Multifactoral disorders

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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)

V

= Vg + Vc + Ve

Vg

Genetic variance

Vc

Cultural/familial variance
part of environmental variance

Ve

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

√Incidence

Recurrence risk for multifactorial disorders for first degree relatives, children, or sibs

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