Multifactorial Inheritance in Human Genetics

Multifactorial Inheritance and Genetic Disorders

Class Topics

  • Block III: Applied Medical Genetics

  • Complex traits

  • Multifactorial inheritance

  • Personalized medicine/Pharmacogenetics

  • Biochemical genetics

Molecular Basis of Traits

Monogenic Traits

  • Definition: Phenotype controlled by a single gene.

  • Example: enzyme

Polygenic Traits

  • Definition: Phenotype controlled by multiple genes.

  • in a polygenic trait, each gene contributes to the phenotype

Multifactorial Traits

  • Definition: Traits controlled by two or more genes that significantly interact with environmental factors.

  • Environmental factors may affect the variation observed in the trait.

  • Despite adherence to Mendelian inheritance for each gene involved, gene interactions may obscure straightforward Mendelian ratios.

Characteristics of Multifactorial Disorders/Traits

  • Traits do not follow clear Mendelian inheritance patterns.

  • Results from complex genetic and environmental interactions.

  • Tend to cluster within families.

  • Major contribution of multifactorial genetic diseases to public health.

  • Cause significant demand for special care due to genetic diseases.

Examples of Multifactorial Disorders

  • Obesity

  • Congenital disorders such as cleft lip and cleft palate.

  • Psychiatric disorders like schizophrenia.

  • Other disorders: Heart disease, Autism Spectrum Disorders (ASD), and hypertension.

Genetic Analysis of Multifactorial Disorders

Methods for Determining Genetic Contributions

  1. Twin Studies

    • Utilizes comparison between monozygotic (MZ) and dizygotic (DZ) twins.

    • Same genotype and same gender for MZ twins; may differ in genetic markers.

    • Assess nature vs. nurture effects on inheritance.

  2. Genome Wide Association Studies (GWAS)

    • Compares genetic markers across genomes of affected and unaffected individuals.

    • Identifies genomic locations associated with traits/diseases.

  3. Heritability Assessment

    • Studies phenotypic variance attributable to genetic differences.

    • Calculated using the formula: H^2 = \frac{VG}{VP}

      • Where $VG$ is genetic variance and $VP$ is total phenotypic variance.

    • Heritability scale: 0 (no genetic contribution) to 1 (all variance is genetic).

Twin Studies Explained

  • Purpose: Measure the genetic contribution to traits.

  • MZ twins share 100% of their genes; DZ twins share about 50%.

  • Twin studies evaluate the concordance of traits between MZ and DZ twins.

    • Higher similarity in MZ twins suggests a genetic influence.

    • Equal similarity in both types indicates environmental influences.

Concordance and Discordance

  • If twins with the same trait are concordant, they share that characteristic.

  • If they differ, they are discordant.

  • Example in schizophrenia:

    • MZ twins: 1 in 2 chance of both being affected

    • DZ twins: 1 in 6 chance of both being affected.

Genome Wide Association Studies (GWAS)

  • Description: Compares genetic markers in two groups (affected vs. unaffected).

  • Purpose: Identify specific parts of the genome common among affected individuals.

  • Employs analysis on affected sibling pairs for shared genetic information.

Heritability Estimates

  • Heritability: Genetic contribution to variation measured in a specific population.

  • Expressed as a percentage, redefining the genetic contribution of a trait. Examples:

    • Obesity in children: Heritability ranges between 0.77 - 0.88.

Recurrence Risks in Families

  • Empiric Risk: Based on population observations to estimate recurrence chances for multifactorial traits.

  • Higher recurrence when:

    1. More family members are affected.

    2. The proband has severe disease expression.

    3. The proband's gender is less commonly affected.

Empiric Risk Example: Neural Tube Defects (NTD)

  • USA: Risk = 1 in 1000.

  • Specific populations may show varied risks (e.g., Irish ancestry: 3 in 1000).

Types of Multifactorial Traits

Qualitative Traits

  • Traits that are either present or absent (e.g., congenital malformations).

  • Distribution: Discontinuous.

Quantitative Traits

  • Traits measured on a continuum with variation influenced by genetics and environment.

  • Example: Height and blood pressure.

  • Follow Mendelian inheritance but exhibit continuous variation due to the aggregate effect of many genes.

Statistical Analysis of Quantitative Traits

  • Factors that influence the accuracy of results:

    1. Sample randomness.

    2. Population representativeness.

  • Normal distribution expected in large, random samples.

Key Parameters

  • Mean: Average value of the trait.

  • Variance: Measure of variability around the mean.

  • Standard Deviation (SD): Active measure of how spread out measurements are around the mean.

The Threshold Model of Multifactorial Inheritance

  • Assumes a liability distribution where genetic and environmental factors contribute to disorder expression.

  • Threshold: The point at which the combination of risk factors causes the development of a disorder.

  • Those below the threshold are unaffected; those above are affected.

Example: Congenital Malformation

  • Like cleft lip where multiple factors determine the abnormal phenotype's occurrence.

  • Frequency among family members reflects threshold effects in populations.

Clinical Examples of Multifactorial Disorders

Pyloric Stenosis

  • Developmental disorder indicated by narrowing/obstruction between stomach and intestine.

  • More prevalent in males; suggests differing liability thresholds between genders.

Type 1 Diabetes Mellitus

  • An autoimmune disease leading to insulin regulation issues.

  • Increased risk associated with family history: 0.4% general population risk, higher if parent is affected.

Obesity

  • Rapidly rising global health issue with multicause origins.

  • Projected obesity rates to increase significantly leading into the future with serious health implications.

  • Heritability of obesity approximately 70%.