Multifactoral Disorders

Question 1

clubfoot

Answer 1

common birth defect with multifactoral inheritance aka not follow mendelian
-genetic (family hx 6x risk)
-environment (smoking 1.4x risk)

Question 2

quantitative trait

Answer 2

multifactoral disease risk can be quantified/measured, not all or nothing
-guassian distribution (normal)
-genetic + environment contributions

Question 3

percentage of disorders

Answer 3

1. single gene/medelian = 2%
2. chromosomal/genomic = 0.38%
3. multifactoral = 60% of pop (diabetes, heart disease)

Question 4

QTL

quantitative trait loci

Answer 4

determines quantitative traits

polymorphic (diff alleles in gene pool)
-alleles are contributing or not to trait

liability to disease so alleles raise or lower risk

Question 5

threshold model

Answer 5

for a trait with 2 genes contributing alleles range from 0 (all recessive) to 4 (all dominant)
-1/2/3 all heterozygous mix

shows normal distribution

Question 6

threshold of liability

Answer 6

indivs above threshold = dev disorder

lower threshold = higher incidence

vary by sex- threshold for boys is lower

Question 7

liability distributions

Answer 7

pop of “indivs w/ affected relative” = higher mean risk than general pop

indivs placed in a pop (general or affected) based on family hx then determine threshold by sex

Question 8

pyloric stenosis

Answer 8

affects boys more freq than girls so threshold of liability lower for males

recurrent risk higher for fams w/ affected female bc more contributing alleles (need more contributions for a female to be affected)

Question 9

twin studies

Answer 9

monozygotic twins = genetically identical
dizygotic = 50% genes

-both MZ and DZ must have similar environ so that genetics is the variable

concordance higher MZ = trait has strong genetic component

Question 10

heritability H2

Answer 10

H2 = (concordance MZ-concordance DZ) x 2

Question 11

adoption studies

Answer 11

adopted kids vs biological parents so genetics shared but environ variable
-high concordance = strong genetics

OR adopted kids vs adoptive parents so environ same but genetics variable
-high concordance = strong environ component

Question 12

Type 1 Diabetes

approaches

Answer 12

1. candidate gene approach- look for polymorphisms in genes involved in immune response then calc how much the risk is elevated by
2. genome wide association study, GWAS-find SNPs that assoc w/ T1D then calc how likely it is not random

Question 13

outcomes for GWAS

Answer 13

1. analyze whole genome for SNP markers in affected families
   -SNP is landmark on chromo NOT variation contributing to disease
2. compare SNP of affected vs unaffected
3. look for markers that occur more often in diseased indivs
4. calc odds that assoc is real vs by chance

Question 14

diabetes risk locus

Answer 14

@chromo VI (6p)
-codes for human leukocyte antigen (HLA) genes
-region is inherited as block aka haplotype so few or no crossovers at locus
-very polymorphic, also called major histocompatibility complex

Question 15

HLA haplotypes

Answer 15

HLA proteins mediate antigen presentation to T cells so

variants can either be susceptive or protective

T1D is autoimmune disorder, HLA genes determine immune specificity

Question 16

HLA haplotype inheritence

Answer 16

as a block
codominant so both maternal and paternal copies expressed

Question 17

other HLA autoimmune disorders

Answer 17

1. spondyloarthropathy, HLA-B
2. psoriatic arthritis, HLA-C

Question 18

risk scores

Answer 18

relative risk (RR) or odds ratio (OR)

ratio less than 1 = allele is protective

don’t need family hx bc risk det by molecular analysis

Question 19

relative risk ratio

Answer 19

prevalence of disease in relative r of affected person / prevalence in general pop

can be det by patient interview, not need molecular genetics

Question 20

characteristic inheritance

Answer 20

-not follow mendelian
-show famial aggregation
-freq show incomplete penetrance
-more common among close relatives

Question 21

typical recurrence risk

Answer 21

est empirically

for common birth defects:
general pop = 0.5%
first degree relative = 3-4%
two first degree relatives = 5-8%

low vs single gene/mendelian (25% or 50%)