Flashcards in Multifactorial Inheritance (Fingerlin L1) Deck (33):
What is a multifactorial (complex) inheritance pattern?
A disease that "runs in families" but is due to complex interactions between genetics and environmental factors.
What is a polygenetic or multigenetic effect?
Collective effect of multiple loci along the genome that either raises or lowers an individuals susceptibility to disease; combined with environmental exposures.
Environmental exposures may trigger, accelerate, exacerbate or protect against the disease
What is a modifier gene?
Gene whose action can affect the occurrence or severity of an otherwise Mendelian disease.
Since we do not understand the underlying mechanisms of gene-gene and gene-environment interactions for most complex disorders, what do clinicians rely on to assess risk for a patient?
Empirically derived risk figures
Concordant vs. Discordant?
Concordant = two related individuals in a family have the same disease
Discordant = only one member of a pair of relatives has the disease
A hallmark feature of complex inheritance is __________; however ________ does not necessarily imply genetic contribution to a disease.
familial aggregation (affected individuals cluster in families)
What is Relative Risk (lambda_r)? How is the value of rel. risk interpreted?
What is lamba_s?
Lambda_r = (prevalence of disease in affected person's relatives) / (prevalence of disease in general population)
Count sick relatives. Divide by sick people in general pop.
Larger lambda_r = greater familial aggregation
lambda_r = 1 means person's risk is same as general pop. risk
lambda_s uses siblings only for numerator value
See table p. 153 for appropriate values
Other than Relative Risk, what is another way to asses familial aggregation?
Case control study.
Frequency of disease in family (positive family history) is compared to control group (matched for age, ethnicity)
Subjct to bias such as ascertainment bias = accurate reporting of disease
Biases, causation issues generally associated with case control studies?
ascertainment bias = likelihood of relatives to report disease
recall bias = not reporting due to not knowing of/about the disease
association does not necessarily imply causation
e.g. ethnicity vs. diet - may not know which is the real causative factor
Disease concordance less than 100% in monozygotic twins is strong evidence that nongenetic factors such as ___________ play a role in the disease.
environmental influences such as exposure to infection or diet
other effects such as somatic mutations, aging, differential X-inactivation in one female twin compared to the other
In type 1 diabetes, what are the following values?
1. Risk in general population?
2. Risk to sibs of type 1 diabetes pt?
3. lambda_s for a sibling of a type 1 diabetes pt?
3. lambda_s = 6/0.4 = 15
What are the 4 characteristics of a complex inheritance disease? (book p. 159)
1. Genetic component but not "single-gene" and not simple mendelian pattern
2. Familial Aggregation
3. Discordance in disease phenotype despite same predisposing allele among relatives.
4. Commonality of disease drops off as relatives become more "distant". Ex: high concordance btwn MZ or DZ twins. low concordance btwn distant cousins
What are the 4 characteristics of a complex inheritance disease? (Lecture notes p. 1)
1. Familial Aggregation
2. Not simple Mendelian inheritance pattern
3. Likely due to gene variants and environmental (non-genetic) factors.
4. No simple relationship between allelic variant & trait when considering the whole population.
Cystic Fibrosis penetrance and expressivity?
Degree of pulmonary disease?
penetrance = 100%
expressivity = variable
mutation of specific alleles in CFTR gene are directly related to pancreatic insufficiency
pulmonary disease not directly correlated to specific mutations in CFTR gene. perhaps genetic modifiers elsewhere in the genome have an expressivity effect. ( and some environmental effects)
Give some examples (from lecture and text) of multifactorial inheritance traits.
Lecture: some cancers, type 1 diabetes, type 2 diabetes, alzheimer disease, inflammatory bowel disease, schizophrenia, cleft lip/palate, hypertension, rheumatoid arthritis, asthma
Text: Digenic Retinitis Pigmentosa (gene-gene interaction)
Venous Thrombosis (gene-gene predisposition to hypercoagulability states)
Hirschsprung Disease (p. 162), Anencephaly, spina bifida and other nerural tube closure defects, coronary artery disease
What is heritibility (h^2) of a complex inheritance trait?
The proportion of variance in a trait that is due to genetic variation.
Characteristics of complex traits from lecture slide?
1. incomplete penetrance
2. variable expressivity
3. heterogeneity - allele and locus
4. presence of phenocopies.
Describe the complex inheritance pattern of Digenic Retinitis Pigmentosa
Two rare mutations in two different unlinked genes for photoreceptor proteins (peripherin locus and ROM1 locus) interact.
Heterozygous for _one_ of either mutation = no disease
Heterozygous for _both_ mutations = disease
Deleterious effects of both genes causes cell damage, photoreceptor death, loss of vision
The two proteins interact noncovalently in the photoreceptors so the compound insult leads to disease state. (p 160)
In type 1 diabetes up to _______% of the population has one of __________ haplotypes, but incidence of disease is only ____%
20%, one of the two highest risk haplotypes
0.4% has disease
Environmental, lifestyle factors?
Type 1 diabetes vs. type 2 diabetes.
Which is insulin dependent?
What proportion of cases does each represent?
type 1 insulin dependent (IDDM) 10% of cases
type 2 non-insulin dependent (NIDDM) 88% of cases
Explain variable expressivity.
individuals with same allelic variant that do not show the same disease or quantitative phenotype characteristics.
Do type 1 and type 2 diabetes display familial aggregation?
yes, but only one of the two types will be present in a given family
Type 1 diabetes incidence and age of onset?
1 in 500 (0.2%), lower in African and Asian populations
onset in childhood or adolescence
Autoimmune destruction of Beta cells in the pancreas that normally produce insulin
Discuss the two types of allelic heterogeneity.
What example was given in lecture of a disease exhibiting allelic heterogeneity?
1. Different alleles in same gene result in same trait.
2. Different alleles in same gene result in different trait.
Describe locus heterogeneity.
What example was given in class for locus heterogeneity?
Variants in different genes result in very similar clinical presentation.
Early onset Alzheimer disease. mutations in 3 different genes all result in same clinical presentation of early onset AD. Basically, a mutation any one of the proteins in the pathway leading to alzheimers (see AD vignette) can cause disease.
environmentally caused phenotype (disease) that mimics the genetic version of the trait.
What is Thalidomide?
morning sickness medication (pregnant women) that caused limb malformations. the same limb malformations were previously seen from genetic disease, but thalidomide increased the prevalence of the malformations thus mimic-ing the genetic disease.
List risk factors for type 2 diabetes
increasing age, obesity, physical inactivity, family history, prior gestational diabetes, impaired glucose tolerance (IGT)
associations: high LDL, triglycerides and blood pressure
control often attained with diet and exercise (but not always)
What are some pieces of evidence for a genetic component in type 2 diabetes?
1. aggregates in families (early 1900's)
2. concordance rates for MZ twins twice that for DZ twins
3. 3 to 4 times risk for relatives of type 2 diabetes patients as compared to the risk of the general population.
4. intermediate traits of blood glucose and insulin levels have heritability rates as high as 50%
Type 2 diabetes pathogenesis...
Insulin resistance + genetic predisposition + environmental factors
---> insulin deficiency ---> impaired glucose tolerance
---> type 2 diabetes
Cystic fibrosis exhibits 100% penetrance but variable expressivity of ____________ and ___________ involvement.
lung and pancreatic
________% of all patients with type ____ diabetes are heterozygous for mutations in the HLA class II locus of the ______.
95% (compared to 50% in the general population)
type 1 diabetes
MHC (major histocompatibility complex)