37 terms

Multifactoral disorders

Multifactorial inheritance
aka complex inheritance
Involves more than one gene, the interactions between them, and their interactions with the environmental exposures that can be influenced by behaviour, age, stage of development etc
10 per 1000 live births
incidence of single gene disorders. Decreases to 3.6 per 1000 at age 25
20 per 1000
The population prevalence of single gene disorders
3.8 per 1000
population prevalence of genome/chromosome disorders
600 per 1000
population prevalence of multifactorial disorders
Genotypic distribution of complex disorders
Tends to look more Gaussian because of the number of loci following the 1:2:1 ratio of traditional Mendelian inheritance
Qualitative traits
Tends to be more of a result of gene-gene interactions
Can't really measure
Type I DM, cleft palate, MS, Schizophrenia, Chron's disease
Quantitative traits
Tends to be more of a result of gene-environment interaction
Can be measured
height, BM, blood pressure, serum cholesterol concentration
Challenges in multifactorial inheritance
Estimating the "genetic" contribution and identify the genes, alleles and mechanism causing a given phenotype.
Identifying the "environmental" contribution to the phenotypic expression of a complex trait (even more complex!)
When one suspects multifactorial genetic conditions
When diseases is clearly familial but there is no obvious Mendelian pattern of inheritance
If continuous traits are observed such that distinct phenotypes cannot be distinguished e.g. height, BMI, etc
Expected rates of concordance for genetic disorders
MZT: 1
DZT: 0.5
Parent-child: 0.5
Sibling-sibling: 0.5
Parent-parent: 0
Relative risk (λr)
(Prevalence of disease in the relatives of an affected person) / (Prevalence of the disease in the general population)
λr = 1
no increased risk for the disease
λr > 1
increased family aggregation
But aggregation may result from shared culture/behaviors, socioeconomic status, diet, environmental exposures
Importance of population prevalence
if a trait is very frequent, you may see it in a family more often coincidentally
Factors changing a recurrence risk
# of affected individuals in the family, their relationship i.e. sib vs. cousins and in some instances, the gender of the proband
Limitations of case-control studies
Ascertainment and recall bias
Choice of controls
Ascertainment bias
affected individuals more like to refer other family members with similar trait than controls
Recall bias
affected relatives of "cases" are more likely recall other family members with the trait
Choice of controls
the only difference distinguishing cases from controls should be "disease" status. Often use spouses (shared environment), adopted siblings/children, or other patients with unrelated disease
Twin studies
A good way to determine genetic vs environmental factors contributing to complex traits
MZT concordance rate
If If a trait is entirely "genetic" then should be 100% if reared together or apart (rare)
DZT concordance rate
If If a trait is entirely "genetic" then should be 50% if reared together
MZT more concordant than DZT
strong evidence for a genetic component in etiology.
MZT and DZT equally concordant
If a trait has little or no genetic component
Limitations of twin studies
do not inform us with regards to patterns of inheritance, penetrence etc.
MZT shared genes ≠ 100% due to somatic rearrangements
Environmental exposures not necessarily identical (adulthood, intrauterine blood supply, development, birth weight may not be identical)
Concordance measures are average estimates - not looking at genetic load in specific individuals
Ascertainment bias: volunteer-based ascertainment (twin recruits twin) vs. population-based ascertainment (ID twins then health status)
Clues implicating genetic-environmental interactions
Incidence in relatives versus spouses
Maternal versus paternal effects
Sex ratio differences
Half-sib risks
Clusters in space and time (epidemics)
Changes in recurrence risks with time and population incidence
Why it is important to distinguish genetic and environmental influences
Better targeting of treatment or preventative measures
Better estimation of recurrence risks for genetic counselling:
-Often need empirical risk data
Calculating heritability (h²)
(V in DZ pairs - V in MZ pairs)/V in DZ pairs

(V = variance)
= Vg + Vc + Ve
Genetic variance
Cultural/familial variance
part of environmental variance
Non-familial variance
part of environmental variance
Proband concordance rates
2x#concordant pairs / (2x#concordant pairs + #discordant pairs)
Genetic risk factors
More severe disease & more affected relatives suggests increased allelic load
Cleft lip and palate
Genes: TBX1, MSX1, FGFR1 = 5%, 2%, and 1% non-syndromic forms, respectively
Environment: teratogenic exposure (rubella embryopathy, thalidomide, anticonvulsants). Maternal smoking
Beyond a certain threshold, individual displays the phenotype
Recurrence risk for multifactorial disorders for first degree relatives, children, or sibs