March 2012
Volume 53, Issue 14
ARVO Annual Meeting Abstract  |   March 2012
Meta-analysis Of Genome-wide Association Studies Identifies 19 Loci Associated With AMD Risk
Author Affiliations & Notes
  • Matthew C. Schu
    Dept. of Medicine (Biomedical Genetics), Boston University, Boston, Massachusetts
  • Wei Chen
    Department of Biostatistics, University of Michigan, Ann Arbor, Massachusetts
  • Lars G. Fritsche
    Institute of Human Genetics, University of Regensburg, Regensburg, Germany
  • Yi Yu
    Ophthalmology, Tufts Medical Center, Lexington, Massachusetts
  • Brian Yaspan
    Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee
  • AMD Gene Consortium
    Dept. of Medicine (Biomedical Genetics), Boston University, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  Matthew C. Schu, None; Wei Chen, None; Lars G. Fritsche, None; Yi Yu, None; Brian Yaspan, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 2259. doi:
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      Matthew C. Schu, Wei Chen, Lars G. Fritsche, Yi Yu, Brian Yaspan, AMD Gene Consortium; Meta-analysis Of Genome-wide Association Studies Identifies 19 Loci Associated With AMD Risk. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2259.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : In industrialized countries, advanced Age-Related Macular Degeneration (AMD) is the most common form of blindness in older adults. Previous genome-wide association studies (GWAS) have identified several AMD risk loci thus providing clues about the biological mechanisms underlying the disease. To extend these insights, we conducted large scale GWAS by combining the resources of the International AMD Genetics Consortium.

Methods: : Over 2.5 million SNPs were genotyped or imputed in 7,650 advanced AMD cases and 51,812 controls from 15 study samples of European and Asian ancestry. Association of each SNP with AMD risk was tested in each dataset using a logistic regression model adjusting for population substructure. Results across datasets were combined by meta-analysis using an inverse variance approach. One SNP from each of the top-ranked (p < 10-5) regions was genotyped in 18 independent samples containing a total of 9,251 AMD cases and 8,036 controls, and was similarly analyzed for replication. The genes implicated by genome-wide significant findings in the meta-analysis were studied further using Ingenuity Pathway Analysis software to identify over-represented biological pathways.

Results: : One SNP from each of the 32 top regional associations from the discovery GWAS was tested for replication. Of these, 19 loci were confirmed with evidence of genome-wide significance(p-values ranging from 4×10-540 - 2×10-8). This study confirmed all 12 previously established AMD risk loci and revealed 7 other loci reaching genome-wide significance: COL8A1/FILIP1L(p=4×10-13), IER3/DDR1(p=2×10-11), SLC16A8(p=3×10-11), TGFBR1(p=3×10-11), RAD51B(p=9×10-11), MIR548A2(p=5×10-9), and B3GALTL(p=2x10-8). Pathway analysis seeded with the 19 genome-wide significant loci revealed a significant over-representation of pathways regulating complement system activity, lipid metabolism and inhibition of angiogenesis.

Conclusions: : These gene associations provide new insights about disease pathogenesis and useful information for developing more accurate AMD risk prediction profiles. Our results double the number of loci outside the complement pathway implicated in AMD, and should lead to important insights about the biological processes underlying the disease. These loci are also potential targets for the development of better strategies for prevention and new therapeutic approaches.

Keywords: age-related macular degeneration • genetics 

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