Multifactorial Inheritance

Multifactorial (complex) inheritance involves the combined effects of multiple genetic variants and environmental factors. These conditions do not follow Mendelian ratios and instead exhibit a continuous distribution of liability in the population. Disease occurs when an individual's combined genetic and environmental burden exceeds a threshold.

• Threshold model: Liability is normally distributed in the population. Individuals who exceed a threshold develop the condition. The threshold may differ by sex (e.g., pyloric stenosis is more common in males, so females require a higher liability to be affected).
• Heritability (h2): The proportion of phenotypic variance attributable to genetic factors, estimated from twin and family studies. Higher heritability means stronger genetic contribution. Example: schizophrenia h2 ~80%, type 2 diabetes h2 ~40-60%.
• Recurrence risk: Empirically derived (not calculated from Mendelian ratios). Typically 2-5% for first-degree relatives, declining sharply for more distant relatives. Risk increases with: (1) more affected relatives, (2) more severely affected proband, (3) proband of less commonly affected sex. The 2-5% figure is a default, not a rule: some highly heritable traits run considerably higher, and autism is the one most often misquoted at the low figure. Always use the empiric number for the specific condition.
• Concordance in twins: Monozygotic (MZ) twin concordance > dizygotic (DZ) concordance indicates genetic contribution. If MZ concordance is <100%, environmental factors are also involved.
• Sex-specific threshold differences: When a condition is more common in one sex, the less commonly affected sex has a higher liability threshold. Their relatives therefore have a higher recurrence risk (Carter effect).
• Environmental factors: Includes teratogens, nutrition, medications, and stochastic developmental variation. Folic acid supplementation reducing neural tube defect risk is the classic example of modifying environmental contribution.
• Polygenic risk scores (PRS): Aggregate effect of many common variants, each with small individual effect. Increasingly used in risk prediction for coronary artery disease, breast cancer, and diabetes but not yet standard of care for most conditions.

• Neural tube defects (NTDs): Recurrence risk ~3-5% after one affected child. Periconceptional folic acid (400 mcg daily, 4 mg if prior affected pregnancy) reduces risk by 50-70%. Higher recurrence when proband has a more severe defect (anencephaly > spina bifida occulta).
• Cleft lip +/- palate (CL/P): Recurrence risk ~4% for siblings of an affected individual. Higher risk with bilateral cleft (more severe) and when the proband is female (less commonly affected sex). Cleft palate alone is genetically distinct from CL/P.
• Congenital heart defects (CHDs): Overall incidence ~1/100 live births. Recurrence risk ~2-4% for siblings. Specific types cluster in families (e.g., left-sided obstructive lesions). Some CHDs have known single-gene causes (22q11.2 deletion, Noonan syndrome) that must be excluded.
• Type 1 diabetes: MZ twin concordance ~30-50%, indicating strong but incomplete genetic contribution. HLA-DR3/DR4 heterozygotes carry the highest risk. Environmental triggers (viral infections, diet) also implicated.
• Autism spectrum disorder: the clearest worked example of the Carter effect on this page. Roughly 3 to 4 affected males per affected female, so an affected girl implies a higher familial liability and raises sibling recurrence, roughly doubling it. Sibling recurrence is ~10-20% overall, well above the usual multifactorial range, against twin heritability estimates of 60-90%. Identifiable single-gene and copy number causes account for a meaningful minority, so a multifactorial label should be applied only after testing is uninformative.