Identifying Rare Genetic Variants Leading to Advanced AMD

Margaret A Pericak-Vance, PhD
University of Miami (Miami, FL, United States)

Co-Principal Investigators

William A Scott, PhD
University of Miami
Year Awarded:
Grant Duration:
July 1, 2011 to June 30, 2013
Macular Degeneration
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Southeastern
Margaret A Pericak-Vance, PhD

Whole Exome Sequencing in Age-Related Macular Degeneration


Despite recent success finding common genetic variations that influence risk of developing AMD, many causes remain to be identified. One under-studied area is the role of rare genetic variation in determining risk of developing AMD, and recent technological advances have enabled large-scale DNA sequencing efforts to find these rare variations. We seek to understand the role of rare genetic variations in determining risk for AMD by examining a set of individuals with advanced AMD but none of the known genetic risk factors, and a set of individuals without AMD at an older age despite having one or more of the known genetic factors.


There are many genes that are linked to the risk of developing age‐related macular degeneration (AMD), but there is still room to discover more. In this proposed project, Drs. Margaret Pericak‐Vance, William Scott, and colleagues will study the DNA of two groups of people that should increase their chances of finding new risk genes. One group has advanced AMD despite not having any of the known risk variants in the genes associated with AMD risk (including CFH and ARMS2) and the other group doesn’t have AMD despite having known risk variants in these genes. These researchers will use new gene reading techniques to look at the “whole exome” or the DNA spelling of the most‐used books in a person’s genetic library. Cataloguing the gene changes in both sets of people with AMD will lead to better understanding of how this disease starts and give clues to future preventions and treatments.

Research Updates

Dr. Pericak-Vance’s and Dr. Scott’s team has competed 100% of the experiments designed for year 1 of this project. Whole exome sequencing (WES) has been successfully completed for four Amish families with suspected inherited AMD (a total of 15 individuals) and for 40 individuals of Caucasian descent with “sporadic” AMD (where there are no other reported cases of AMD in their family) and control healthy individuals. Findings from the four Amish families were analyzed with bioinformatics computer programs, and had their sequences confirmed/validated through a second method. A total of 26 genetic changes or “rare variants” (17 novel and 9 known) were identified. In the future, these rare variants will be checked for their presence in the DNA from a larger group of individuals with AMD.

About the Researcher

Margaret A. Pericak-Vance, Ph.D., is a founding fellow of the American College of Medical Genetics and a board-certified Ph.D. medical geneticist. She is a global leader in the genetics of common diseases. She has a particular interest in neurogenetic diseases such as Alzheimer’s disease. Her research group’s seminal 1993 paper describing the genetic role of APOE in Alzheimer disease remains one of the most-cited papers in biomedical research. Currently, she chairs the analysis committee of the Alzheimer Disease Genetics Consortium whose recent efforts have had a major impact on our understanding of the genetic architecture of late-onset Alzheimer disease (Naj et. al., Nat. Gen. 2011). In addition to her AHAF award, Dr. Pericak-Vance was named to the “Century Club: 100 People to Watch as We Move to the Next Millennium” by Newsweek magazine. She also received the international “Louis D” Scientific Prize from the Institut de France’s Académie des Sciences for her AD APOE discovery. Her other research honors include: the Hauptman-Woodward Pioneer of Science in 2004, the McKnight Memory and Brain Disorders Award and Alzheimer’s Association Zenith Award in 2001 and the Alzheimer’s Association T.L.L. Temple Foundation Discovery Awards for Alzheimer's Disease Research in 1998. She was elected to the Institute of Medicine in 2004. In 2011, she was honored with the Provost’s Award for Scholarly Activity at the University of Miami and the Alzheimer’s Association Bengt Winblad Lifetime Achievement Award. In 2012, she was named a fellow of the American Association for the Advancement of Science, for her distinguished contributions to the field of genetics.


D’Aoust L, Hoffman J, Cummings Ac, Agarwal A, Brantley MA, Kovach JL, Schwartz SG, Scott WK, Pericak-Vance MA, Haines JL. Genome-Wide Study for Age-related Macular Degeneration in the Amish. Poster Presentation at 2012 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, Ft. Lauderdale, Florida, May 5-10, 2012. (3301/A446).

Ayala-Haedo JA, Scott WK, Cade W, Gallins PJ, Agarwal A, Schwartz SG, Kovach JL, Wang G, Haines JL. Pericak-Vance MA. Exome Sequencing in Multiplex AMD Families. Poster Presentation at 2011 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, Ft. Lauderdale, Florida, May 1-5, 2011. (#5224/D1108)
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