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Family history is a risk factor for many common diseases, capturing both shared genetic variation and shared environment between family members. Because our understanding of genetic risk factors for common diseases is incomplete, family history remains an important component of any medical assessment. A family history of a common disease is usually associated with a two to threefold increased risk of disease in bloodline family relatives. To put this in context, this risk is much higher than for most known individual genetic variants for common diseases (average increased risk for variants discovered to date are about 1.18-fold).


Positive family history, but not genetic

A positive family history of disease does not always mean there is an inherited genetic basis. Family history may reflect shared environment (e.g., exposure of siblings to second-hand smoke). Family history may also reflect chance. For example, cardiovascular disease is the leading cause of death in the United States, where one in three adults have at least one type. Therefore, it would not be surprising to find a positive family history in most cases.

Genetic, with no family history

The absence of a family history does not rule out a genetic basis of disease. Depending on the mode of inheritance and genetic background, a person can inherit a variant and not develop disease, and thus would not contribute to a family history. For example, recessive diseases require two gene variants. X-linked diseases usually require two gene variants in females. De novo variants are not inherited at all, but acquired during the formation of the gametes (though the patient can then pass them to his children). In addition, genetic background may affect penetrance, such as in breast cancer where inherited variants show reduced penetrance for breast cancer in males.


When capturing family history of disease, it is important to consider the type of relative as well as age of onset and other unusual aspects of disease (Fig. A4-1). Some key points to remember include the following:

Figure A4-1.

Age of onset and other unusual cases of disease may lend clues to a disease having a genetic etiology. MI, myocardial infarction; Ca, cancer.

  • A disease clearly segregating in multiple individuals on either the maternal or paternal side is more significant than having a single affected family member on both sides of the family, particularly for common diseases.

  • A history of the disease in first-degree family members (parents, siblings, children) is more significant than in distant relatives.

  • Early age of onset, especially for a typically later-onset disease, is more significant than later-onset disease (e.g., myocardial infarction in a 25-year-old, vs. an 80-year-old).

  • A disease manifesting in ...

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