Kwong Alan, Zawistowski Matthew, Fritsche Lars G, Zhan Xiaowei, Bragg-Gresham Jennifer, Branham Kari E, Advani Jayshree, Othman Mohammad, Ratnapriya Rinki, Teslovich Tanya M, Stambolian Dwight, Chew Emily Y, Abecasis Gonçalo R, Swaroop Anand
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, United States.
Southwestern Medical Center, University of Texas, 5323 Harry Hines Blvd, Dallas, TX 75390, United States.
Hum Mol Genet. 2024 Feb 1;33(4):374-385. doi: 10.1093/hmg/ddad189.
Genome-wide association studies have contributed extensively to the discovery of disease-associated common variants. However, the genetic contribution to complex traits is still largely difficult to interpret. We report a genome-wide association study of 2394 cases and 2393 controls for age-related macular degeneration (AMD) via whole-genome sequencing, with 46.9 million genetic variants. Our study reveals significant single-variant association signals at four loci and independent gene-based signals in CFH, C2, C3, and NRTN. Using data from the Exome Aggregation Consortium (ExAC) for a gene-based test, we demonstrate an enrichment of predicted rare loss-of-function variants in CFH, CFI, and an as-yet unreported gene in AMD, ORMDL2. Our method of using a large variant list without individual-level genotypes as an external reference provides a flexible and convenient approach to leverage the publicly available variant datasets to augment the search for rare variant associations, which can explain additional disease risk in AMD.
全基因组关联研究在发现与疾病相关的常见变异方面做出了巨大贡献。然而，遗传因素对复杂性状的影响在很大程度上仍难以解释。我们通过全基因组测序对2394例年龄相关性黄斑变性（AMD）患者和2393例对照进行了全基因组关联研究，共检测了4690万个遗传变异。我们的研究在四个位点揭示了显著的单变异关联信号，以及在CFH、C2、C3和NRTN中基于基因的独立信号。利用外显子聚合联盟（ExAC）的数据进行基于基因的检测，我们证明了CFH、CFI以及AMD中一个尚未报道的基因ORMDL2中预测的罕见功能丧失变异的富集。我们使用大量无个体水平基因型的变异列表作为外部参考的方法，提供了一种灵活便捷的途径，利用公开可用的变异数据集来加强对罕见变异关联的搜索，这可以解释AMD中额外的疾病风险。
