The Genetics Of Complex Diseases

Question 0

Complex disorders

Answer 0

Common
Polygenic-> individual genetic variants of low penetrance
Gene-gene or gene-environment interactions 
Multiple genes contribute to disease susceptibility
Severity of symptoms/age of onset
Aetiological mechanisms may differ
Eg
Heart disease
Diabete
Alzheimer's 
Bipolar
Chrons

Question 1

Mendelian disorders

Answer 1

Rare
Monogenci
Highly penetrant genetic variations
Clear models of inheritance

Question 2

Familial tendency

Answer 2

Relative risk ratio-> risk in relatives of affected subjects/risk in population 
Sibling relative risk (ds)
Cystic fibrosis ds 500, life time 0.05%
Huntingtons ds 5000, life time 0.01%
Coronary heart disease ds 2-7 
T1DM ds 15 
T2Dm ds 3
Alzheimer's ds 3
Bipolar ds 7-10
Chrons 17-34

Question 3

Factors influencing relative risk

Answer 3

Shared environment factors
Shared genes
Use twin studies to differentiate
T1DM mz twins 50%
Chrons mz twins 50% dz 10%

Question 4

Heritability

Answer 4

The phenotypic variability due to genetic variation 
T1DM 85%
T2DM 30-70%
Alzheimer's 60-80%
Bipolar 80-90%

Question 5

Human genome

Answer 5

3,000,000,000 nucleotide bases

95% of genome is interagenic-> som RNA used to dampen other RNA action-> not all RNA produces protiens

Question 6

DNA variation

Answer 6

Polymorphism
Common
Variable number of tandem repeats-> highly polymorphic, function uncertain, valuable genetic markers
-> repeats can have no phenotypic effect, no difference in having a larger number of repeats->above 30 is unstable-> expansion or repeat during mitosis-> cause disease phenotype
Single nucleotide polymorphism-> over 10 million confirmed-> 1 per 500 bases-> many appear to have no function-> some effect encoded protein or gene regulation

Question 7

Using Polymorphisms as genetic markers

Answer 7

Genetic variants with similar chromosomal positions are seldom separated by recombination at mitosis
Increased distance between snaps increased chance of recombination
Co inheritance of a genetic marker and a disease suggests that the marker is close to a disease gene

Question 8

Genome wide screening

Answer 8

Panel of Polymorphisms spread throughout genome
Genotype affected and unaffected individuals
Identify genetic Polymorphisms which segregate with disease
Assume that causal genetic variants lie close to this marker
-> genome wide linkage analysis (family based)
-> genome wide association screen (case control)

Question 9

Genome wide linkage screens

Answer 9

Multicase families
VNTR marker genotyping -> success in families with uncommon monogenic variants of the disease
Monogenic Alzheimer’s-> deposition of amyloid plaques in brain -> early age onset-> rare, highly penetrant mutations in amyloid
Monogenic T2DM-> MODY-> 2-5% MODY genes identified so far-> all affect insulin by B cells
Monogenic coronary vascular disease-> related to lipoprotien metabolism, familial hypercholesterolemia-> LDL R gene mutation -> myocardial infarction before 50 in males
Less success in complex disease
HLA regions of T1DM
Apo E in Alzheimer’s
Genes with unusually large effect

Question 10

Patterns of complex diseases

Answer 10

Minority of affected individuals -> multicast families, early onset severe disease, monogenic inheritance -> genes with large effect size
Majority of individuals-> gene-gene and gene-environment interaction, phenotypic diversity, genes with individually small effect size, not detectable by genome wide linkage analysis

Question 11

Genome wide association screening

Answer 11

Compare frequency of gene variants, usually SNP’s in cases and controls
Doesn’t require multicast families
Compare SNPs across pop
Don’t need to do all of them due to correlation between nearby SNPs
May find causative SNP and associated SNP

Question 12

Linkage disequilibrium

Answer 12

Combinations of alleles in a segment of the genome are know as halo types
Nearby SNPs not inherited independently -> limited number of halo types observed
Geneotyping a carefully select panel for tagSNPs can capture most of the variation in a single halo type block-> requires map of genetic variation and linkage disequilibrium -> hap map project-> map of human genetic variation in 4 populations

Question 13

Genotyping platforms

Answer 13

High throughput array technology genotyping put to 1 million SNPs in a single experiment
Identified 5 new genes for T1DM, 3 for T2DM

Question 14

GWAS design

Answer 14

Case selection-> defined phenotype
Control selection-> match pop, possibility for miss classification bias! issue for common traits
Biggest sample size possible -> more likely to detect complex diseases with small effect sizes
Population substructure-> minimise phenotype

Question 15

GWAS validation

Answer 15

Replication in independent samples
Replication should be for same allele or halotype for same disease phenotype -> if not replicated the first finding was wrong or there is heterogeneity

Question 16

GWAS dats analysis

Answer 16

Manhattan plot -> findings with respect to genomic position

Question 17

Re sequencing

Answer 17

Association in A-B regions
To identify common variants re sequence this region in 200 individuals
Sequencing of a larger region may be necessary to identify al l common variants, contributing to susceptibility regions
The affected gene may be difficult to find

Question 18

Why identify susceptibility loci

Answer 18

Clues to disease mechanisms
Presymptomatic screening -> no better than existing criteria
Pharmocogentics-> personalised drug therapies