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

Authors

Lars G. Fritsche
Wilmar Igl
Jessica N. Cooke Bailey
Felix Grassmann
Sebanti Sengupta
Jennifer L. Bragg-Gresham
Kathryn P. Burdon
Scott J. Hebbring
Matthew P. Johnson, The University of Texas Rio Grande Valley
John Blangero, The University of Texas Rio Grande Valley

Document Type

Article

Publication Date

2-2016

Abstract

Advanced 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, most rare, protein-altering variant. 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. While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9 (difference-P = 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.

Comments

Original published version available at https://doi.org/10.1038/ng.3448

Recommended Citation

Fritsche, L. G., Igl, W., Bailey, J. N. C., Grassmann, F., Sengupta, S., Bragg-Gresham, J. L., ... & Zhang, K. (2016). A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nature genetics, 48(2), 134-143. https://doi.org/10.1038/ng.3448

Publication Title

Nature Genetics

DOI

10.1038/ng.3448

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics