Humans have 23 pairs of chromosomes with two copies of most genes, one donated from the maternal side and one donated from the paternal side. Each location that generates a protein is termed a gene, and each gene consists of numerous base pairs of DNA that may have mutations or single nucleotide substitutions (SNPs). The term exon refers to specific regions of DNA that encode for messenger RNA. Genes have their own taxonomy. They may be grouped into families or into functional classes. Gene families may be regulatory or structural. Genes have alternate forms called alleles. Alternate alleles at a single genetic locus are known as polymorphisms.

The first polymorphism to be described in humans was for the ABO blood groups in 1901 [28]. Millions of polymorphisms have been subsequently identified in human populations with the advent of whole genome sequencing. Polymorphisms may be considered “usually normal” variations; they are not necessarily indicative of pathology. Linkage data (the phenotype data being gathered from medical and research reporting) following transmission of a disease gene with specific chromosome markers through a family of affected individuals can be used to narrow the initial field of more than 20,000–25,000 human genes to a chromosomal subregion containing several hundred genes.

The three basic modes of inheritance are autosomal dominant in which a variant gene passed from one parent generates a unique protein whenever it is present, autosomal recessive in which two copies of the same variant gene have to be present before it is expressed, and sex-linked, in which case it may appear if an individual is male, XY, but not if the individual is female, because they have two X chromosomes.

Mutations occurring in DNA result in phenotypes that include both aberrant RNA and protein products. A phenotype is any characteristic or trait of an organism (e.g., its morphology), development, or biochemical properties. Conceptually, phenotypes result from gene expression as well as environmental factors and possible interactions of the two. In glaucoma, environmental factors affecting glaucoma might include oscillations and pulsations that may be of physiologic importance, nutrition, and blood flow.

There are several major categories of mutation including the following:

Mutations may arise de novo in germ cells and appear without warning in an affected individual (e.g., as is sometimes seen in pediatric glaucoma). Most de novo mutations are found in X-linked recessive conditions and in severe conditions with autosomal dominant inheritance. If the affected individual reproduces, the new mutation will be inherited according to the usual rules of Mendelian transmission. Mutations may also arise in differentiated tissues.

Targeted mutagenesis (artificial genetic mutation) is a laboratory technique in which mutations are made to elucidate the function of a particular gene and has been successfully used in mice. This procedure, called gene knockout technology, is useful and many gene knockouts have been created. Most common human diseases, including glaucoma, are thought to result from mutations in multiple genes, and the knockout technique may be particularly useful in studying how particular combinations of mutations interact with one another. Because of the genetic differences between mice and humans, some mutations known to cause disease in humans do not result in a similar phenotype in mice. Thus, knockouts are not always informative.

There are a number of strategies for finding genes causing human disease:

Although the initial discoveries of glaucoma loci appeared to be monogenic, very few human diseases are monogenic, and currently the prevailing wisdom is that glaucoma is highly complex and that a variety of pathological processes are involved. It is likely that each of the open-angle glaucomas have different yet subtle phenotypic characteristics. The direct implication of this is that some may respond better to medicines, while others ought to have surgery because of the aggressive nature of the disease, since the diseases may vary in terms of their time course and their tendency to progress. Other major phenotypic differences may exist with regard to corneal thickness, diurnal fluctuation, and appearance of the optic nerve head (perhaps detected by an optic nerve analyzer before clinical glaucoma is actually detected) (Table 4.2).

Transcription factors are one example of a functional class of genes that have potential importance for glaucoma. These are genes that alter the production of messenger RNA by other genes. Transcription factors bind directly to promoters that are specific DNA sites in the genes that the factors regulate. These factors are proteins that bind DNA sequence and thereby control the transfer of genetic information from DNA to RNA. They may either do this alone or in combination with other proteins in the form of a complex. There are many genes that encode for DNA-binding transcription factors. Technology at the time of this writing is about to make array testing of many transcription factors available and, in so doing, may substantially transform our understanding of glaucoma (Genefac, Portland Oregon). A second important type of gene is the homeobox genes. The homeobox is a 180 base pair DNA sequence that is highly conserved among the genes of all vertebrates. A third important type of gene is the zinc-finger gene. Here the DNA-binding motif consists of a small loop of amino acids held together by a single zinc atom.

Single nucleotide polymorphisms (SNPs) are variations in single nucleotides resulting in a DNA sequence variation that may generate complicated protein changes and may themselves be associated with diseases. Numerous SNP associations have been found with diseases, and it is now possible to do a cheek swab test and submit ones’ own DNA for testing to any of several services available on the Web (e.g., http://​www.​navigenic.​com and http://​www.​23andMe.​com). Indeed, some of these services actually provide an annual subscription to provide updates as clinically important SNPs are found. At the time of this writing, none offer glaucoma-related testing but that is likely to change in the near future. SNPs can be assigned a minor allele frequency, the lowest frequency at a locus that is observed with a particular population. An SNP allele that is found in one geographic or ethnically defined group may be much rarer than in another. SNPs found in a coding sequence will not always change the amino acid sequence of the protein that is produced, since there is some degeneracy in the genetic code. An SNP in which both forms lead to the same peptide sequence is termed synonymous. If a different polypeptide is produced, as in the case of exfoliation, then it is termed nonsynonymous. SNPs that are not in specific protein coding regions may still have substantial consequence for transcription factor binding and for gene splicing. While it is obvious that DNA sequences can affect how humans respond to chemical drugs and vaccines, they are useful in comparing groups of individuals with specific diseases [29].

Kass and Becker [1] were among the first to observe a relationship between family history and glaucoma and focused their research on cup-to-disc ratio, elevated pressure, and glucocorticoid response. Their early investigations into hereditary aspects of glaucoma noted that there was a relationship between family history and the presence of glaucoma but that it seemed to defy simple genetic analysis. Becker, and later Armaly [30], found that glucocorticoid treatment re-elevated IOP more often in glaucoma patients than in other individuals. Testing of family members showed that this response was usually inherited as an autosomal recessive trait. Subsequently, Polansky [31] theorized that the mutations of these genes in the trabecular meshwork were associated with a corticoid steroid response. He called the specific induced proteins “trabecular meshwork inducible glucocorticoid response protein” (TIGR), the same protein later being termed “myocilin.” Initially, this protein was thought to be associated uniquely with juvenile glaucoma, but, later, it was found to be associated with up to 3 % of the glaucomas in the general population. The myocilin gene was subsequently mapped to chromosome 1. Since then, a number of additional genetic loci have been identified that are associated with open-angle glaucoma. They all appear to be autosomal dominant.

Open-angle glaucoma is the most common form of glaucoma affecting more than 33 million people worldwide [32]. Although many types of subdivisions are possible, for our purposes, open-angle glaucomas may be divided into adult or primary open-angle glaucomas (POAG), juvenile open-angle glaucomas (JOAG), and low-tension glaucomas (LTG) – also referred to as normal tension glaucoma. The reasons for the distinction between LTG and POAG are addressed elsewhere in the text (see Chaps.​ 12 and 13), but the distinction may be somewhat artificial, especially from a genetic perspective. However, the lack of distinction between JOAG and POAG is very important. JOAG is defined as having an earlier age of onset, in the range of age 3 to age 25, as discrete from pediatric glaucoma, which is discussed in Chap.​ 22. JOAG seems to be an autosomal dominant disorder, whereas POAG seems to be an inherited as autosomal dominant with incomplete penetrance.

The first gene found for open-angle glaucoma, GLC1A or myocilin, has both juvenile and adult phenotypes, depending on which mutation is present. At the time of this writing, there are 14 well-documented chromosomal loci for POAG that are listed by the Human Genome Organization (HUGO), which can be accessed at http://​www.​genenames.​org/​index.​html. Most loci were elucidated using genetic linkage analysis in families. Table 4.3 lists selected loci and genes for open-angle glaucoma, although it is not comprehensive as the list continues to expand, and in some instances, loci designations have been claimed without full publication or disclosure at the time of this writing, but it is quite likely that this list will lengthen and that additional details will be available in the near future.