3. Multifactorial Inheritance and Common Disorders

Dr. Jillian Parboosingh

What is the difference between monogenic and polygenic disorders?

• Monogenic disorder: single gene disorder; pathogenic variant(s) in a single gene are sufficient to cause the trait

  • Ex. Cystic fibrosis

• Polygenic disorder: variant(s) in multiple genes are needed to cause a trait

  • Ex. Coronary artery disease

What is a multifactorial disorder?

• “complex disorder”

• Variant(s) in multiple genes AND environmental factors are needed to cause the trait

  • Lifestyle, environmental exposures (viruses, carcinogens, etc.)

How common are monogenic and polygenic disorders?

Monogenic disorders are rare, and multifactorial disorders are common

• Chromosomal (Aneuploidies or structural abnormalities) → 0.5-1% prevalence (detected prenatally)

• Monogenic (single gene defect) → 1-2% (high penetrance, clear inheritance, low ind. disease frequency)

• Multifactorial (genetic predisposition + environment) → 5-10% (no simple inheritance pattern, lower recurrence risk than monogenic disorders but higher population risk)

How do genes work together?

• For the appropriate expression of genes (Transcription factors, chaperones)

• Forming functional complexes (2 alpha globin + 2 beta globin = hemoglobin unit)

• In a pathway (citric acid cycle, electron transport chain)

What are the examples discussed in class of how genes respond to the environment?

• High glucose levels → insulin receptors stimulate increased production of insulin

• Hormones (sex-dependent) → baldness and lactation

• Temperature changes → coat color changes in snowshoe hares

• Exposure to teratogens → birth defects during fetal development

  • Ingestion of thalidomide during pregnancy mimics genetic disorder phocomelia with disruption of limb development

• Viral exposure → disease manifestation

What were the other three environmental influences we discussed?

• Nutrition (in utero, childhood and adulthood)

• Lifestyle choices (exposure to toxins like smoking or drugs, exercise and stress)

• Socioeconomic (affects access to healthcare, good nutrition and safe housing - which also increases stress levels)

What is the Waddington Hypothesis?

• Biological processes such as development are finely tuned..

• A perturbation of the process can produce very different results

  • On a continuum of max height potential vs short stature, factors like genes and optimal environment, poor nutrition and growth hormone deficiency (congenital) can all affect how tall you become

Genotype to Phenotype: How do changes at the DNA level lead to sickle cell anemia?

1. DNA alteration (HBB c.20A>T)

2. Primary amino acid change (p.Glu7Val)

3. Three dimensional alteration of beta globin subunit

4. Abnormal aggregation of sickle cell proteins

5. Phenotype: Red blood cell sickling and clinical sequelae

→ monogenic disorders are very predictable and well known

How are the mechanisms leading to multifactorial disease less understood? Like in the case of albinism and skin color?

• Albinism: genetic heterogenous condition characterized by little or no melanin production

  • Single gene phenotype (monogenic with a mutation in one gene causing one phenotype; however heterogenous means that multiple genes can cause differing phenotypes)

• Skin colour continuum: interaction between genes and environment (sun exposure) alters the amount of melanin produced

  • Multifactorial phenotype

What produces melanin in skin and other tissues?

Melanocytes (production is complex requiring coordination of environmental cues, signaling pathways and compartmentalized intracellular metabolism)

Can multifactorial traits be explained by Mendelian Inheritance?

No, multifactorial traits like skin color demonstrate a complex pattern of inheritance which cannot be explained by simple models of Mendelian inheritance

What are the two classes of multifactorial disease?

Quantitative and Qualitative

What are the differences between Qualitative and Quantitative multifactorial diseases?

Qualitative

• Discrete (present or absent)

• Heart attack, cancer, rheumatoid arthritis

Quantitative

• Continuum (varies from one extreme through normal to another extreme)

• Height, BMI, cholesterol level

What are the two models that represent both classes of multifactorial disease?

Quantitative → Quantitative trait model (Basic model): accumulation of quantitative trait loci (QTL’s)

Qualitative → Threshold model: accumulation of liability/risk factors beyond a certain threshold

What produces a continuous spectrum? What creates even more variation around a specific phenotype?

The additive effect of many genetic and environmental factors produces a continuous spectrum of phenotypes

• Single gene (2 co-dominant alleles acting = 3 phenotypes)

• Two genes (2 codominant alleles each = 5 phenotypes

• Multiple genes (multiple co-dominant alleles acting = phenotypic continuum)

  • Add in environmental factors = variation around a given phenotype

What does increasing the number of genetic risk factors (multiple alleles at one or multiple genes) do?

Increases the number of possible phenotypic classes

• Polygenic inheritance reflects the additive effects of a large number of alleles