A large genome-wide association study of age-related macular degeneration highlights contribution of rare and common variants

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dc.contributor.authorFritsche, Lars G
dc.contributor.authorIgl, Wilmar
dc.contributor.authorCooke-Bailey, Jessica N
dc.contributor.authorGrassmann, Felix
dc.contributor.authorSengupta, Sebanti
dc.contributor.authorBragg-Gresham, Jennifer L
dc.contributor.authorBurdon, Kathryn Penelope
dc.contributor.authorHebbring, Scott J
dc.contributor.authorWen, Cindy
dc.contributor.authorGorski, Mathias
dc.contributor.authorKim, Ivana K
dc.contributor.authorCho, David
dc.contributor.authorZack, Donald
dc.contributor.authorSouied, Eric
dc.contributor.authorScholl, Hendrik P N
dc.contributor.authorBala, Elisa
dc.contributor.authorLee, Kristine E
dc.contributor.authorHunter, David J
dc.contributor.authorSardell, Rebecca J
dc.contributor.authorMitchell, Paul
dc.contributor.authorMerriam, Joanna E
dc.contributor.authorCipriani, Valentina
dc.contributor.authorHoffman, Joshua D
dc.contributor.authorSchick, Tina
dc.contributor.authorLechanteur, Yara T E
dc.contributor.authorGuymer, Robyn H
dc.contributor.authorJohnson, Matthew P
dc.contributor.authorJiang, Yingda
dc.contributor.authorStanton, Chloe M
dc.contributor.authorBuitendijk, Gabrielle H S
dc.contributor.authorZhan, Xiaowei
dc.contributor.authorKwong, Alan M
dc.contributor.authorBoleda, Alexis
dc.contributor.authorBrooks, Matthew
dc.contributor.authorGieser,Linn
dc.contributor.authorRatnapriya, Rinki
dc.contributor.authorBranham, Kari E
dc.contributor.authorFoerster, Johanna R
dc.contributor.authorHeckenlively, John R
dc.contributor.authorOthman, Mohammad I
dc.contributor.authorVote, Brendan J
dc.contributor.authorLiang, Helena Hai
dc.contributor.authorSouzeau, Emmanuelle
dc.contributor.authorMcAllister, Ian L
dc.contributor.authorIsaacs, Timothy
dc.contributor.authorHall, Janette
dc.contributor.authorLake, Stewart
dc.contributor.authorMackey, David A
dc.contributor.authorConstable, Ian J
dc.contributor.authorCraig, Jamie E
dc.contributor.authorKitchner, Terrie E
dc.contributor.authorYang, Zhenglin
dc.contributor.authorSu, Zhiguang
dc.contributor.authorLuo, Hongrong
dc.contributor.authorChen, Daniel
dc.contributor.authorOuyang, Hong
dc.contributor.authorFlegg, Ken
dc.contributor.authorLin, Danni
dc.contributor.authorMao, Guanping
dc.contributor.authorFerreyra, Henry
dc.contributor.authorStark, Klaus
dc.contributor.authorvon Strachwitz, Claudia N
dc.contributor.authorWolf, Armin
dc.contributor.authorBrandl, Caroline
dc.contributor.authorRudolph, Guenther
dc.contributor.authorOlden, Matthias
dc.contributor.authorMorrison, Margaux A
dc.contributor.authorMorgan, Denise J
dc.contributor.authorSchu, Matthew
dc.contributor.authorAhn, Matthew
dc.contributor.authorSilvestri, Giuliana
dc.contributor.authorTsironi, Evangelia E
dc.contributor.authorPark, Kyu Hyung
dc.contributor.authorFarrer, Lindsay A
dc.contributor.authorOrlin, Anton
dc.contributor.authorBrucker, Alexander
dc.contributor.authorLi, Mingyao
dc.contributor.authorCurcio, Christine
dc.contributor.authorMohand-Saïd, Saddek
dc.contributor.authorSahel, Jose-Alain
dc.contributor.authorAudo, Isabelle
dc.contributor.authorBenchaboune, Mustapha
dc.contributor.authorCree, Angela J
dc.contributor.authorRennie, Christina A
dc.contributor.authorGoverdhan, Srinivas V
dc.contributor.authorGrunin, Michelle
dc.contributor.authorHagbi-Levi, Shira
dc.contributor.authorCampochiaro, Peter
dc.contributor.authorKatsanis, Nicholas
dc.contributor.authorHolz, Frank G
dc.contributor.authorBlond, Frederic
dc.contributor.authorBlanche, Helene
dc.contributor.authorDeleuze, Jean-Francois
dc.contributor.authorIgo Jr, Robert P
dc.contributor.authorTruitt, Barbara
dc.contributor.authorPeachey, Neal S
dc.contributor.authorMeuer, Stacy M
dc.contributor.authorMyers, Chelsea E
dc.contributor.authorMoore, Emily M
dc.contributor.authorKlein, Ronald
dc.contributor.authorHauser, Michael A
dc.contributor.authorPostel, Eric A
dc.contributor.authorCourtenay, Monique D
dc.contributor.authorSchwartz, Stephen G
dc.contributor.authorKovach, Jaclyn L
dc.contributor.authorScott, William K
dc.contributor.authorLiew, Gerald
dc.contributor.authorTan, Ava G
dc.contributor.authorGopinath, Bamini
dc.contributor.authorMerriam, John C
dc.contributor.authorSmith, R Theodore
dc.contributor.authorKhan, Jane C
dc.contributor.authorShahid, Humma
dc.contributor.authorMoore, Anthony T
dc.contributor.authorMcGrath, J Allie
dc.contributor.authorLaux, Rene
dc.contributor.authorBrantley Jr., Milam A
dc.contributor.authorAgarwal, Anita
dc.contributor.authorErsoy, Lebriz
dc.contributor.authorCaramoy, Albert
dc.contributor.authorLangmann, Thomas
dc.contributor.authorSaksens, Nicole T M
dc.contributor.authorde Jong, Eiko K
dc.contributor.authorHoyng, Carel B
dc.contributor.authorCain, Melinda S
dc.contributor.authorRichardson, Andrea J
dc.contributor.authorMartin,Tammy M
dc.contributor.authorBlangero, John
dc.contributor.authorWeeks, Daniel E
dc.contributor.authorDhillon, Bal
dc.contributor.authorvan Duijn, Cornelia M
dc.contributor.authorDoheny, Kimberly F
dc.contributor.authorRomm, Jane
dc.contributor.authorKlaver, Caroline C W
dc.contributor.authorHayward, Caroline
dc.contributor.authorGorin, Michael B
dc.contributor.authorKlein, Michael L
dc.contributor.authorBaird, Paul N
dc.contributor.authorden Hollander, Anneke I
dc.contributor.authorFauser, Sascha
dc.contributor.authorYates, John R W
dc.contributor.authorAllikmets, Rando
dc.contributor.authorWang, Jie Jin
dc.contributor.authorSchaumberg, Debra A
dc.contributor.authorKlein, Barbara E K
dc.contributor.authorHagstrom, Stephanie A
dc.contributor.authorChowers, Itay
dc.contributor.authorLotery, Andrew J
dc.contributor.authorLéveillard, Thierry
dc.contributor.authorZhang, Kang
dc.contributor.authorBrilliant, Murray H
dc.contributor.authorHewitt, Alex W
dc.contributor.authorSwaroop, Anand
dc.contributor.authorChew, Emily Y
dc.contributor.authorPericak-Vance, Margaret A
dc.contributor.authorDeAngelis, Margaret
dc.contributor.authorStambolian, Dwight
dc.contributor.authorHaines, Jonathan L
dc.contributor.authorIyengar, Sudha K
dc.contributor.authorWeber, Bernhard H F
dc.contributor.authorAbecasis, Goncalo R
dc.date.accessioned2016-02-22T23:09:43Z
dc.date.available2016-02-22T23:09:43Z
dc.date.issued2015-12-21
dc.descriptionAuthor manuscript version (post print) made available following 6 month embargo from date of publication (21 December 2015) in accordance with publisher copyright policy.en
dc.description.abstractAdvanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.en
dc.identifier.citationFritsche LG, Igl W, Bailey JN, Grassmann F, Sengupta S, Bragg-Gresham JL, Burdon KP, Hebbring SJ, Wen C, Gorski M, Kim IK, Cho D, Zack D, Souied E, Scholl HP, Bala E, Lee KE, Hunter DJ, Sardell RJ, Mitchell P, Merriam JE, Cipriani V, Hoffman JD, Schick T, Lechanteur YT, Guymer RH, Johnson MP, Jiang Y, Stanton CM, Buitendijk GH, Zhan X, Kwong AM, Boleda A, Brooks M, Gieser L, Ratnapriya R, Branham KE, Foerster JR, Heckenlively JR, Othman MI, Vote BJ, Liang HH, Souzeau E, McAllister IL, Isaacs T, Hall J, Lake S, Mackey DA, Constable IJ, Craig JE, Kitchner TE, Yang Z, Su Z, Luo H, Chen D, Ouyang H, Flagg K, Lin D, Mao G, Ferreyra H, Stark K, von Strachwitz CN, Wolf A, Brandl C, Rudolph G, Olden M, Morrison MA, Morgan DJ, Schu M, Ahn J, Silvestri G, Tsironi EE, Park KH, Farrer LA, Orlin A, Brucker A, Li M, Curcio CA, Mohand-Saïd S, Sahel JA, Audo I, Benchaboune M, Cree AJ, Rennie CA, Goverdhan SV, Grunin M, Hagbi-Levi S, Campochiaro P, Katsanis N, Holz FG, Blond F, Blanché H, Deleuze JF, Igo RP Jr, Truitt B, Peachey NS, Meuer SM, Myers CE, Moore EL, Klein R, Hauser MA, Postel EA, Courtenay MD, Schwartz SG, Kovach JL, Scott WK, Liew G, Tan AG, Gopinath B, Merriam JC, Smith RT, Khan JC, Shahid H, Moore AT, McGrath JA, Laux R, Brantley MA Jr, Agarwal A, Ersoy L, Caramoy A, Langmann T, Saksens NT, de Jong EK, Hoyng CB, Cain MS, Richardson AJ, Martin TM, Blangero J, Weeks DE, Dhillon B, van Duijn CM, Doheny KF, Romm J, Klaver CC, Hayward C, Gorin MB, Klein ML, Baird PN, den Hollander AI, Fauser S, Yates JR, Allikmets R, Wang JJ, Schaumberg DA, Klein BE, Hagstrom SA, Chowers I, Lotery AJ, Léveillard T, Zhang K, Brilliant MH, Hewitt AW, Swaroop A, Chew EY, Pericak-Vance MA, DeAngelis M, Stambolian D, Haines JL, Iyengar SK, Weber BH, Abecasis GR, Heid IM. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nature Genetics . 2016 Feb;48(2):134-43. doi: 10.1038/ng.3448en
dc.identifier.doihttps://doi.org/10.1038/ng.3448en
dc.identifier.issn1061-4036
dc.identifier.urihttp://hdl.handle.net/2328/35971
dc.language.isoen
dc.oaire.license.condition.licenseIn Copyright
dc.publisherNature Publishing Groupen
dc.relationhttp://purl.org/au-research/grants/NHMRC/1023911en
dc.relation.grantnumberNHMRC/1023911en
dc.rightsCopyright (2016) Nature America, Inc. All rights reserved.en
dc.rights.holderNature America, Inc.en
dc.titleA large genome-wide association study of age-related macular degeneration highlights contribution of rare and common variantsen
dc.typeArticleen
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