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What is an association study? Define linkage disequilibrium. Martina Owens 17.12.10. Essay Plan. Association - definition - causes (direct causation, epistatic effect, population stratification, LD) Linkage Disequilibrium definition HapMap project
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- causes (direct causation, epistatic effect, population stratification, LD)
A tendency of two characters (diseases, marker alleles etc) to occur together at non-random frequencies
Statistical statement about the co-occurrence of alleles or phenotypes: allele A is associated with disease D if people who have disease D also have allele A significantly more often (or perhaps left often) than would be predicted from the individual frequencies of D and A in the population. E.g. HLA-DR4 is found in 36% of the population but in 78% of people with rheumatoid arthritis. Thus, HLA-DR4 is associated with RA
The association of two alleles at separate but linked loci more frequently than would be expected by chance, normally as the result of a particular ancestral haplotype being common in the population studied.
Two unrelated individuals with a disease susceptibility allele inherited from an ancient common ancestor will be separated by many meisosis and recombination events – the shared chromosomal segment will therefore be very small. Only alleles at loci tightly linked to the disease susceptibility locus will still be shared.
To study LD, a sample of individuals from the chosen population is genotyped for a series of linked polymorphic markers and the data phased (converted into haplotypes) prior to analysis. Computer programs can be used to convert genotypes to haplotypes.
The international HapMap project involved typing several million SNPs in individuals from four human populations (CEU, YRI, CHB, JPT) and identified blocks of strong LD of ~5-15kb containing 30-70 SNPs - genotyping ~2-4 tag-SNPs in each block may enable capture most of the genetic variability
The ability of SNPs to tag surrounding blocks of ancient DNA (haplotypes) underlies the rationale for GWAS. Used to test the hypothesis that one or more common variants explain part of the genetic risk for a disease
Typically case–control design:
Nearly 600 genomewide association studies covering 150 distinct diseases and traits have been published, with nearly 800 SNP–trait associations reported as significant (P<5×10−8).
Consortia have been established to perform case-control studies with 1000 or more subjects in each arm funded by, for example, the Genetic Association Information Partnership (GAIN) in the US, and the Wellcome Trust Case-Control Consortium (WTCCC) in the UK.
Typed 2000 well-phenotyped cases of each of seven diseases: bipolar disorder, coronary heart disease, Crohn disease, hypertension, rheumatoid arthritis, T1DM and T2DM.
3000 healthy controls were also collected.
Case-control comparisons identified 24 independent association signals at P<5 x 10-7
All signals identified reflect genuine susceptibility effects based on prior findings and replication studies completed
Observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied
Replication studies are required to establish a definitive relationship with disease.
Large copy number variants (CNVs) in the genomes of healthy people
- account for a greater number of variable nucleotides than do all the SNPs.
- possible that these are susceptibility factors for common disease.
- newer generations of SNP genotping assays include assays for common CNVs.
The common disease-common variant hypothesis proposes that susceptibility factors have ancient origins
- the fact that GWAS are identifying associations that can be replicated indicates that some susceptibility factors are common variants but modest size of their effects leaves open the question of how much of the total susceptibility they will explain.
- E.g. GWAS by Easton et al identified 5 new factors in Breast cancer but despite the very large scale of the study (>20,000 patients) these factors together only accounted for 3.6% of the excess familial risk.
The mutation-selection hypothesis suggests that a heterogeneous collection of recent mutations accounts for most disease susceptibility
A complete account of genetic susceptibility will require contributions from both the common disease-common variant and mutation-selection hypothesis and they should therefore not be seen as being mutually exclusive
Under either hypothesis, the problem of distinguishing pathogenic from neutral remains
Association studies only flag the chromosomal location of the causative factor to a relatively large region or haplotype block. Therefore there is always a problem of identifying the actual causal variant.
Large numbers of cases and controls are required – can be challenging to organise
Detects only alleles that are common (>5%) in a population
Replication studies are needed
Strachan and Read 4th edition chapter 15
Hardy & Singleton 2009, NEJM, 360(17): 1759
Feero & Guttmacher 2010, NEJM, 363(2): 166