Sunday, February 14, 2016

Rare Diseases are Monogenic; Common Diseases are Polygenic (mostly)

"Most [rare diseases] result from a dysfunction of a single pathway due to a defective gene. Understanding the impact of a single defect may therefore yield insights into the more complex pathways involved in common diseases which are generally multifactorial" - Segolene Ayme and Virginie Hivert, in "Report on rare disease research, its determinants in Europe and the way forward," 2011 (1)

In 1865, Mendel published his laws of inheritance, which were universally ignored until about 1900. In 1915, Thomas Hunt Morgan integrated Mendel's laws into what was then known about the role of chromosomes, as carriers of genetic material. In the 1950s, when DNA was found to be the carrier molecule of genetic information, the concept of Mendelian genetics was once more integrated into molecular biology.

Back in 1909, nearly a half century before we understood that our inheritance was encoded in molecules of DNA, scientists knew that inborn errors of metabolism had a pattern of inheritance much like the pattern reported by Mendel for his pea garden (2).

Mendelian inheritance, in one sentence, comprises the now familiar genetic diseases inherited from one or both parents with patterns typical of autosomal dominant, autosomal recessive, or with linkage to the X or Y chromosome. Mendelian inheritance is the low-hanging fruit of clinical genetics. When the inheritance is Mendelian, the cause of the disease is monogenic.

Non-Mendelian inheritance is a murky topic. Whenever a biological concept is named for what it is not (i.e., not Mendelian), rather than being named for what it is, you can expect to encounter a certain degree of confusion and ignorance. Suffice it to say that a disease has a non-Mendelian pattern if knowledge of disease occurrences in ancestors cannot yield the simple inheritance ratios for offspring, that Mendel might have predicted. In general, diseases that exhibit non-Mendelian inheritance occur in family clusters, but predicting which offspring will be affected is impossible.

We shall see in other blog posts that several biological processes can account for a non-Mendelian pattern of inheritance, but polygenic inheritance plays a role in most of the examined common diseases. For now, let us concentrate on the inheritance patterns of polygenic diseases.

A polygenic disease is caused by variations in numerous genes that work in concert to produce a disease or to heighten susceptibility to disease. Imagine that a common disease is caused by a set of 10 variant genes that, together, confer susceptibility to an environmental toxin. How would you predict that an offspring will develop the disease? If the gene variation were rare, each variant might have about a 50% chance of appearing in the offspring's DNA, but there are ten genes involved, and the chance of all of them being passed to the offspring would be small. If the variant were common within the population, then inheritance odds would increase, and we would need to take into account homozygosity (i.e., the gene on both chromosomes from one parent being variant), as well as the likelihood that the other parent carried the gene varation. If one of the ten gene variants were necessary to produce disease, while the other nine genes had less effect, then the calculations would change. If there were alternate gene variants that could substitute for, supplement, or modify any of the original ten gene variants, then the calculations would change again. In point of fact, the inheritance of polygenic diseases defies prediction; it is all too complex.

How many genes are necessary to produce a non-Mendelian pattern of inheritance? Just two may do. Bruning and coworkers developed a digenic model of type 2 diabetes in mice. Like the common disease in humans, diabetes arose in offsprings in an age-dependent manner, and the pattern of inheritance was non-Mendelian (3).

The rare disease Bardet-Biedl syndrome is characterized obesity in infancy, retinal dystrophy, polydactyly, and abnormalities of multiple organs. In most cases, Bardet-Biedl syndrome is a monogenic rare disease with an autosomal recessive pattern of inheritance. In a small percentage of cases Bardet-Biedl syndrome is polygenic, and does not exhibit the usual Mendelian) pattern of inheritance. These exception cases are caused by three mutations occurring at two of the loci known to be associated with the syndrome (4).

In a well controlled experiment, in a simple yeast cell system, Gerke and coworkers tried to predict outcome for a set of four gene variants known to influence a specific yeast phenotype, in this case, yeast sporulation efficiency (5). As expected, genotype could not predict phenotype; four genes made the system too complex to pre-determine sporulation efficiency in progeny.

Rule - The genetic component of common diseases is polygenic
Brief Rationale - In the past several decades, medical scientists have found thousands of rare diseases, each with a monogenic cause. Genome-wide association studies indicate that most of the common diseases are highly polygenic.

Every good scientist knows that the absence of a positive finding can never constitute proof of a negative finding. Nonetheless, there is a long, unbroken tradition of searching for, and failing to find, a monogenic cause for any of the common diseases. Accumulated experience would suggest that the common diseases of clinical importance are all polygenic.

Quibblers might argue that Glucose-6-phosphate dehydrogenase deficiency (G6PD) is an exception to the rule: a common disease with a monogenic cause. One gene is involved, and the number of people with the deficiency is large, approximately 400 million people worldwide. Most people with G6PD deficiency are totally asymptomatic, and some might say that the deficiency does not rise to the level of a disease; it is more like a trait. Some individuals with G6PD will develop hemolysis after ingesting certain types of drugs, foods, or chemicals (e.g., primaquine, sulfonamides, fava beans, methylene blue, naphthalene, nalidixic acid, aspirin). Others with the same deficiency will be unaffected by the same substances. Why does nature preserve this potentially harmful trait? Having the G6PD trait protects against Plasmodium falciparum, the most serious form of human malaria. The trait is most common in geographic areas where malaria is, or has been, endemic.

- Jules Berman (copyrighted material)

key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity jules j berman

Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.


[1] Ayme S, Hivert V (eds.), "Report on rare disease research, its determinants in Europe and the way forward", INSERM, May 2011. Available from:, viewed February 26, 2013.

[2] Garrod AE, Harris H. Inborn Errors of Metabolism. Henry Frowde and Hodder and Stoughton, London, 1909.

[3] Bruning JC, Winnay J, Bonner-Weir S, Taylor SI, Accili D, Kahn CR. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88:561-572, 1997.

[4] Eichers ER, Lewis RA, Katsanis N, Lupski JR. Triallelic inheritance: a bridge between Mendelian and multifactorial traits. Ann Med 36:262-272, 2004.

[5] Gerke J, Lorenz K, Ramnarine S, Cohen B. Gene environment interactions at nucleotide resolution. PLoS Genet 6(9): e1001144, 2010