A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci

作者：Choquet Helene; Paylakhi Seyyedhassan; Kneeland Stephen C; Thai Khanh K; Hoffmann Thomas J; Yin Jie; Kvale Mark N; Banda Yambazi; Tolman Nicholas G; Williams Pete A; Schaefer Catherine; Melles Ronald B; Risch Neil; John Simon W M; Nair K Saidas; Jorgenson Eric

来源：Nature Communications, 2018, 9(1): 2278.

DOI：10.1038/s41467-018-04555-4

<jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>P</jats:italic> &lt; 5.0 × 10<jats:sup>−8</jats:sup>), including 14 novel, of which 9 replicate (near <jats:italic>FMNL2</jats:italic>, <jats:italic>PDE7B</jats:italic>, <jats:italic>TMTC2</jats:italic>, <jats:italic>IKZF2</jats:italic>, <jats:italic>CADM2</jats:italic>, <jats:italic>DGKG</jats:italic>, <jats:italic>ANKH</jats:italic>, <jats:italic>EXOC2</jats:italic>, and <jats:italic>LMX1B</jats:italic>). Functional studies support intraocular pressure-related influences of <jats:italic>FMNL2</jats:italic> and <jats:italic>LMX1B</jats:italic>, with certain <jats:italic>Lmx1b</jats:italic> 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.</jats:p>

• 出版日期2018-6-11