Division of Research, Kaiser Permanente Northern California (KPNC), Oakland, CA, 94612, USA.
Department of Ophthalmology, School of Medicine, University of California San Francisco (UCSF), San Francisco, CA, 94143, USA.
Nat Commun. 2018 Jun 11;9(1):2278. doi: 10.1038/s41467-018-04555-4.
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), 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.
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未得到解释，尤其是在罹患 POAG 风险更高的非裔美国人中。我们在 GERA 队列中进行了一项多民族全基因组关联研究 (GWAS)，在 UKB 中进行了复制，反之亦然，在 UKB 中进行了 GWAS，在 GERA 中进行了复制。我们确定了 24 个位点 (P < 5.0 × 10)，包括 14 个新的位点，其中 9 个重复 (在 FMNL2、PDE7B、TMTC2、IKZF2、CADM2、DGKG、ANKH、EXOC2 和 LMX1B 附近)。功能研究支持 FMNL2 和 LMX1B 与眼内压相关的影响，某些 Lmx1b 突变导致高眼压和类似于 POAG 的青光眼在小鼠中。新确定的位点增加了每个 GERA 种族/民族群体中可解释变异的比例，在非裔美国人中获益最大 (0.5-3.1%)。一项结合 GERA 和 UKB 的荟萃分析确定了 24 个额外的位点。我们的研究为青光眼发病机制提供了重要的见解。
