Multifactorial traits

Question 1

How do we know if a genetic component is non-Mendelian?

Answer 1

Twin studies (concordance rate)

Question 2

Common multifactorial diseases involve

Answer 2

many DNA changes, each with a predisposing effect

Question 3

A gene variant is

Answer 3

a single nucleotide polymorphism (SNP) that is associated with an increased risk of developing disease

it is present more frequently in those with the phenotype

Question 4

Polymorphism

Answer 4

the presence of genetic variation within a population, upon which natural selection can operate

Question 5

single nucleotide polymorphism

Answer 5

single base change
most common genomic variation
a substitution of a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population
can predispose to conditions

Question 6

The additive model is

Answer 6

a linear effect whereby if you have two copies of the disease allele, your risk is doubled
(think of graph)
GG

Question 7

examples of common multifactorial quantitative traits

Answer 7

BMI, height, BP, CRP, LDL, fasting glucose

quantitative traits have more frequent gene variants that are specifically associated with higher/lower levels of the trait

Additive model applies, though environment ultimately controls (e.g. obesity)

Question 8

The heritability of multifactorial diseases and continuous traits is due to

Answer 8

a large number of variants (more variants = more polygenicity)

Question 9

GWAS

Answer 9

genome wide association studies

Hypothesis Free Approach - no prior knowledge

Question 10

Types of GWAS

Answer 10

SNP-chip microarrays

whole genome sequencing (millions of SNPs)

hybrid alternatives (imputation)

Question 11

SNP-chips

Answer 11

500-1m SNPs
high-density oligo arrays containing up to several million probes of smaller length, which allow for the genotyping of hundreds of thousands of selected SNPs across all chromosomes in a single reaction
cheap but limited to variation known about

Question 12

whole genome sequencing

Answer 12

Whole genome sequencing is ostensibly the process of determining the complete DNA sequence of an organism’s genome at a single time. This entails sequencing all of an organism’s chromosomal DNA as well as DNA contained in the mitochondria

capturs more variation than SNP microarrays including variation which might not be catalogued BUT expensive

Question 13

Hybrid alternatives

Answer 13

Imputation: refers to the statistical inference of unobserved genotypes.

cheap but based on statistical modelling - assay preferred for very rare variation

Question 14

the point of GWAS is to develop

Answer 14

personalised medicine

DNA variant > molecular biology > physiology > disease

Question 15

Predicting disease with genetic variants

Answer 15

ROC is the receiver operating characteristic
The ROC curve, is a graphical plot that illustrates the diagnostic ability of a binary classifier system as its discrimination threshold is varied

The ROC curve is created by plotting the true positive rate (TPR) against the false positive rate (FPR) at various threshold settings

area under the curve (AUC) is the measure of accuracy: AUC=50 no better than flipping coin

AUC=0.8 clinically useful

Question 16

Autoimmune diseases are heavily influence by

Answer 16

HLA
human leukocyte antigen
on chromosome 6
e.g type 1 diabetes exception to ROC curve

Question 17

Linkage disequilibrium

Answer 17

the occurrence in members of a population of combinations of linked genes in non-random proportions.

Question 18

Linkage disequilibrium creates

Answer 18

correlation among genetic variants

Question 19

Missing heritability is

Answer 19

the fact that GWAS has identified 1000s of genetic associations for disease risk and quantitative traits

but most of the observed effects are small: 1.1x increase in type 2 diabetes for every risk increasing allele

Question 20

Reasons for missing heritability (4)

Answer 20

larger sample sizes (resolution?)

rare/structural variants not tested

genetic interactions (epistasis, environment)

over-estimation of heritability

Question 21

In contrast to Mendelian diseases which are largely caused by protein coding changes, complex traits are mainly driven by

Answer 21

non coding variants that affect gene regulation

Question 22

Pleiotropy and epistasis

Answer 22

Pleiotropy:
a single gene at a give locus affects many phenotypes
e.g. albinism affects hair, eye and skin pigment

Epistasis:
2 or more alleles at one locus affect the expression of genes at a different locus