The threshold effect is a concept that explains the inheritance of certain traits and diseases that do not follow predictable patterns. These complex traits, often called discontinuous, only appear when a combination of genetic and environmental influences surpasses a specific trigger point. Imagine a reservoir behind a dam where the water level represents the combined risk factors; the observable trait only occurs when the water overtops the dam’s wall, or threshold.
This model is used for conditions that are either present or absent, with no in-between state, and helps explain why their appearance in families can seem sporadic.
The Liability Model Explained
The mechanism behind the threshold effect is the liability model. This model proposes that for any given complex trait, every individual has an underlying, unobservable scale of risk known as “liability.” This liability is a theoretical combination of all predisposing factors, including an individual’s genetic predispositions and environmental exposures.
In any population, this liability is distributed along a continuum, much like height or weight, typically forming a bell-shaped curve. Most people will have a liability level near the average, while fewer have very low or very high liability. The threshold is a fixed point on this scale, and individuals whose liability remains below this point will not develop the trait.
Only when the cumulative liability crosses this fixed threshold does the trait or disease manifest. This explains how a trait can be discontinuous (present or absent) even though the underlying risk is continuous.
The position of the threshold can be estimated based on the prevalence of the condition in the population. For common conditions, the threshold is lower, meaning less liability is needed to express the trait. For rarer conditions, the threshold is higher, requiring a greater accumulation of risk factors.
Genetic and Environmental Contributions to Liability
An individual’s liability is multifactorial, influenced by multiple genetic and environmental factors. The genetic component is polygenic, meaning many different genes contribute to the overall risk. Each of these genes has a small, additive effect, so no single gene is powerful enough on its own to cause the condition.
These numerous genes create a genetic background of susceptibility. The more risk-associated gene variants a person inherits, the higher their baseline liability will be, pushing them closer to the threshold. This is why these traits often appear to run in families, as relatives share a proportion of their genes and these risk-contributing variants.
The other component of liability comes from environmental factors. These influences can range from diet and lifestyle choices to exposure to specific chemicals or toxins during sensitive developmental periods. For example, maternal diet during pregnancy or the use of certain medications can act as an environmental trigger.
Neither genetics nor environment alone causes the trait to appear. A person with a high genetic predisposition might not develop a condition if they avoid environmental triggers. Conversely, someone with low genetic susceptibility might develop it after a significant environmental exposure, as it is the combination of factors that determines expression.
Common Examples of Threshold Traits
Several human health conditions are understood through the threshold model. Neural tube defects (NTDs), such as spina bifida and anencephaly, are birth defects of the brain and spine that occur when the neural tube fails to close during early development. The inheritance of NTDs is explained by a multifactorial model where genes interact with environmental factors.
A well-established environmental factor for NTDs is the availability of folic acid. An individual may inherit a combination of genes that makes them susceptible, but the defect may only manifest if the mother has an insufficient intake of folic acid during early pregnancy. Public health initiatives to fortify grain products with folic acid have lowered the population’s liability, leading to a decrease in the prevalence of these conditions.
Cleft lip and/or palate is another common birth defect that follows a threshold pattern. Liability is influenced by many genes involved in facial development, combined with environmental factors like maternal smoking or certain medications. The defect only occurs when the cumulative liability prevents the developmental processes from completing correctly.
Pyloric stenosis, a condition in newborns where the passage from the stomach to the small intestine narrows, also fits this model. It is more common in males than in females, suggesting the sexes have different liability thresholds. Females are thought to have a higher threshold, meaning they require a greater number of risk factors to develop the condition.
Understanding Inheritance and Recurrence Risk
The threshold model explains why multifactorial traits run in families but do not adhere to the predictable inheritance patterns of single-gene conditions. Because liability is partly determined by genes, close relatives of an affected person will have a higher average liability than the general population. They share a percentage of their genes and are more likely to have inherited some of the same predisposing genetic variants.
This shared liability means their risk of developing the condition, known as the recurrence risk, is elevated. For most multifactorial conditions, the recurrence risk for first-degree relatives (siblings, children, parents) is in the range of 2-5%. This is higher than the population risk but much lower than the risk seen in simple dominant or recessive traits.
The recurrence risk is influenced by several factors. The risk is higher for relatives of an individual who is more severely affected, as severe expression implies a greater underlying liability. If a condition is more common in one sex, relatives of an affected person of the less common sex have a higher recurrence risk, as this implies a stronger genetic liability in the family.