Lecture #61: Human Genetics IV: Multifactorial and Complex Diseases

Define multifactorial inheritance.

Inheritance resulting from the interaction of multiple genes and environmental factors rather than a single gene mutation.

List examples of multifactorial disorders.

Heart disease, diabetes, neural tube defects, hypertension, and many cancers.

How does multifactorial inheritance differ from Mendelian inheritance?

Multifactorial traits do not follow simple dominant/recessive patterns and involve multiple genetic loci with environmental influence.

What is the relationship between genetic relatedness and recurrence risk in multifactorial disorders?

Risk increases with closer genetic relationship to the affected individual.

List principles of multifactorial inheritance.

(1) No simple Mendelian segregation; (2) Increased recurrence risk among relatives; (3) Risk decreases with distant relatives; (4) Greater severity = higher risk; (5) Sex bias may exist.

What role do environmental factors play in multifactorial disorders?

Environmental exposures such as diet, lifestyle, and toxins significantly modify disease risk.

Define a quantitative trait.

A measurable characteristic that shows continuous variation in a population (e.g., height, blood pressure, BMI).

Define a qualitative trait.

A trait with discrete categories (e.g., blood type, presence/absence of a disease).

Give an example of a quantitative trait.

Height – determined by many genes and environmental influences.

What is the threshold model of disease expression?

A model proposing that disease occurs only when a person’s genetic and environmental liability exceeds a critical threshold.

What does the “threshold of liability” refer to?

The point beyond which an individual expresses a multifactorial disease phenotype.

Explain sex bias in threshold traits.

When a disease is more common in one sex, relatives of affected individuals of the less commonly affected sex are at higher risk.

What is empirical risk?

Observed probability of a disease based on population and family data rather than theoretical prediction.

Why can’t recurrence risk in multifactorial diseases be calculated precisely?

Because multiple genes and environmental factors interact unpredictably.

What are examples of multifactorial congenital malformations?

Cleft lip/palate, neural tube defects, pyloric stenosis.

What is the recurrence risk of neural tube defects after one affected child?

2–5%; increases to 5–10% after two affected children.

What is the recurrence risk for cleft lip/palate when one parent is affected?

About 3% (increases with number of affected relatives).

Describe the gender bias in pyloric stenosis.

Males are more commonly affected; female probands confer higher risk to offspring.

What is the recurrence risk for offspring of a male with pyloric stenosis?

Son ≈ 5.5%, daughter ≈ 2.4%.

What is the recurrence risk for offspring of a female with pyloric stenosis?

Son ≈ 19%, daughter ≈ 7%.

What percentage of hypertension is due to single-gene mutations?

Only a small percentage (e.g., Liddle syndrome); most cases are multifactorial.

What is the heritability of blood pressure?

Approximately 30–50%.

List environmental risk factors for hypertension.

Diet, obesity, stress, sedentary lifestyle, and socioeconomic conditions. 

Differentiate Type I and Type II diabetes.

Type I: autoimmune, insulin deficiency, early onset. Type II: insulin resistance, adult onset, obesity-related.

What is the sibling recurrence risk for Type I diabetes?

1–6%.

What is the sibling recurrence risk for Type II diabetes?

15–40%.

What is the MZ twin concordance for Type I vs Type II diabetes?

Type I: 0.35–0.5; Type II: ~0.9.

What gene variant is associated with increased risk of Type II diabetes?

Variants in TCF7L2 gene across all studied populations.

Define proto-oncogene.

A normal gene that regulates cell growth and differentiation; mutations can activate it into an oncogene.

Define oncogene.

A mutated proto-oncogene that promotes uncontrolled cell proliferation (gain-of-function).

Define tumor suppressor gene.

A gene that normally inhibits cell growth; loss-of-function mutations lead to cancer.

Explain the two-hit hypothesis.

Both alleles of a tumor suppressor gene must be inactivated (one inherited, one somatic) for cancer to develop.

Give examples of tumor suppressor genes.

RB1, TP53, BRCA1, BRCA2, WT1.

What is the penetrance of hereditary retinoblastoma?

Approximately 90%.

Differentiate hereditary vs nonhereditary retinoblastoma.

Hereditary: germline mutation + somatic hit (bilateral). Nonhereditary: two somatic mutations (unilateral).

What are BRCA1 and BRCA2 associated with?

Familial breast and ovarian cancer; increased risk for pancreatic and prostate cancers.

What is the general population risk of breast cancer in women?

≈12%.

What is breast cancer risk with BRCA1 or BRCA2 mutation?

BRCA1: 50–80%; BRCA2: 40–70%.

What is ovarian cancer risk with BRCA mutations?

BRCA1: 24–40%; BRCA2: 11–18%.

List additional genes associated with hereditary breast cancer.

ATM, PALB2, TP53, CHEK2, PTEN, CDH1, STK11.

What is the function of p53?

A transcription factor that induces cell cycle arrest or apoptosis after DNA damage.

What syndrome is caused by inherited TP53 mutation?

Li-Fraumeni syndrome.

What percentage of all sporadic cancers involve p53 mutations?

Over 50%.

What oncogene is activated in chronic myelogenous leukemia (CML)?

BCR-ABL1 fusion gene (Philadelphia chromosome).

What is the role of Ras in cancer?

A small GTPase; Ras mutations (gain-of-function) found in ~30% of all cancers.

List major environmental carcinogens.

Smoking (benzopyrene), PAHs, asbestos, radiation, vinyl chloride, aromatic amines.

How does smoking contribute to cancer risk?

Accounts for ~30% of cancer deaths; introduces >50 carcinogens including benzopyrene.

What percentage of cancers are linked to obesity and poor diet?

≈14–30% of cancer deaths.