Ophthalmic Genetics: Title and subTitle BreakAt the Dawn of Discovery

Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.—Winston Churchill, 1942

Ophthalmic genetics is undergoing a major transformation. The role of heredity in ocular disease has been explored for more than 100 years, with the early focus on conditions that could be identified specifically as straightforward mendelian inherited disorders. In these disorders replication of the trait is easily observed, and clear-cut probabilities of transmission can be readily calculated. The discovery of DNA and advances in DNA-related technologies have led to significant advances in the genetics of all diseases (and traits), including those affecting the visual system. Progress in the field has accelerated, aided by the completion of the Human Genome Project in 2003 and the International HapMap Project in 2005. The Human Genome Project aimed to identify all of the approximately 20 000 to 25 000 genes in human DNA and to determine the sequences of the 3 billion base pairs that make up human DNA.^{1 - 2} The HapMap Project's goal was to develop a haplotype map of the human genome, the HapMap, which describes the common patterns of human DNA sequence variation, thus providing a necessary infrastructure for single nucleotide polymorphism–based genetic analyses.³ Because of the success of these projects, the research community now has access to a vast amount of publicly available genetic data and new tools that facilitate novel and efficient approaches to study the genetic contribution to heritable diseases. This explosion of information has heightened our appreciation of the role of genetics in human disease and has stimulated the development of new research fields such as genomics, proteomics, computational biology, and bioinformatics. Furthermore, existing research methods in epidemiology and biostatistics have expanded to address the extensive complexities of the newly available data. As a result, the approach to genetic research has experienced a paradigm shift from single investigator–initiated projects to investigations requiring collaborative multidisciplinary teams of health care professionals, molecular biologists, epidemiologists, biostatisticians, and other scientists who merge their basic science and clinical and statistical expertise to translate basic science into clinical and population-based domains.

The availability of new genetic approaches for both mendelian and complex diseases has made it possible for increasing numbers of investigators in the ophthalmic research community to take full advantage of the potential to explore the role of genetic factors in a wide range of eye conditions. Using data from the HapMap Project, vision researchers applied these new techniques to successfully identify an association between the complement factor H gene and age-related macular degeneration, a landmark discovery in ophthalmic genetics. Since the first reports by 3 independent research groups in May 2005,^{4 - 6} several additional reports, including 3 in this issue,^{7 - 13} have confirmed or expanded on this finding and have sought to evaluate further related associations and gene-environment interactions.

The idea for this theme issue was conceived as a result of the many advances in ophthalmic genetics and the rapidly increasing number and complexity of articles appearing in the literature that involve genetics. These recent articles include information from a variety of disciplines that use new methods and technical terms, presenting challenges to our readership in their interpretation and appropriate application for clinical practice. In an effort to provide our readers with the necessary tools to help decipher the relevance of these recent developments, it is timely to publish 2 issues devoted to ophthalmic genetics: this issue focuses on complex ocular diseases, and the February issue will focus on ocular diseases with mendelian inheritance. The purpose of these issues is to (1) provide an overview of the status and future directions of this rapidly changing field and (2) bring the community up to date in the interpretation of genetic results of studies using recent advances and methods. For these issues we invited separate reviews on the genetics of age-related maculopathy, glaucoma, refractive error, cataract, strabismus, and inherited retinal degenerations. Another highlight in this issue includes an invited article that provides valuable insight into the current approaches and tools needed to evaluate findings from genetic studies (eg, statistical genetics and genetic epidemiology) and suggests how these methods can be used in the future to advance our understanding of the etiology, pathogenesis, and treatment of different eye conditions. The February issue will include an article providing a perspective on the contributions of recent genetic advances to our understanding of inherited retinal degenerations and age-related macular degeneration, as well as the potential for and limitations of genetic information, another article on molecular diagnosis and genetic counseling that provides health care professionals with some guidelines for communicating genetic risks to the average patient, and a separate article that presents a new paradigm for genetic testing of inherited eye diseases. Additionally, a glossary of commonly used terms is included in the online version of this issue to assist readers with specific terms, thereby enhancing the value of this issue as an educational tool. We hope that the balance of articles in these 2 issues will provide a framework for our readership to interpret the current status of the field as well as to gain insight into recent advances and future directions.

This is an exciting period for ophthalmic genetics. In addition to providing some answers, the plethora of new genetic information has led to increased complexity and raised new questions. As a result, there is now a strong and urgent need for new approaches to translate the information from the Human Genome Project to clinical practice. The process of unraveling causes of disease that may substantially influence disease incidence or treatment is only beginning. The enthusiasm for the accomplishments of the Human Genome and HapMap projects is well justified; the information they provide offers real potential for targeting particular genes for specific eye conditions and identifying high-risk groups for interventions, including gene therapies. Although this information is necessary, it only partially defines the causal chain of factors leading to disease onset or disease progression, particularly for complex diseases. As an example, one can consider the high frequency of individuals with the “high-risk” complement factor H variant, many of whom will never develop age-related macular degeneration. Identified genes or regions may also be directly associated with a disease or may increase susceptibility through, for example, gene-gene or gene-environment interactions, increasing the complexity of sorting out the causal chain for disease.

As advances in genetic contributions to disease become clarified, knowledge of specific genes in the future may become useful for screening purposes, particularly if treatments become available and early intervention is deemed beneficial. With the ability to target high-risk groups, future studies can be designed to focus on individuals who carry the identified genes, thus improving potential for the success of these studies and the applicability of their findings.

The substantial research activity in ophthalmic genetics and the increased collaboration across clinical and research disciplines increase the likelihood of successfully identifying genes associated with specific ocular conditions. However, the gap between gene identification and various outcomes such as improved understanding of causes of disease, development of suitable treatments, and improved ability to decrease disease risk or slow progression remains considerable. In addition, the information potentially available on an individual's genetic composition or disease risk raises new ethical, legal, and moral concerns. It will be increasingly important for the ophthalmic community to understand and interpret these new findings as they become available, fully recognizing how they can be translated into clinical practice and what their limitations are. These theme issues are one step toward that goal.

We are most grateful to our many colleagues who have contributed articles to these special issues and who have served as reviewers for these manuscripts. We offer this excellent collection of articles to provide the ophthalmic community with an up-to-date guide to the rapidly changing field of ophthalmic genetics.

Correspondence: Dr Hyman, Department of Preventive Medicine, Stony Brook University and Medical Center, Bldg HSC, Floor L3, Suite 086, Stony Brook, NY 11794 (lhyman@notes.cc.sunysb.edu).

Financial Disclosure: None reported.

Additional Materials: A glossary of commonly used ocular genetics terms is available here.