complex disease

Question 1

what is gnomAD used for?

Answer 1

a database used to map genome and exome datasets
also maps rare mutations

Question 2

what is GWAS used for?

Answer 2

examines a panel of SNPs for association with disease
compares the disease phenotype with the wild-type phenotype

Question 3

what is the missing heritability problem?

Answer 3

GWAS cannot entirely explain the heritability of complex diseases

Question 4

define linkage disequilibrium

Answer 4

• a term for linked alleles
• instead of alleles being independent and evenly distributed in the genome, they are inherited together

Question 5

define haplotype blocks

Answer 5

one SNP which maps to a group of alleles
these are patterns of linkage disequilibrium

Question 6

define the odds ratio

Answer 6

finds the strength of the association between two genetic events

Question 7

what odds ratio implies the independence of alleles?

Answer 7

1

Question 8

what odds ratio implies a positive correlation of alleles?

Answer 8

> 1

Question 9

what odds ratio implies a negative correlation of alleles?

Answer 9

<1

Question 10

why are complex diseases considered multifactorial?

Answer 10

genetic and environmental components contribute to getting the disease

Question 11

what does a low odds ratio of several factors imply?

Answer 11

the factors contribute equally

Question 12

what is the threshold for genome-wide significance?

Answer 12

p < 5 x10^-8

Question 13

in a GWAS study, what proportion of events is expected to be nonsignificant?

Answer 13

1 in 20

Question 14

what is the significance of the TCF7L2 allele in diabetes?

Answer 14

intronic variant
a transcription factor for pancreatic variants

Question 15

what is the significance of the FTO intronic variant in diabetes?

Answer 15

involved in body weight regulation

Question 16

what is the significance of the CDKN2A allele in diabetes?

Answer 16

a non-coding regulatory variant

Question 17

what is the lifetime risk of breast cancer for females?

Answer 17

8-12%

Question 18

how many common low-risk alleles for breast cancer have been identified?

Answer 18

66 in the non-coding region

Question 19

what are the two risk alleles for breast cancer?

Answer 19

BRCA-1 and BRCA-2; autosomal dominant mutation

Question 20

what percentage of sufferers have the large risk alleles for breast cancer?

Answer 20

5%

Question 21

define heritability

Answer 21

the degree of variation within a population caused by genetic variation

Question 22

name 3 sources of missing risk

Answer 22

• epigenetics
• false positives
• difference in the 3D structuring of the genome

Question 23

what is the lifetime risk of developing complex disease?

Answer 23

66%

Question 24

how is complex disease multifactorial?

Answer 24

they are polygenic and influenced by environmental factors

Question 25

define the minor allele frequency

Answer 25

the frequency at which the 2nd most common allele is present in the population, usually a mutation

Question 26

at what percentage do common SNPs lie?

Answer 26

> 5%

Question 27

at what percentage do rare SNPs lie?

Answer 27

< 5%

Question 28

what is the equation for heritability?

Answer 28

genetic variance / phenotypic variance

Question 29

what is the benefit of GWAS over family-based studies?

Answer 29

- family-based studies are too small of a scale - GWAS studies a much larger population and is better at finding rare risk alleles - but GWAS is not deterministic

Question 30

what is the equation for phenotypic variation?

Answer 30

genetic variation + phenotypic variation

Question 31

what is the common disease common variant model?

Answer 31

complex diseases like type ii diabetes have many risk alleles that confer small increase in risk

Question 32

describe an intermediate complex disease

Answer 32

has one major risk allele and several other small ones eg. breast cancer

Question 33

describe the risk alleles of parkinson's

Answer 33

a small number of dominant risk alleles confer large risk

Question 34

how do twin studies assess the role of genetic input in disease?

Answer 34

- monozygotic twins share 100% genetic information - dizygotic twins share 50% genetic information - both share 100% environment

Question 35

what would we expect to see in a twin study for a disease with a strong genetic component?

Answer 35

we would see higher rates of disease in monozygotic twins than dizygotic

Question 36

what would we expect to see in a twin study for a disease with a strong environmental component?

Answer 36

we would see similar rates of disease among mono and dizygotic twins

Question 37

what does a high difference in concordance between mono and dizygotic twins tell us about heritability

Answer 37

there is high heritability, i.e. there is a larger genetic component

Question 38

do phenotypes show continuous or discontinuous variation?

Answer 38

continuous - phenotypes can blend

Question 39

what is the threshold for disease theory?

Answer 39

- complex disease is caused by several different genes conferring risk - risk alleles accumulate until the threshold for disease is reached - susceptibility to disease is continuous but reaching the threshold is discontinuous

Question 40

what is the curve of liability caused by?

Answer 40

a combination of genetic and phenotypic influences

Question 41

does major depression have a continuous or discontinuous phenotype?

Answer 41

continuous - every person has a lower or greater susceptibility

Question 42

how many genetic risk factors are there for depression?

Answer 42

44

Question 43

what is pyloric stenosis?

Answer 43

narrowing between the stomach and the small intestine

Question 44

how is pyloric stenosis distributed among males and females?

Answer 44

5x more common in males than in females due to men having a lower disease threshold than women

Question 45

what does the pylori stenosis threshold for females imply about female relatives of suffers?

Answer 45

female relatives have more risk alleles