Multifactorial Inheritance in Human Genetics

This set of flashcards covers key vocabulary related to multifactorial inheritance in human genetics, including important terms and their definitions that will aid in understanding complex traits and diseases.

Multifactorial Inheritance

A form of inheritance where traits are affected by multiple genes and environmental factors.

Monogenic Trait

A trait that is controlled by a single gene.

One gene → phenotype

Polygenic Trait

A trait that is influenced by multiple genes, with each gene contributing a small effect.

Genotype

The genetic makeup of an individual, consisting of the alleles inherited from parents.

Phenotype

The observable physical or biochemical characteristics of an organism as determined by both genetics and environment.

Cohort Studies

Studies that follow a group of people over a period to assess the effects of various factors, including genetics.

Quantitative Trait

Traits that can be measured on a continuous scale and are influenced by multiple genes.

Qualitative Trait

Traits that are either present or absent and usually determined by a single gene.

Concordance

The occurrence of the same trait in both members of a twin pair.

GWAS (Genome Wide Association Studies)

Research studies that look for associations between genetic variants and traits across the genome.

Heritability

A measure of how much of the variation in a trait can be attributed to genetic differences within a population.

Environmental Factors

Non-genetic influences that can affect the development and manifestation of traits.

Threshold Model

A model that describes the point at which a combination of genetic and environmental factors leads to the expression of a trait.

Empiric Risk

The observed risk of a trait or disease based on real-world data.

Liability Distribution

A representation of the risk of developing a trait based on genetic and environmental factors.

Twin Studies

Studies that compare traits in monozygotic and dizygotic twins to assess genetic and environmental influences.

Recurrence Risk

The probability that a trait or condition will occur again in a family or population after an initial case.

Complex Disorders

Health conditions that arise from interactions between multiple genetic and environmental factors.

SNP (Single Nucleotide Polymorphism)

A single base pair variation in the DNA that may contribute to an individual's risk of disease.

Familial Aggregation

The tendency for certain traits or diseases to occur more frequently in families than in the general population.

Multifactorial Traits/Disorders

Traits that DO NOT FOLLOW ANY CLEAR PATTERN OF MENDELIAN INHERITANCE. Instead they result from complex interactions between a number of genetic and environmental factors

They tend to cluster in families

Polygenic traits + environmental factors = multifactorial disorders

examples of Multifactorial Diseases

Congenital disorders

• Cleft lip and cleft palate

• Pyloric stenosis

Psychiatric disorders

• schizophrenia

Other disorders

• heart disease

• Obesity

• Autism spectrum disorder (ASD)

• Hypertension

How do we determine the contribution of the Genetic factors?

1. Twin Studies

2. Genome Wide Association Studies (GWAS)

3. Heritability

How do we determine the recurrence risk in a family?

1. Empirical Risk

2. Relative Risk

3. Quantitative and Qualitative trait risk analysis

What can Twin Studies tell us about nature and nurture? Concordant vs Discordant?

Twin studies are used to measure the contribution of genetics or genetic factors to a given trait or condition of interest.

Twin studies are used to study gene-environment interaction

Comparing Monozygotic twins to Dizygotic twins allows researchers to separate genetic from environmental influences without direct measure of the genes

If twins have the same phenotypic characteristic, they are concordant. If they differ, they are discordant with regard to this characteristic.

Genome Wide Association Studies (GWAS)

Research methods that identify genetic variants associated with traits or diseases by scanning genomes from many individuals.

These studies compare a large set of genetic markers across the genome between two large groups of people; one with a trait/disease and one without the trait/disease

Heritability measure?

A statistic that estimates the proportion of phenotype variation in a population attributable to genetic variation.

Heritability measures the genetic contribution to phenotypic variation in a certain population at a certain time

Heritability of a trait (H²) is the amount of phenotypic variation caused by genetic differences

H² = proportion of total variance caused by genetic variance

Vg/Vp

H² heritability is represented on a scale of 0 -1

Heritability is 100% when H²=1.0 (phenotypic variation is largely genetic, and environmental contribution is low)

H² = 0.0 (when there is little genetic contribution, but environmental contribution is high)

Empiric Risk

geneticists use empiric risk to predict the chance that a multifactorial trait will occur in a particular individual. The Empiric Risk is a population statistic that is based on observations, and very specific to the population that was studied.

Relative Risk

The likelihood that an individual will develop a multifactorial trait compared to the general population. It is used to assess the risk of developing a condition based on various genetic and environmental factors.

Relative Risk is the ratio of the frequency of the train in relatives divided by its frequency in the general population

How do we calculate Relative Risk?

= (freq. of disease in family of affected person) / (freq. of the disease in general population)

The more common a disease in a population → the more likely that aggregation may be just a coincidence, and less likely it is because of sharing the alleles that predispose to disease

Types of Multifactorial (complex) traits

1. Quantitative Trait: Traits that determined by physiological or biochemical measurements

   1. These measurable physiological quantities vary among individuals in a population and are important determinants of an individuals health and disease

      1. Height, blood pressure, serum cholesterol levels, body mass index

2. Qualitative Trait: A genetic disease that either present or absent

   1. These traits are discontinuous in distribution, only 2 classes of individuals:

      1. Affected, and unaffected

      2. Major example = congenital malformation

Quantitative Multifactorial Trait

the phenotypic variation in traits observed within a population that are due to BOTH genotypic differences and environmental factors.

Tratis that are controlled by several genes, each of which makes a small contribution to the phenotype, display a continuous distribution of phenotypes in the F2 generation, even though each gene follows Mendelian inheritances

Example: height in humans is an example of continuous variation, height is a polygenic trait.

Phenotypic variance

Vp = Vg + Ve

Vg: phenotypic variance

Vg: genetic variance

Ve: environmental variance

statistical analysis of quantitative traits

normal distribution of quantitative trains in the population

The graph produces a BELL-SHAPED CURVE of the normal distribution

• Y-axis number of individuals in the population

• X-axis: a particular value of that physiological trait

Three parameters determine the shape of the distribution

• Mean: the peak of the curve is at the mean value, more individuals in the population have their values near the mean

• Variance: the variance for a sample is the average squared distance of all measurements from the mean (how far a set of numbers is spread out)

  • Standard Deviation: Variation around the mean. The SD determines the extent of the curve

Qualitative Complex Disorders

The challenge with these traits/disorders is that they do NOT follow a single pattern of Mendelian inheritance, since each gene contributes to the phenotype and each gene has its own pattern of inheritance

The Threshold Model of Multifactorial Inheritance or Liability Distribution best analyzes these traits

Threshold Model

in multifactorial diseases, a threshold of liability must be crossed before the disease is expressed.

Genotype, environmental factors, or in most cases a combination of both can determine the threshold.

Evidence for a threshold in a multifactorial disorder is INDIRECT and only comes from population and family studies.

Consider a multifactorial trait that is twice as common in females as in males. Indicate which type of mating is at higher risk for producing affected children

A) affected father & normal mother

B) normal father & affected mother

Is the recurrence risk higher for their sons or daughters?

• twice as common in females: this means that females have a lower liability threshold (they need fewer risk factors to express the disease)

• Males have a higher threshold (they need more genetic and environmental risks to be affected)

Males have the higher threshold, so if a male is affected → he must carry MORE genetic liability than an affected female would

→ affected male will contribute MORE RISK alleles TO HIS CHILDREN → higher recurrence risk

Since females have a LOWER threshold, they need fewer risk alleles to be affected → they will cross the threshold more easily → daughters will be at a higher recurrence risk

Clinical examples of Human Complex Disorders

1. Type 1 Diabetes Mellitus, insulin dependent diabetes

2. Crohn’s disease

3. Obesity

Polygenic trait vs. Multifactorial trait

A polygenic trait is influenced by multiple genes, while a multifactorial trait is influenced by multiple genes and environmental factors.

Concordance vs Discordance

Concordance refers to the presence of the same trait or condition in both twins, while

Discordance indicates that one twin has the trait and the other does not. This comparison is often used in genetic studies to assess heritability.