A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci.
A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci.
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原发性开角型青光眼的多种族全基因组关联研究确定了新的风险位点
DOI：
10.1038/s41467-018-04555-4
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发表时间：
2018-06-11
影响因子：
16.6
通讯作者：
Jorgenson E
中科院分区：
文献类型：
--
作者：
Choquet H;Paylakhi S;Kneeland SC;Thai KK;Hoffmann TJ;Yin J;Kvale MN;Banda Y;Tolman NG;Williams PA;Schaefer C;Melles RB;Risch N;John SWM;Nair KS;Jorgenson E
原发性开角型青光眼（POAG）是导致不可逆视力丧失的主要原因，但大部分遗传风险仍无法解释，特别是在非洲裔美国人中，他们患POAG的风险更高。我们在GERA队列中进行POAG的多种族全基因组关联研究（GWAS），在英国生物库（UKB）中进行复制，反之亦然，在UKB中进行GWAS，在GERA中进行复制。我们确定了24个基因座（P < 5.0 × 10−8），包括14个新的，其中9个重复（靠近FMNL 2，PDE 7 B，TMTC 2，IKZF 2，CADM 2，DGKG，ANKH，EXOC 2和LMX 1B）。功能研究支持FMNL 2和LMX 1B的眼内压相关影响，某些Lmx 1b突变可导致高IOP和类似于小鼠POAG的青光眼。新发现的基因座增加了每个GERA种族/民族群体中解释的方差比例，非洲裔美国人的增幅最大（0.5-3.1%）。结合GERA和UKB的荟萃分析鉴定了24个额外的基因座。我们的研究为青光眼的发病机制提供了重要的见解。原发性开角型青光眼（POAG）导致视力逐渐丧失。在这里，Choquet等人在多种族队列中对POAG进行了全基因组关联分析，确定了总共9个新的遗传基因座，并使用细胞系和小鼠实验显示了FMNL 2和LMX 1B的相关功能。
Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG. We conduct a multiethnic genome-wide association study (GWAS) of POAG in the GERA cohort, with replication in the UK Biobank (UKB), and vice versa, GWAS in UKB with replication in GERA. We identify 24 loci (P < 5.0 × 10−8), including 14 novel, of which 9 replicate (near FMNL2, PDE7B, TMTC2, IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). Functional studies support intraocular pressure-related influences of FMNL2 and LMX1B, with certain Lmx1b mutations causing high IOP and glaucoma resembling POAG in mice. The newly identified loci increase the proportion of variance explained in each GERA race/ethnicity group, with the largest gain in African-Americans (0.5–3.1%). A meta-analysis combining GERA and UKB identifies 24 additional loci. Our study provides important insights into glaucoma pathogenesis. Primary open-angle glaucoma (POAG) leads to progressive vision loss. Here, Choquet et al. perform genome-wide association analysis for POAG in a multi-ethnic cohort, identify a total of nine novel genetic loci and show relevant function of FMNL2 and LMX1B using cell line and mouse experiments.
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影响因子：
16.6
作者：
Choquet H;Thai KK;Yin J;Hoffmann TJ;Kvale MN;Banda Y;Schaefer C;Risch N;Nair KS;Melles R;Jorgenson E
通讯作者：
Jorgenson E
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
3.7
作者：
Burridge K;Guilluy C
通讯作者：
Guilluy C
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
30.8
作者：
Gharahkhani, Puya;Burdon, Kathryn P.;Fogarty, Rhys;Sharma, Shiwani;Hewitt, Alex W.;Martin, Sarah;Law, Matthew H.;Cremin, Katie;Bailey, Jessica N. Cooke;Loomis, Stephanie J.;Pasquale, Louis R.;Haines, Jonathan L.;Hauser, Michael A.;Viswanathan, Ananth C.;McGuffin, Peter;Topouzis, Fotis;Foster, Paul J.;Graham, Stuart L.;Casson, Robert J.;Chehade, Mark;White, Andrew J.;Zhou, Tiger;Souzeau, Emmanuelle;Landers, John;Fitzgerald, Jude T.;Klebe, Sonja;Ruddle, Jonathan B.;Goldberg, Ivan;Healey, Paul R.;Mills, Richard A.;Wang, Jie Jin;Montgomery, Grant W.;Martin, Nicholas G.;Radford-Smith, Graham;Whiteman, David C.;Brown, Matthew A.;Wiggs, Janey L.;Mackey, David A.;Mitchell, Paul;MacGregor, Stuart;Craig, Jamie E.
通讯作者：
Craig, Jamie E.