Exam 5: Multifactorial Disorders

Question 1

adoption studies

Answer 1

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

Question 2

affected sibpair analysis

Answer 2

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

Question 3

codominant

Answer 3

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

Question 4

concordance rate

Answer 4

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

Question 5

Multifactorial diseases

Answer 5

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

Question 6

contributing allele

Answer 6

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

Question 7

category distribution of multifactorial disease

Answer 7

distribution of phenotypes like a bell curve

more genes involved, more category distribution and more bell curve

Question 8

More genes involved in multifactorial disease means

Answer 8

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

Question 9

disease association of an allele

Answer 9

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

Question 10

dizygotic twins (DZ)

Answer 10

simultaneous fertilization of two eggs by two sperm

no more genetically similar than independently conceived siblings

Question 11

empirical risks

Answer 11

risk based on observation - from epidemiological studies

empirical measures to describe complex diseases are incidence and prevalence

Question 12

haplotype

Answer 12

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

Question 13

human leukocyte antigens (HLA)

Answer 13

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

Question 14

variation in HLA region

Answer 14

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

Question 15

HLA-B haplotypes

Answer 15

risk for spondyloarthropathy

Question 16

HLA-C haplotypes

Answer 16

risk for psoriatic arthritis

Question 17

incidence

Answer 17

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

Question 18

liability distribution

Answer 18

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

Question 19

major histocompatibility complex (MHC)

Answer 19

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

Question 20

model-free linkage analysis

Answer 20

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

Question 21

monozygotic twins (MZ)

Answer 21

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

Question 22

noncontributing allele

Answer 22

allele that does not contribute to multifactorial disease

Question 23

prevalence

Answer 23

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

Question 24

prevalence figures for genetic diseases show

Answer 24

multifactorial inheritance most common genetic diseases

Question 25

prevalence of chromosomal and genomic disorders of population

Answer 25

0.38%

Question 26

prevalence of single gene disorders of population

Answer 26

2%

Question 27

prevalence of multifactorial inheritance disorders of population

Answer 27

60%

Question 28

protective alleles

Answer 28

alleles that decrease risk of disease

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

Question 29

susceptibility alleles

Answer 29

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

Question 30

pyloric stenosis

Answer 30

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)

Question 31

quantitative traits

Answer 31

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

Question 32

recurrence risk

Answer 32

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)

Question 33

relative risk (RR)

Answer 33

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

Question 34

Relative risk ratio (lamda-r)

Answer 34

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

Question 35

Risk for multifactorial birth defects in general population

Answer 35

0.5%

Question 36

Risk for multifactorial birth defect if second degree relative is affected

Answer 36

0.7-2% (2-4x)

Question 37

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

Answer 37

3-4% (6-8x)

Question 38

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

Answer 38

5-8% (10-16x)

Question 39

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

Answer 39

9-12% (18-24x)

Question 40

Risk for multifactorial birth defect if identical twin is affected

Answer 40

20-30% (40-60x)

Question 41

threshold of liability

Answer 41

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)

Question 42

twin studies

Answer 42

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

Question 43

heritability (H^2)

Answer 43

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

Question 44

high heritability value

Answer 44

trait is determined predominantly by genetic factors

Question 45

type 1 diabetes

Answer 45

autoimmune destruction of beta cells of the pancreatic islet
common
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

Question 46

Pedigree characteristics of multifactorial diseases

Answer 46

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