Multifactorial Genetics Flashcards
What is the most common genetic condition and what is its incidence?
Multifactoral disorders affect 20-40% of people with genetic conditions.
What are some examples of multifactorial disorders and their incidence in population?
- Oral clefts (1/500 - 1/1,500)
- Neural tube defects (1/100 - 1/1000)
- Congenital heart defects (1/100)
- Diabetes (1/100)
- Schozophrenia (1/100)
- Hydrocephalus
What is the most common multifactorial condition found in newborns?
Congenital heart defects (1%)
What are some difficulties in understanding multifactorial genetics?
- Inheritance of multifactorial conditions is more difficult to analyze
- Genetic patterns are not clear cut in individuals families
- Multifactorial conditions are difficult to replicate in animal studies due to environmental conditions
- Separating the effects of genetics and the envrionment to study the conditions is hard
Quantitative traits
Traits that can be measured with a number (i.e. weight, height, enzymatic BP, IQ)
- Inheritance of quantitative traits is multifactorially determined: caused by additive effects of genetics and environmental conditions
What are some of the characteristics of inheritance patterns of multifactorial conditions?
- Follow a bell shaped curve
- Additive effects of genetic and environmental factors
Concordance
Means that both twins in a twin study are affected.
Twin Studies
One approach to solve the influence of genetics vs. environment. The frequency of concordance of monozygotic twins is compared with that of dizygotic twins.
In twin studies, what is the expected concordance rate in a pure genetic condition?
For monozygotic twins it is 100% and for dizygotic twins it is less than 100% and similar to the concordance rate among siblings
In twin studies, what is the expected concordance rate in a pure environmental condition?
Concordance rates for monozygotic and dizygotic twins will be the same/very close
In twin studies, what is the expected concordance rate in a multifactorial condition?
In multifactorial conditions, the concordance rate of monozygotic twins is higher than dizygotic twins but not 100%
How is the effect of the environment on a genotype studied?
Monozygotic twins reared apart
What are the difficulties with twin studies?
- Monozygotic twins are treated differently than dizygotic twins
- Somatic mutations can occur during development leaving monozygotic twins not completely identical
- Uterine environment for monozygotic twins may not be identical
- Number of monozygotic twins reared apart is small
Relative risk ratio
Lambda r = (prevalance of the disease in a relative “r” of an affected person)/(population prevalance of the disease)
- Compares the frequency of a disease within a family to the disease’s frequency in the general population
Heritability
Percentage of the population variation in a trait that is due to genes
Heritability formula
H=2(cmz-cdz)
- cmz: concordance rate for monozygotic twins
- cdz: concordance rate for dizygotic twins
For a pure genetic condition, H is close to 1
For different relationships, what is the proportion of alleles family members have in common?
- Monozygotic twins = 1
- First degree (mom & dad) = 1/2
- Second degree (aunts & uncles) = 1/4
- Third degree relatives (cousins) = 1/8
What is the recurrence risk for multifactorial conditions for first degree relatives?
The square root of the prevalance of the condition on the general population
Which population has a higher empiric risk for NTD?
Britian
Anencephaly
Failure of the brain to develop normally. Fatal.
Spina bifida
Failure of the spine to develop normally
Encephalocele
Sac-like protusion from base of skull. Frequent mental retardation & neurological defects.
Genetics of NTD
Mutations in MTHFR 5,10 (methylenetetrahydrofolate reductase) cause instability of the enzyme. This hinders the recycling of tetrahydrofolate and interferes with the methylation of homocysteine to methionine.
Mekel-Gruber Syndrome
Autosomal recessive condition that can cause polydactyly, encephalocele, polycystic kidneys, and seizures.
Multifactorial genetics of diabetes
Mutation in PTPN1 (protein tyrosine phosphatase N1) (found in 35% of population) on chromosome 20. The gene product represses the insulin response. Excessive amounts of the protein would decrease inability to responde to insulin and thus people tend to develop diabetes.
Chron’s disease
Multifactoral inheritance. 20% of cases are causes by mutation on IBD1 (Nod2, Card15) located on chromosome 15. THe gene is responsible for non-specific immune response. Carriers of 1 mutation have 2-3% chance of developing mild Chrons. Carriers of 2 mutations have 20-40% risk of developing severe Chrons.
MTHFR
Gene involved in development of NTD. Mutations in NTHFR 5,10 (methylenetetrahydrofolate reductase) cause instability of the enzyme. This hinders the recycling of tetrahydrofolate and interferes with the methylation of homocysteine to methionine.
PTPN1
Gene involved in increased risk of diabetes. Mutation in PTPN1 (protein tyrosine phosphatase N1) (found in 35% of population) on chromosome 20. The gene product represses the insulin response. Excessive amounts of the protein would decrease inability to responde to insulin and thus people tend to develop diabetes.
IBD1
Gene involved in Chron’s Disease. 20% of Chron’s cases are causes by mutation on IBD1 (Nod2, Card15) located on chromosome 15. THe gene is responsible for non-specific immune response. Carriers of 1 mutation have 2-3% chance of developing mild Chrons. Carriers of 2 mutations have 20-40% risk of developing severe Chrons.
Which ethnicity has the highest incidence of CL/P? The lowest?
Highest is Asian populations. Lowest is African Americans.
What teratogens can cause CL/P?
Dilantin, alcohol, valproic acid, anticonvulsants.
TGFA, TGFB3, IRF6, MSX1
Genes involved in the etiology of non-syndromic oral clefts. The more at risk genes present in the family, the more severe the clefting is.
What gense contribute to nonsyndromic oral clefts?
TGFA, TGFB3, IRF6, MSX1
Van der Woude Syndrome
LOWER LIP PITS, hypodontia, cleft lip w/ or w/o palate
- Autosomal dominant inheritance.
- Linkage to chromosomes 1 & 17
What inheritance pattern does Van der Woude Syndrome follow?
Autosomal dominant
