Common Risk Allele Results
- Common complex disorders such as heart disease, diabetes, and most cancers develop as a result of both genetic and environmental factors.
- The impact of a common risk allele with disease risk is often modest, as is its impact on clinical care.
- Use of common risk alleles for changes in clinical management can be challenging without a professional guideline.
Differences in the DNA sequence at a specific location in a gene are called variants, or alleles. Alleles with a high population frequency, typically defined as >1%, are referred to as polymorphisms. These small differences in DNA sequence, or genetic variation, may or may not affect gene function. However, some common variants can interfere with a biological process, leading to illness, typically in combination with other factors. Such conditions are considered to have a genetic basis, and are typically classified as “common complex” disorders.
In contrast to Mendelian disorders (e.g., Huntington’s disease, sickle cell anemia) in which variation in a single gene causes disease, common complex disorders, such as heart disease, diabetes, and most cancers, develop as a result of both genetic and environmental factors. Because common complex diseases can be associated with alterations in many different genes, and because each of these alterations is usually associated with only small increases in risk, the finding of a common risk allele has much less impact on clinical care than finding a gene mutation associated with a Mendelian disorder.
Risk alleles for common complex diseases are usually defined by the minor, or least common, allele frequency (MAF). This allows for differentiation between common and rare alleles in the population. The MAF of common risk alleles can range from 5% to 50%. However, just because an allele is common does not necessarily mean it has a meaningful impact on disease susceptibility.
Common risk alleles are often detected by genome-wide association studies (GWAS)1,2. GWAS are a type of case-control study in which people with the condition being studied are compared to similar people without the condition. Each person’s complete set of DNA, or genome, is surveyed by examining a strategically selected “panel” of genetic markers that tag areas of known variation, called single nucleotide polymorphisms (SNPs).
If certain genetic variations are found to be more frequent in people with the disease compared to people without disease, the variant alleles are said to be “associated” with the disease. The presence of an association suggests that the variant, or some other nearby variant, is influencing disease susceptibility.
The association of an allele with disease is a measure of statistical, not clinical significance. Effects are often modest, and the associated variants themselves may not directly cause the disease. Given this, genetic tests for such conditions can only provide an estimate of probability or risk. For common diseases, the presence of a high-risk allele may only mildly increase the chance of disease. Further, there are currently no validated ways of combining multiple risk alleles for the same disease. These limitations can make the interpretation of common risk alleles challenging.
One risk allele that is relatively common in the population and that has been associated with an increased risk for disease susceptibility is factor V Leiden and risk for deep venous thrombosis (DVT). Between 3- 8% of people of European descent carry one copy of the factor V Leiden allele and 1 in 5,000 people have two copies. Risk of DVT for individuals in the general population is 1 in 1,000. However, having one copy of the factor V Leiden allele increases the risk of DVT from 1 in 1,000 to 3-8 in 1,000. Having two copies raises the risk to as high as 80 in 1,000. A test that identifies the factor V Leiden allele can have implications for clinical management and may indicate the need for preventative measures to reduce clotting risk2.
In contrast, variants in the MTHFR gene have been associated with increased risk of neural tube defects and cardiovascular disease; however, 60-70% of individuals in the general population have one of the two most common MTHFR gene polymorphisms. Most of these individuals do not develop disease. Therefore, a genetic test that identifies one of these MTHFR gene variants has no real clinical implications.
In the case of breast cancer, several alleles that increase susceptibility have been identified. Pathogenic mutations in the BRCA1 and BRCA2 genes associated with the Mendelian disorder Hereditary Breast and Ovarian Cancer Syndrome are associated with lifetime risks for breast cancer of 40-80%. In contrast, more than 70 other common alleles have been associated with breast cancer susceptibility, most of which confer only a mild to moderate increase in risk. Thus, identifying one of these common alleles would not have the same implications for medical management as would finding a pathogenic mutation in BRCA1 or BRCA2. To what extent the associated symptoms are expressed in the presence of the variant is captured by a term called penetrance. If it is not always expressed, it is considered incompletely penetrant.
If an associated allele is identified, it may explain disease susceptibility. Common risk alleles with a known association with a condition can inform an individual of an increased or decreased risk of developing the condition in question; however, the degree of certainty is often unknown. The presence of a common risk allele can indicate a need for increased surveillance, while a negative result implies a risk similar to the general population.
Common risk alleles have unclear implications for family members. In addition, the clinical sensitivity of tests for common risk alleles is not necessarily high. Common complex diseases are caused by multiple genetic and environmental factors, many of which remain unknown.
Next Steps to Consider
- Use of risk allele information to guide medical management is rarely done in the absence of a practice guideline
- Explore current knowledge about the specific genetic variant utilizing resources such as the medical literature, professional guidelines and NHGRI GWAS catalog
- In most cases, testing of family members is not recommended apart from a specific practice guideline
- dbSNP (https://www.ncbi.nlm.nih.gov/projects/SNP/:) a public-domain archive for a broad collection of simple genetic polymorphisms.
- Human Genome Variation (HGV) database (http://www.nature.com/hgv/): a searchable online database of genome variations published in a variety of peer-reviewed sources. HGV is searchable and able to be filtered by different variables, including specific disease, gene, population or region.
- Iles, M.M. 2008. “What can genome-wide association studies tell us about the genetics of common disease?” PLoS Genet. 2008 Feb;4(2):e33.
- OMIM (http://www.ncbi.nlm.nih.gov/omim): an online resource about human genes and associated phenotype (symptoms).
- Vineis P., Schulte, P., McMichael, A.J.. “Misconceptions about the use of genetic tests in populations.” Lancet. 2001 Mar 3;357(9257):709-12.
- Hirschhorn, J.N., Lohmueller, K., Byrne, E., Hirschhorn, K. “A comprehensive review of genetic association studies.” Genet Med. 2002 Mar-Apr;4(2):45-61.
- Raychaudhuri, S. “Mapping rare and common causal alleles for complex human diseases.” Cell. 2011 Sep 30;147(1):57-69.
- Geerts, W.H., et al. “Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).” Chest. 2008;133(6_suppl):381S-453S.