Why inherited diseases occur?

P geneticsRisk of common inherited diseases like cancer, heart disease, and autism are determined by a combination of genetic and environmental factors. It’s not just DNA that is a contributing factor – diet, lifestyle, physical activity, and exposure to toxins play a role too. Occasionally, a risk factor is erroneously attributed to a disease – like the infamous claim that vaccines cause autism, a predominantly genetic disease. The question is – how much of our health is dictated by genetics? How much can be attributed to the environment and a person’s lifestyle? Here we explain the science behind disease risk estimates and how scientists determine inherited diseases.

How are diseases inherited?

Diseases like sickle-celled anemia, Tay-Sachs disease and Downs’s syndrome are entirely genetic. In Mendelian disease like these, a single defective gene causes the disease. Mutations can be dominant – the trait is expressed even when one copy of the defective gene is present, as in Huntington’s disease. These diseases are highly penetrant, if the person carries the mutated gene the disease is unavoidable, and affected person’s children have a 50/50 chance of inheriting the disease predisposition.

Recessive diseases are expressed only when 2 defective copies are inherited, as in Cystic Fibrosis. If the disease is recessive, and both parents carry one defective gene (but are not affected by the disease) then their progeny has a 25% chance of developing the disease.

Although ‘heritability’ in Mendelian diseases is quite straightforward, not all affected individuals exhibit a similar time line for manifestation of the disease. In Cystic Fibrosis, a mutation in the CFTR gene causes the disease – being a recessive mutation, two copies of the mutated cystic fibrosis gene are needed for expression of the disease. Disease severity is largely determined by mutations in the CFTR gene but not all mutations have the same effect – some mutations result in a severe form of the disease at an early age with others result in a milder form of the disease. Furthermore, mutations in additional genes known as ‘genetic modifiers’ play a role in disease severity and secondary manifestations.

What types of diseases are inherited?

In many cases a single defective gene is not sufficient to cause a disease and multiple mutations lead to increased disease risk. Polygenic diseases are caused by the impact of many different genes, each with a small influence on the final condition, and interactions with environmental and behavioral components. Although these diseases ‘run in families’, their inheritance patterns are not as obvious and the responsible genes cannot be easily identified.

Scientists try to estimate the impact of genetic component of diseases by studying the disease in genetically identical twins (monozygotic) versus dizygotic twins, who are only 50% genetically identical. If the disease occurs more frequently in both the identical twin pairs than it does in the non-identical twins, the disease has an underlying genetic component. If the incidence of a disease is similar between monozygotic and dizygotic twins then its risk is not affected by genetics, but rather, by extraneous factors.

Twin Concordance for Common Diseases

Trait Concordance* (%)
Adult Diseases Monozygotic Dizygotic
Twin Twin
Type1 Diabetes 50 10
Hypertension 30 10
Manic depression 80 10
Multiple sclerosis 20 5
Schizophrenia 40 10
Alzheimer’s disease 40 10

*presence of the same trait in both members of a pair of twins.

Source: http://www.geneticalliance.org.uk/education4.htm

Heritable diseases examples:

Epilepsy

Monozygotic and dizygotic twins were studied in Denmark to identify the role of genetic and environmental factors in the development of epilepsy. Genetic factors were found to account for 70-88% of the risk of developing the disease.

Diabetes

A study on Finnish twin pairs established that 88% of the risk of developing Type1 diabetes was from genetic factors. In Type2 diabetes, the role of non-genetic factors was evident, with the heritability estimate being a low 26%, and environmental factors playing a dominant role in determining whether a genetically-predisposed individual progressed to Type2 diabetes. Behavioral aspects like obesity and sedentary life style contribute to causing Type2 diabetes or exacerbating it.

Cancer

Heritability of cancer is highly variable – some breast cancers are inherited, frequently caused by mutations in BRCA1 and BRCA2 genes, while others are considered ‘sporadic mutations’, triggered by environmental factors. Genetically inherited breast cancer manifests at an earlier age (30-45yr) while incidence of sporadic breast cancer increases with increasing age (60yr+). Similarly, ovarian, colon and prostate cancers can be due to inherited genetic factors or sporadic mutations, with an earlier age of onset for disease caused by inheriting a cancer susceptibility gene.

There are exceptions to this rule – early onset childhood leukemia are caused by sporadic mutations in bone morrow cells and there is a very low risk of the disease occurring in siblings of affected children.

Autism

Population based studies on autism spectrum disorder have identified several autism susceptibility genes. Researchers believe that multiple genetic mutations interact to cause the heterogeneous spectrum of disorders observed in autism. The ‘vaccines cause autism’ argument probably arose due to a coincidence – the period when children are scheduled for a number of vaccinations overlaps and the age when autism becomes clinically visible.

What you can do – Concerns and Consultations

If you are concerned about your risk of a disease because of prior family history, talk to your physician, genetic counselor or a qualified genetic consultant to understand if you are at risk and if genetic diagnostics can help you to mitigate disease risks. Remember, some genetic diseases are preventable, and many diseases can be managed much better if you and your healthcare team is equipped with a detailed knowledge of your specific disease predisposition. Knowing your carrier status for recessive diseases can be relevant when planning a family, to understand if your children will be at risk for inherited conditions. Knowing your genes enables awareness and possible prevention

What’s next?

If you would like to learn more about inherited diseases such as autism, continue reading this related blog post: “What Causes Autism in Children?”.

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Image Source: By User:Kontos (Own work) [Public domain], via Wikimedia Commons

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