Multifactorial Traits and Heritability

Complex Disease Characteristics

• Monogenic (Mendelian) Phenotypes: Direct gene-allele relationship, strong genotype-phenotype correlation (high penetrance), often qualitative (e.g., Cystic Fibrosis).

• Polygenic Phenotypes: Many genes contribute additively to the trait/disease.

• Multifactorial (Complex) Phenotypes: Result from interplay of many genes (polygenic) and environmental factors. Low correlation between genotype and trait; variants predispose, not cause. Often quantitative (continuous).

• Quantitative Traits: Show continuous variation (e.g., height, weight).

• Inheritance Patterns: Monogenic diseases show predictable generational patterns; complex diseases aggregate in families but lack clear patterns.

• Multifactorial Disorder Prevalence: Most common cause of congenital malformations and acquired diseases; more prevalent than single-gene disorders; difficult to identify specific genetic causes.

Variance in Polygenic Traits & Multiple-Gene Hypothesis

• Continuous Phenotypic Variation: Polygenic traits (e.g., height) often follow a normal distribution.

• Multiple-Gene Hypothesis (Nilsson-Ehle, 1909): Explains continuous traits by many genes contributing in a cumulative/quantitative additive way.

  • Assumptions: Quantitative trait can be measured; two or more loci contribute additively; each locus has additive/non-additive alleles; additive alleles contribute approximately equally.

  • Caveats: Epistasis and complete dominance counter these assumptions; equal contribution is rare.

• Calculating Polygenes (for low $n$):

  • $1/4^n = \text{ratio of F2 individuals expressing one extreme phenotype}$

  • $(2n + 1) = \text{number of distinct phenotypic classes observed}$

  • where $n$ = number of polygenes.

• Meristic Traits: Genetic variation results in whole number phenotypes (e.g., number of offspring).

• Threshold Traits: Phenotype appears upon cumulative effect of many predisposing alleles, often with environmental factors (e.g., common diseases like asthma, diabetes; congenital malformations like cleft lip).

Heritability

• Phenotypic Variation ($V_P$): Total variation in a population.

  • $V<em>P = V</em>G + V<em>E + V</em>{GxE}$ (Genotypic, Environmental, Gene x Environment interaction variance).

• Heritability Definition: Proportion of total phenotypic variation due to genetic factors in a specific population.

  • What it is NOT: Not how much of an individual's trait is genetic, nor fixed for a trait. Differs by environment.

• Broad-Sense Heritability ($H^2$):

  • $H^2 = V<em>G / V</em>P$

  • Measures proportion of variance due to all genetic factors (additive, dominance, epistatic).

  • $V<em>G = V</em>A + V<em>D + V</em>I$ (Additive, Dominance, Interactive variance).

  • Useful for understanding full genetic picture.

• Narrow-Sense Heritability ($h^2$):

  • $h^2 = V<em>A / V</em>P = V<em>A / (V</em>E + V<em>A + V</em>D)$ (ignoring $V_I$).

  • Considers only additive genetic variance ($V_A$).

  • More accurate for predicting response to selection (e.g., in breeding).

  • Quantified by correlating offspring values against midparent values. Higher correlation suggests higher heritability.

Identifying Genetic Contribution in Humans

• Relative Risk Ratio ($\lambda_R$):

  • $\lambda_R = \text{disease prevalence in relatives R of probands} / \text{disease prevalence in the population}$

  • $>1$ implies increased risk due to familial aggregation, suggesting a genetic component.

  • Confounded by shared environment.

• Twin Studies: Compares concordance rates between monozygotic (MZ, identical, $100\%$ genes shared) and dizygotic (DZ, fraternal, $50\%$ genes shared) twins.

  • Concordance Ratio (r): $r = \text{Concordance in MZ} / \text{Concordance in DZ}$

  • $r > 1$ indicates genetic influence.

  • Heritability estimate: $h^2 = 2(\text{r}<em>{\text{MZ}} – \text{r}</em>{\text{DZ}})$ (using concordance rates).

  • Limitations: MZ twins may share more environment; epigenetic factors, X-inactivation, somatic mutations.

• Adoption Studies: Gold standard for disentangling genetic vs. environmental factors.

  • Compares disease incidence in adopted individuals with their biological vs. adoptive families.

  • Obstacles: Lack of biological family history, timing of adoption, intrauterine factors, selective placement.