Claudia N.} and Wolf, {Armin H.} and Caroline Brandl and G{\"u}nther Rudolph and Matthias Olden and Morrison, {Margaux A.} and Morgan, {Denise J.} and Schu, {Matthew C.} and Jeeyun Ahn and Giuliana Silvestri and Evangelia Tsironi and Park, {Kyuhyung Hyung} and Farrer, {Lindsay A.} and Anton Orlin and Brucker, {Alexander J.} and Mingyao Li and Curcio, {Christine A.} and Saddek Mohand-Sa{\"i}d and S{\"a}hel, {Jos{\'e} Alain} and Audo, {Isabelle S.} and Mustapha Benchaboune and Cree, {Angela Jane} and Rennie, {Christina A.} and Goverdhan, {Srinivas V.} and Michelle Grunin and Shira Hagbi-Levi and Campochiaro, {Peter Anthony} and Nicholas Katsanis and Holz, {Frank Gerhard} and Fr{\'e}d{\'e}ric Blond and H{\'e}len{\'e} Blanch{\'e} and Deleuze, {Jean Fran{\c c}ois} and Igo, {Robert P.} and Truitt, {Barbara J.} and Peachey, {Neal S.} and Meuer, {Stacy M.} and Myers, {Chelsea E.} and Moore, {Emily L.} and Klein, {Ronald L.} 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, {Adrian G.} and Bamini Gopinath and Merriam, {John C.} and Smith, {Roland Theodore} and Khan, {Jane C.} and Humma Shahid and Moore, {Anthony Thomas} and McGrath, {Josephine Allie} and Laux, {Rene{\'e} A.} and Brantley, {Milam A.} and Agarwal, {Aniruddha Kishandutt} 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 Jane} and Martin, {Tammy M.} and Blangero, {John C.} and Weeks, {Daniel E.} and Dhillon, {Baljean J.} and {Van Duijn}, {Cornelia M.} and Doheny, {Kimberly Floy} and Romm, {Jane M.} and Klaver, {Caroline C.W.} and Caroline Hayward and Gorin, {Michael B.} and Klein, {Michael L.} and Baird, {Paul Nigel} and {Den Hollander}, {Anneke I.} and Sascha Fauser and Yates, {John R.W.} and Allikmets, {Rando L.} and Jiejin Wang and Schaumberg, {Debra Ann} and Klein, {Barbara Eden} and Hagstrom, {Stephanie A.} and Itay Chowers and Lotery, {Andrew John} and Thierry L{\'e}veillard and Kang Zhang and Brilliant, {Murray H.} and Hewitt, {A. W.} and Anand Swaroop and Chew, {Emily Y.} and Kunkle, {Brian W.} and DeAngelis, {Margaret M.} and Stambolian, {Dwight E.} and Haines, {Jonathan L.} and Iyengar, {Sudha K.} and Weber, {B. H.} and Abecasis, {Gon{\c c}alo R.} and Heid, {Iris M.}",

year = "2017",

month = feb,

doi = "10.1534/genetics.116.195966",

language = "English",

volume = "205",

pages = "919--924",

journal = "Genetics",

issn = "0016-6731",

publisher = "Genetics",

number = "2",

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TY - JOUR

T1 - Recombinant haplotypes narrow the ARMS2/HTRA1 association signal for age-related macular degeneration

AU - Grassmann, Felix

AU - Heid, Iris M.

AU - Weber, Bernhard H.F.

AU - International AMD Genomics Consortium (IAMDGC)

AU - Fritsche, Lars G.

AU - Igl, Wilmar

AU - Cooke-Bailey, Jessica N.

AU - Grassmann, F.

AU - Sengupta, Sebanti

AU - Bragg-Gresham, Jennifer L.

AU - Kathryn P. Burdon, Kathryn Penelope

AU - Hebbring, Scott J.

AU - Wen, Cindy H.

AU - Gorski, Mathias M.

AU - Kim, Ivana K.

AU - Cho, David

AU - Zack, Donald J.

AU - Souïed, Éric H.

AU - Scholl, Hendrik P.N.

AU - Bala, Elisa

AU - Lee, Kristine E.

AU - Hunter, D. J.

AU - Sardell, Rebecca J.

AU - Mitchell, Paul G.

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 M.

AU - Ratnapriya, Rinki

AU - Branham, Kari E.

AU - Foerster, Johanna R.

AU - Heckenlively, John R.

AU - Othman, Mohammad I.

AU - Vote, Brendan J.T.

AU - Liang, Helena Hai

AU - Souzeau, Emmanuelle

AU - McAllister, Ian L.

AU - Isaacs, Timothy William

AU - Hall, Janette Eve

AU - Lake, Stewart R.

AU - Mackey, David A.

AU - Constable, Ian Jeffery

AU - Craig, Jamie Evan

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 A.

AU - Stark, Klaus J.

AU - Von Strachwitz, Claudia N.

AU - Wolf, Armin H.

AU - Brandl, Caroline

AU - Rudolph, Günther

AU - Olden, Matthias

AU - Morrison, Margaux A.

AU - Morgan, Denise J.

AU - Schu, Matthew C.

AU - Ahn, Jeeyun

AU - Silvestri, Giuliana

AU - Tsironi, Evangelia

AU - Park, Kyuhyung Hyung

AU - Farrer, Lindsay A.

AU - Orlin, Anton

AU - Brucker, Alexander J.

AU - Li, Mingyao

AU - Curcio, Christine A.

AU - Mohand-Saïd, Saddek

AU - Sähel, José Alain

AU - Audo, Isabelle S.

AU - Benchaboune, Mustapha

AU - Cree, Angela Jane

AU - Rennie, Christina A.

AU - Goverdhan, Srinivas V.

AU - Grunin, Michelle

AU - Hagbi-Levi, Shira

AU - Campochiaro, Peter Anthony

AU - Katsanis, Nicholas

AU - Holz, Frank Gerhard

AU - Blond, Frédéric

AU - Blanché, Hélené

AU - Deleuze, Jean François

AU - Igo, Robert P.

AU - Truitt, Barbara J.

AU - Peachey, Neal S.

AU - Meuer, Stacy M.

AU - Myers, Chelsea E.

AU - Moore, Emily L.

AU - Klein, Ronald L.

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, Adrian G.

AU - Gopinath, Bamini

AU - Merriam, John C.

AU - Smith, Roland Theodore

AU - Khan, Jane C.

AU - Shahid, Humma

AU - Moore, Anthony Thomas

AU - McGrath, Josephine Allie

AU - Laux, Reneé A.

AU - Brantley, Milam A.

AU - Agarwal, Aniruddha Kishandutt

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 Jane

AU - Martin, Tammy M.

AU - Blangero, John C.

AU - Weeks, Daniel E.

AU - Dhillon, Baljean J.

AU - Van Duijn, Cornelia M.

AU - Doheny, Kimberly Floy

AU - Romm, Jane M.

AU - Klaver, Caroline C.W.

AU - Hayward, Caroline

AU - Gorin, Michael B.

AU - Klein, Michael L.

AU - Baird, Paul Nigel

AU - Den Hollander, Anneke I.

AU - Fauser, Sascha

AU - Yates, John R.W.

AU - Allikmets, Rando L.

AU - Wang, Jiejin

AU - Schaumberg, Debra Ann

AU - Klein, Barbara Eden

AU - Hagstrom, Stephanie A.

AU - Chowers, Itay

AU - Lotery, Andrew John

AU - Léveillard, Thierry

AU - Zhang, Kang

AU - Brilliant, Murray H.

AU - Hewitt, A. W.

AU - Swaroop, Anand

AU - Chew, Emily Y.

AU - Kunkle, Brian W.

AU - DeAngelis, Margaret M.

AU - Stambolian, Dwight E.

AU - Haines, Jonathan L.

AU - Iyengar, Sudha K.

AU - Weber, B. H.

AU - Abecasis, Gonçalo R.

AU - Heid, Iris M.

PY - 2017/2

Y1 - 2017/2

N2 - Age-related macular degeneration (AMD) is the leading cause of blindness in ageing societies, triggered by both environmental and genetic factors. The strongest genetic signal for AMD with odds ratios of up to 2.8 per adverse allele was found previously over a chromosomal region in 10q26 harboring two genes, ARMS2 and HTRA1, although with little knowledge as to which gene or genetic variation is functionally relevant to AMD pathology. In this study, we analyzed rare recombinant haplotypes in 16,144 AMD cases and 17,832 controls from the International AMD Genomics Consortium and identified variants in ARMS2 but not HTRA1 to exclusively carry the AMD risk with P-values between 10 × 10-773 and 6.7 × 10-5. This now allows prioritization of the gene of interest for subsequent functional studies.

AB - Age-related macular degeneration (AMD) is the leading cause of blindness in ageing societies, triggered by both environmental and genetic factors. The strongest genetic signal for AMD with odds ratios of up to 2.8 per adverse allele was found previously over a chromosomal region in 10q26 harboring two genes, ARMS2 and HTRA1, although with little knowledge as to which gene or genetic variation is functionally relevant to AMD pathology. In this study, we analyzed rare recombinant haplotypes in 16,144 AMD cases and 17,832 controls from the International AMD Genomics Consortium and identified variants in ARMS2 but not HTRA1 to exclusively carry the AMD risk with P-values between 10 × 10-773 and 6.7 × 10-5. This now allows prioritization of the gene of interest for subsequent functional studies.

KW - Age-related macular degeneration

KW - ARMS2/HTRA1 gene locus

KW - Genetic association studies

KW - Haplotypes

KW - Linkage disequilibrium

UR - http://www.scopus.com/inward/record.url?scp=85020305656&partnerID=8YFLogxK

U2 - 10.1534/genetics.116.195966

DO - 10.1534/genetics.116.195966

M3 - Article

SN - 0016-6731

VL - 205

SP - 919

EP - 924

JO - Genetics

JF - Genetics

IS - 2

ER -

Recombinant haplotypes narrow the ARMS2/HTRA1 association signal for age-related macular degeneration

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Keywords

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