Association Analysis

Question 1

describe genetic association

Answer 1

presence of an allele at a higher frequency in unrelated subjects with a particular trait, compared to those that do not have the trait

Question 2

case-control genetic study

Answer 2

• large no. of well defined cases
• equal numbers of matched controls
• reliable genotyping technology
• standard statistical analysis
• positive associations should be replicated

Question 3

genetic markers

Answer 3

diversity higher in population than in a single family

we need reliable genetic markers to capture genetic diversity

genetic markers are alleles that we can genotype and assess whether they are associated with disease

Question 4

ideal genetic marker

Answer 4

polymorphic 
randomly distributed across genome 
fixed location in genome 
frequent in genome 
frequent in population 
stable with time 
easy to assay

Question 5

single nucleotide polymorphism

Answer 5

common in genome = 1/300 nucleotides
12 millions SNPs identified in human genome

generated by mismatch repair during mitosis

Question 6

where can SNPs be found

Answer 6

gene coding region

non coding region

intergenic region

Question 7

define these:

Answer 7

synonymous = no amino acid change

non synonymous = amino acid change

nonsense = new stop codon

promoter = mRNA and protein level changed

terminator = mRNA and protein level changed

splice site = altered mRNA , altered protein

Question 8

what are SNP MAFs

Answer 8

SNPs are chosen for genetic association studies on basis of their MAF

common diseases likely to be caused by common variants

SNPs with Maf > 5% are used in association studies

exceptions are known monogenic disease SNPs

Question 9

GWAS results plot

Answer 9

• presented as a single graph called Manhattan plot
• all results plotted, typically for >1m SNPs
• x axis is position of the SNP on chromosome
• y axis is -log10 of the association

Question 10

GWAS results

Answer 10

peak of association often does not identify the gene causing the disease

the peak identifies the genomic region associated with disease and is usually small than 100kb

Question 11

describe meta analysis

Answer 11

difficult to do large studies

easier to combine smaller studies

pre experiment = consortium
post experiment = meta analysis

meta analysis allows statistical combination of results from multiple studies

Question 12

problems with GWAS

Answer 12

contribution to genetic component of disease is estimated to be low, 5%

• SNPs small effect
• rare snps
• copy number variation
• epigenetic variation

Question 13

is obesity strongly genetic

Answer 13

• twin studies = 70-80% of body shape genetically determined
• adoption studies = 30-40%
• family studies = 40-60%

Question 14

large scale meta analysis

Answer 14

• BMI meta analysis in 322k subjects
• 97 BMI associated loci
• 125 separate studies
• > 600 authors and >2000 collaborators