Simple versus complex genetic diseases

Until recently, genetics in equine medicine has focused primarily on single-gene (monogenic) diseases, where a mutation within a single gene that is inherited in a simple Mendelian pattern (autosomal dominant, autosomal recessive, sex-linked traits) results in significant disease in the affected individual. For example, Hyperkalemic Periodic Paralysis (HYPP)^1,2, Severe Combined Immunodeficiency (SCID)³, Overo Lethal White Syndrome (OWLS)⁴, Junctional Epidermolysis Bulosa (JEB) in Belgians (J.D. et al.) and Saddlebreds⁶, Glycogen Branching Enzyme Deficiency (GBED)⁷, Malignant Hyperthermia (MH)⁸, Hereditary Equine Regional Dermal Asthenia (HERDA)⁹, type 1 Polysaccharide Storage Myopathy (type 1 PSSM)¹⁰, Lavender Foal Syndrome (LFA)¹¹, and Fell Pony Syndrome (Foal Immunodeficiency Syndrome, FIS)¹². All of these diseases are considered single gene diseases, and although this list is short these diseases are surprisingly prevalent, due to selective breeding practices that can result in a common ancestor disseminating the same genetic mutation to numerous offspring. If highly popular sires carry a genetic mutation, their descendants can very rapidly produce many thousands of related offspring carrying that same mutation.

In the simplest monogenic diseases, the disease gene genotype unambiguously predicts the presence or absence of the disease phenotype. For example, in an autosomal recessive disease, a horse must have 2 copies of the mutation to have disease and in an autosomal dominant disease only one copy of the mutation is needed to cause disease (see Mendelian inheritance). However, even for single gene diseases, this relationship is not always clear. For example, the phenotype of horses with the GYS1 mutation responsible for type 1 PSSM varies considerably from subclinical disease to severe rhabdomyolysis (muscle damage and muscle cell death), which can result in complications that lead to death of the animal. The role of environmental factors in this disease has also been well established. Horses with PSSM can sometimes be managed clinically with a high-fat, low-starch diet and consistent daily exercise 13. Further, we have demonstrated that horses with the GYS1 mutation that have a concurrent mutation in a second gene, the same gene responsible for MH, have a clinically more severe phenotype that is less responsive to management 14. Thus, although type 1 PSSM is the result of a single gene autosomal dominant mutation, management of this disease is complicated by both environmental and additional genetic factors.

Many other genetic traits are caused by the effects of multiple genes (polygenic traits) or the combination of more than one gene and environmental factors (multifactorial traits). The inheritance and expression of these traits is complex, although it can be demonstrated that they have some a genetic component. Examples of polygenic and/or multifactorial traits in equine medicine include Recurrent Exertional Rhabdomyolysis (RER), Equine Metabolic Syndrome (EMS), Osteochondrosis/Osteochondrosis Dessicans (OC/OCD) and equine asthma. Quantitative traits, or those traits that are measured on a continuous numerical scale, are also often multifactorial traits. Alleles (or mutations) that contribute to multifactorial disorders can have either disease-causing or protective roles in the overall disease process.

Polygenic disease should not be confused with allelic heterogeneity, where different alleles within the same gene can each cause disease independently. Allelic heterogeneity is common in human monogenic disease, for example many different mutations in the CTFR gene that cause Cystic Fibrosis or different mutations in the dystrophin gene that cause Duchenne Muscular Dystrophy. An equine example of allelic heterogeneity is the multiple mutations in the aggrecan gene (ACAN) that cause dwarfism in Miniature horses¹⁵.

While monogenic diseases are common in domestic animal populations when compared to human populations, monogenic diseases only account for a relatively small portion of genetic diseases in veterinary practice. Multifactorial diseases account for a much larger portion of equine practice. This may be due in part to the fact that the underlying genetic predispositions to these diseases go unnoticed when environmental conditions are favorable, or that genetic predisposition is simply not recognized as a component of the disease, resulting in genetically-susceptible individuals remaining in the breeding population.  Thus, monogenic diseases have had a large impact on the health of a relatively small number of equine patients, whereas polygenic and multifactorial diseases tend to have a moderate impact on the health of a larger number of patients.

In equine patients, the detection of disease-causing mutations in monogenic disease is typically pursued as a definitive diagnosis, or as part of pre-breeding, or pre-purchase assessments. In cases such as PSSM and HYPP, where appropriate management (diet and exercise) and treatment (acetazolamide) are available, genetic testing allows for preventative care. Similarly, identification of the underlying genetic predispositions in the multifactorial diseases, such as equine asthma or EMS, will allow for the identification of susceptible individuals and the implementation of preventative measures prior to clinical manifestation of disease.

Inheriting a genetic mutation in a complex disease does not guarantee that the individual will develop the disease; it just means that they are at increased risk. A common example of a complex disease in humans is the BRCA (1 or 2) mutation. If a woman inherits a BRCA mutation, she has a five times greater risk of developing breast cancer. The BRCA mutation is not a guarantee that breast cancer will develop, other factors including diet, exercise and overall health play a role in whether or not cancer develops. However, because of the increased risk, women with a BRCA mutation are screened for breast cancer more frequently starting at a younger age.

Underlying genetic predispositions are also important in understanding the susceptibility to infectious diseases. The classic example of this in human medicine is the protective effect of a mutation in the CCR5 gene. Humans homozygous for this CCR5 mutation are completely resistant to HIV infection¹⁶. In the future, identification of genetic bases for susceptibility of horses to infections, for example Rhodococcus equi infections, could help clinicians identify susceptible individuals on a farm where R. equi is endemic.

Beyond disease diagnosis and genetic susceptibility, a patient’s genetic make-up will also eventually be used to predict a patient’s response to certain drugs. It is estimated that 20-95% of the variation in drug disposition and effect in human patients is due to genetic effects. And, variation in responses to certain drugs such as prednisone and omeprazole is known in horses.  This impact of genetic factors has lead to the formation of an entirely new discipline term “pharmacogenetics.”