Exam 5: Multifactorial Disorders Flashcards Preview

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Flashcards in Exam 5: Multifactorial Disorders Deck (46):

adoption studies

obtains information of genetic and environmental factors
adopted child grow up in different environment than biological parent or siblings and develops same disease - significant genetic component
adopted child grow up in same environment as adopted parent and siblings and develops same disease - strong environmental condition


affected sibpair analysis

genome of affected sib pairs is analyzed for the presence of shared polymorphic SNP markers - loci shared by affected siblings are more expected to be associated with disease than by chance along



each parent has two alleles and expresses both of them at the same time
each parent transmits one allele to the children


concordance rate

presence of same trait in both members of twin pair;
probability that pair will both have a certain characteristic, given that one has a characteristic
concordant when both twins either have or do not have the trait - discordant trait when trait is not shared
Diseases with significant genetic component will show higher concordance rate in monozygotic twins than in dizygotic twins


Multifactorial diseases

arise from a combination of polymorphic alleles coding for proteins with slightly varying functions that are not ideal for the current environment
more than one gene contributes to the phenotype
quantitative trait - can be measured


contributing allele

alleles which contribute to the expression of a certain trait - quantitative and can be measured (like height)


category distribution of multifactorial disease

distribution of phenotypes like a bell curve
more genes involved, more category distribution and more bell curve


More genes involved in multifactorial disease means

lower probability of offspring inheriting all or none of contributing alleles
lower fraction of extreme phenotypes at fringes of bell curve


disease association of an allele

statistical measure that quantifies how the allele in question influences the risk for the disorder
alleles with stronger disease association will cause a larger increase in relative risk


dizygotic twins (DZ)

simultaneous fertilization of two eggs by two sperm
no more genetically similar than independently conceived siblings


empirical risks

risk based on observation - from epidemiological studies
empirical measures to describe complex diseases are incidence and prevalence



transmission unit - individual allele combination in these regions are transmitted as a unit
several allele variants and genes in one chromosomal region
HLA genes are haplotypes


human leukocyte antigens (HLA)

HLA gene encodes cell surface proteins used in initiation of immune response
polymorphic with dozens of allelic variants - transmitted as a unit (haplotypes)
expressed in a codominant manner
when finding a donor for organ transplant - match HLA haplotypes of donor and recipient as closely as possible
certain HLA haplotypes favor genetic diseases


variation in HLA region

accounts for 40% of genetic risk for T1D, particularly in DR-DQ haplotypes


HLA-B haplotypes

risk for spondyloarthropathy


HLA-C haplotypes

risk for psoriatic arthritis



describes how many new cases are recorded in a given time, divided by size of population


liability distribution

bell curve of phenotype distribution in a population - used in multifactorial diseases
extreme phenotypes: all or none contributing alleles present
Fewer extremes: lower likelihood to obtain all or none of contributing alleles


major histocompatibility complex (MHC)

locus found on chromosome 6
contains multiple genes of three classes
MHC class I & II genes encode cell surface proteins that are important in initiating immune response - HLA
very little meitotic recombination inside MHC


model-free linkage analysis

mapping an unknown number of contributing loci - based on assumption that relatives that are affected by same disorder will have disease-causing alleles in common
avoids making incorrect assumptions about number of genes involved
insensitive - need a very large sample size to detect significant deviation from 50% allele sharing in siblings
rare alleles making minor contributions will be missed
imprecise - maps contributing allele to very large chromosomal region


monozygotic twins (MZ)

arise from single fertilized egg that splits and gives rise to two genetically identical children


noncontributing allele

allele that does not contribute to multifactorial disease



proportion of population that is affected by disease at any given time


prevalence figures for genetic diseases show

multifactorial inheritance most common genetic diseases


prevalence of chromosomal and genomic disorders of population



prevalence of single gene disorders of population



prevalence of multifactorial inheritance disorders of population



protective alleles

alleles that decrease risk of disease
such as certain DR-DQ haplotypes that decrease risk for T1D


susceptibility alleles

alleles that increase the risk for a disease (found more often associated with disease)
such as certain DR-DQ haplotypes that increase risk for T1D


pyloric stenosis

area between stomach and duodenum is narrowed - vomiting and constipation
more common in males (1/200 males vs 1/1000 females)
low threshold for male births and higher threshold for female births (males need fewer contributing alleles to express disease than females)
Since affected female has more contributing alleles than an affected male, has a higher risk of having affected sibling than male and even higher risk of having an affected brother (need fewer contributing alleles to develop disease)


quantitative traits

traits that can be measured like height
determined by many genes - multifactorial
in multifactorial disease called liability


recurrence risk

chance of having another sibling born with disease
in multifactorial disorders recurrence risk is higher than occurrence risk
Every time affected child is born into a family, increases (assume higher number of contributing alleles in parents)


relative risk (RR)

risk prediction based on genotype
calculated from strength of disease association of an allele - stronger disease association = increased RR
RR = (a/(a+b))/(c/(c+d))
a = occurrence of diseased patients with allele
b = control of people with allele
c = occurrence of diseased patients without allele
d = control of people without allele
if R for allele X is 1.5 and you have allele X, your risk of having disease is 1.5 times risk of non-carrier


Relative risk ratio (lamda-r)

risk prediction based on family history - family members more likely to be affected
comparing empirical measures for frequency of a disease in relatives of affected and unaffected probands
"r" designates relationship (s for siblings, p for parents)
lamda-r = prevalence of disease in relative "r" of affected person / prevalence in general population


Risk for multifactorial birth defects in general population



Risk for multifactorial birth defect if second degree relative is affected

0.7-2% (2-4x)


Risk for multifactorial birth defect if first-degree relative is affected

3-4% (6-8x)


Risk for multifactorial birth defect if two first degree relatives are affected

5-8% (10-16x)


Risk for multifactorial birth defect if three first degree relatives are affected

9-12% (18-24x)


Risk for multifactorial birth defect if identical twin is affected

20-30% (40-60x)


threshold of liability

disease results if threshold of liability is crossed (above threshold in liability distribution)
variable - often different for males and females & influenced by environmental factors
if have a higher threshold - disease needs more contributing alleles to be present
if females have a higher threshold, an affected female has more contributing alleles and has a higher risk of having affected siblings than a male (because parents likely have more contributing alleles)


twin studies

used to study environmental influence on development of disease - assumed to grow up under same environment
diseases with significant genetic component is more likely shared by monozygotic twins than dizygotic twins
used to calculate heritability


heritability (H^2)

estimate of how much of the observed phenotypic variation between individuals is due to genetic factors
Heritability = (Concordance MZ - Concordance DZ) x 2


high heritability value

trait is determined predominantly by genetic factors


type 1 diabetes

autoimmune destruction of beta cells of the pancreatic islet
concordance rate in MZ twins is 40% - not due to genetic factors alone
sibling of an affected person is 12 times as likely to develop T1D
variation in HLA gene accounts for 40% of genetic risk - strong but not exclusive


Pedigree characteristics of multifactorial diseases

closely resemble autosomal dominant inheritance with incomplete penetrance
Do not follow Mendelian patterns
Show familial aggregation - # of contributing alleles is high in affected families
incomplete penetrance - influcence of environment factors
more common among close relatives