Genes and MS in Tasmania cont Lecture 5 Statistics 246 February 3 2004 1 Mapping genes contributing to complex diseases MS susceptibility genes are difficult to map MS is a complex disease Analyses with traditional methods such as single marker association studies and standard linkage approaches affected sib pairs pedigrees etc have failed to agree on genomic regions other than the HLA region There are a variety of possible reasons for this Allelic and locus heterogeneity no single gene model fits all Significant environmental influences Imprecise phenotyping 3 Linkage vs Association studies Linkage mapping tests for cosegregation of a marker allele with the disease within families Association mapping seeks a marker allele that is present more frequently in cases than in controls all affected individuals are treated as distant relatives Case control studies Transmission disequilibrium test needs triads We will do a quick review of association mapping before turning to our MS study 4 Linkage disequilibrium Suppose that we have a marker with just two alleles M and m say having frequencies p and 1 p and a not necessarily linked disease locus with alleles D and d having frequencies q and 1 q A haploid gamete must have one of the four combinations haplotypes DM Dm dM or dm Let the frequencies in a population of these four haplotypes be x1 x2 x3 and x4 Under independence we would have x1 pq etc Deviations of the observed haplotype frequencies from these products is termed linkage disequilibrium LD or better gametic association If inheriting the allele D at the disease locus increases the chance of getting the disease and the disease and marker loci are in LD then the frequencies of the marker alleles M and m will differ between diseased and nondiseased individuals This observation is the basis of association studies 5 Case control studies in genetic epidemiology Case control studies compare case and control allele frequencies at markers or candidate genes the exposure variables All the standard potential drawbacks of such studies apply with the similarity of the two base populations being the most critical here It is thought to be relatively easy for samples from racially mixed populations to differ in allele frequencies and hard to deal with this in the genetic context Key term population structure If our cases are MS patients who are our controls It would be rare for a study to be able to afford or get ethics approval to carry out random sampling of the relevant background population More commonly controls are people such as blood donors whose blood DNA has been collected for other purposes How close will they be to a random sample from the case population In an effort to deal with this the TDT which follows in effect uses 6 untransmitted genotypes as controls bypassing any population structure The transmission disequilibrium test The TDT as it is called in its simplest form starts with parents and an affected child and considers a biallelic marker locus at which all three are typed and we can determine which maternal and paternal alleles were transmitted and which were not For example if the parents were a1 a2 and a1 a1 and the affected offspring was a1 a2 then a2 was transmitted and a1 was not transmitted by the first parent From a random sample of such trios called triads a 2 2 table can be built up giving the number of times a1 and a2 were transmitted and were not transmitted respectively and a simple test can be derived Many generalizations of this procedure now exist see notes for Stat 260 1998 Week 5 7 What is a haplotype A collection of alleles derived from the same chromosome Genotypes 2 1 9 4 1 2 9 2 7 6 1 13 6 15 17 9 6 17 12 12 14 7 Haplotypes Haplotype Re construction 18 18 1 4 10 10 Chromosome phase is unknown 2 6 9 17 1 6 9 2 12 14 7 18 1 10 13 1 15 4 9 2 17 12 7 6 1 18 4 10 Chromosome phase is known 8 Haplotype mapping If alleles at a disease locus are associated with alleles at one nearby marker locus on gametes they are likely to be associated with alleles at other nearby marker loci and hence with marker haplotypes A potentially more powerful way to locate disease genes is to search for associations between marker haplotypes and disease There are two possible problems here stemming from the fact that there can be a very large number of marker haplotypes we may have to deal with very small frequencies and we have a multiple testing problem 9 LD haplotype mapping and background LD Searching for common or rare haplotypes in cases alone is one form of association mapping It has been successful as very substantial LD can arise around disease loci In general controls are necessary as the background LD can be large That is there can be substantial LD between putative disease gene alleles and alleles of nearby markers without there being any causal link between the gene and the disease We call this background LD Background LD can be large when the population is young when the of founders is small bottlenecks through admixture of populations 10 Exercises on LD 1 Under a random mating assumption the long term values of the frequencies x1 x2 x3 and x4 on page 5 above are pq 1 p q p 1 q and 1 p 1 q Week 5 Stat 260 1998 2 Demonstrate that a mixture e g 50 50 of two populations initially in linkage equilibrium at two loci will typically not be in LE 3 Explain why a single mutant arising by chance will initially be in strong LD with alleles at loci near the locus on which it arises 11 Mapping MS genes in Tasmania Tasmania Area 67 800 km2 Population 470 000 Capital city Hobart 200 000 13 Tasmanian Population Growth 1 First settled by Europeans 1803 2 24 000 free settlers 19 000 convicts 1836 3 Civil registration of births and marriages 1838 4 End of convict transportation 1853 5 The Gold Rush 1860 s 1 23 45 Mapping with haplotype sharing Premise Tasmanians share large ish segments of haplotypes because they are distantly related Similarly our MS patients should share these large ish segments but even more so in size and in number in regions around MS susceptibility genes Time 1800 1850 s 2000 6 8 generations 15 Haplotypes are eroded by recombination Ancestral chromosome MS MS MS MS MS MS 25 cM SD 18 Time generations meioses Recombination events can help to map genes with precision but erode haplotypes making them more difficult to detect 16 What might have happened in the population A mutation arises in or is introduced to a population leading to disease say MS in those
View Full Document
Unlocking...