1-33 Multifactorial Traits

Question 1

Monogenic vs. complex/multifactorial trait disorders

Answer 1

monogeneic: single gene tracked through family, mendelian pattern of inheritance

complex/multifactorial/polygenic: non mendelian pattern of inheritance, contributions from multiple genes with variance and contributions of environmental factors- more affected in a family than we would expect but not following mendelian inheritance

most common reason for congenital malformations

Question 2

Qualitative vs quantitative multifactorial traits

Answer 2

qualitative: trait is present or absent (cleft lip)
quantitative: trait varies in degree (height intelligence)

Question 3

relative risk

Answer 3

risk to individual / risk to general population

Question 4

Cleft lip +/- cleft palate

Answer 4

example of multifactorial trait inheritence

cleft lip: most often unilateral (75%) and left side, 65% of cases associated with cleft palate, most cases not syndromic (they are stand alone)

twice as common in males

100 fold higher risk of sibling having CL+-CP than normal population

when index case is female, the recurrence risk is higher than when the index case is male

multiple genes AND environmental factors contribute

Question 5

multifactorial threshold model

Answer 5

• multi genes and environmental factors contribute to liability to the trait
• liability is a continuous variable within the population
• the explain the dichotomoty of trait we set a threshold; the trait appears when an individual’s liability exceeds the threshold (for cleft lip/palate, the threshold for males is lower than the threshold for females)
• every additional family member expressing the trait makes it more likely for another one to express it
• the less frequently affected sex is more likely to transmit the trait

Question 6

mixed model

Answer 6

combines single gene effect with multifactorial threshold model: a major contribution form one or a few genes, polygenic component, environmental component

helpful to ID individual genes that might drive a phenotype

Question 7

heritability

Answer 7

applies to quantitative traits
the fraction of the total phenotypic variance that is attributable to genes

calculated from variance in MZ twins vs DZ twins

measure the extent to which different alleles at various loci are responsible for a give trait in a population

LIMITS: only applicable to the population from which it is derived, doesn’t well separate environmental from genetic contributions, should not be considered immutable (ex PKU, high heritability but can alter effect by controlling diet)

Question 8

Empiric data

Answer 8

in the absence of good models we use empiric data to predict recurrence risks

do not account for possible herogeneity (ex. that a trait is multifactorial in some families and has a major single gene effect in others)

empiric data must be based on same population (ex. caucasians vs Japanese)