April 2009
Volume 50, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2009
Genetic Profile for Five Common Variants Associated With Age-Related Macular Degeneration in Densely Affected Families: A Novel Analytic Approach
Author Affiliations & Notes
  • L. Sobrin
    Retina/Uveitis, Harvard Med Mass Eye & Ear Infirmary, Boston, Massachusetts
  • J. B. Maller
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
  • B. M. Neale
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
  • R. C. Reynolds
    Ophthalmology, Tufts Medical Center, Boston, Massachusetts
  • J. A. Fagerness
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
  • M. J. Daly
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
  • J. M. Seddon
    Ophthalmology, Tufts Medical Center, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  L. Sobrin, None; J.B. Maller, None; B.M. Neale, None; R.C. Reynolds, None; J.A. Fagerness, None; M.J. Daly, None; J.M. Seddon, None.
  • Footnotes
    Support  NIH Grant EY16335-02; NIH Grant EY11309; Research to Prevent Blindness; Foundation Fighting Blindness; Massachusetts Lions Research Fund, Inc; the Macular Degeneration Research Fund, Tufts Medical Sch
Investigative Ophthalmology & Visual Science April 2009, Vol.50, 1593. doi:
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    • Get Citation

      L. Sobrin, J. B. Maller, B. M. Neale, R. C. Reynolds, J. A. Fagerness, M. J. Daly, J. M. Seddon; Genetic Profile for Five Common Variants Associated With Age-Related Macular Degeneration in Densely Affected Families: A Novel Analytic Approach. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1593.

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

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Abstract

Purpose: : About 40% of the genetic variance of age-related macular degeneration (AMD) can be explained by common variation at five common single nucleotide polymorphisms (SNPs). The purpose of this study was to evaluate the degree to which these known variants explain the clustering of AMD in a group of densely affected families.

Methods: : A total of 1265 probands and siblings from 322 families with a proband with advanced AMD were genotyped for five SNPs in four genes that were previously found to be associated with AMD: Complement Factor H, Complement Component 2, Complement Factor B, and LOC387715/HTRA1. We used the statistical package R for the creation of a comparison population of families. Empirical p-values were calculated based on the simulation results. In addition, the distribution of the individual families’ genotypic loads was plotted against their expected mean genotypic loads from the simulation. The slope of the line for individual families and the 2.5% and 97.5% confidence intervals for the mean genotypic load for each family configuration were determined.

Results: : For most family configurations, there was no statistically significant difference between the actual average genotypic load and the average genotypic load from the simulation. However, the actual average genotypic load was lower than expected by the simulation in families with 4 out of 4 and 4 out of 5 siblings affected (p=0.05 and p=0.020, respectively). For the distribution of the mean genotypic loads for the individual families in relation to the expected average genotypic load from the simulation, most of the families’ genotypic loads fell within the 95% confidence interval. There were 28 outlying families, which was slightly higher than what would be predicted by chance alone. The slope of the line for the individual families’ genotypic loads vs. mean genotypic loads, by family configuration, was 0.4594. This was smaller than expected from the simulation to a statistically significant degree (p<0.001).

Conclusions: : Although the genotypic load for most of our AMD families did not deviate significantly from the expected load, we did identify some families, particularly in the 4 out of 4 and 4 out of 5 affected configurations, which had a lower than expected genotypic load. Given that these densely affected families may harbor rare, more penetrant variants for AMD, linkage analyses and resequencing targeting these families may be an effective approach to finding additional implicated genes.

Keywords: age-related macular degeneration • genetics • retina 
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