NATUREIVol 437 27 October 2005 ARTICLES varies by chromosome; when plotted against average recombination explain different patterns on the X chromosome: lower SNP density rate on each chromosome (estimated from pedigree-based genetic smaller sample size, restriction of recombination to females and maps)these differences largely disappear(Supplementary Fig. 6). lower effective populatio on sIze Similarly, the distribution of haplotype length across chromosomes is less variable when measured in genetic rather than physical A view of LD focused on the putative causal SNI distance. For example, the median length of haplotypes is 54.4 kb Although genealogy and recombination provide insight into why on chromosome 1 compared to 34.8 kb on chromosome 21. When nearby SNPs are often correlated, it is the redundancies among SNPs measured in genetic distance, however, haplotype length is much that are of central importance for the design and analysis of more similar: 0.104 cM on chromosome I compared to 0. 111 cM on association studies. A truly comprehensive genetic association chromosome 21(Supplementary Fig 9) study must consider all putative causal alleles and test each for its The exception is again the X chromosome, which has more potential role in disease. If a causal variant is not directly tested in the rate(median haplotype length=0.135 cM), Me or recombination disease sample, its effect can nonetheless be indirectly tested if it is extensive haplotype structure after accoun factors could correlated with a SNP or haplotype that has been directly tested. ENr131.2q37.1 ENm014.7q31.33 CEU 2s08卡5E8 Figure 8 Comparison of linkage disequilibrium an ENCODE regions. For each region(ENr131.2q371 and ENm0147 D' plots for the YRI, CEU and CHB-+JPT analysis panels are shown D <I and LOD<2: blue, D= 1 and LOD< 2; pink, D< I and 三二三 LOD 22; red, D= I and LOD 2 2. Below each of these plots is shown the as red triangles 2005 Nature Publishing Group© 2005 Nature Publishing Group varies by chromosome; when plotted against average recombination rate on each chromosome (estimated from pedigree-based genetic maps) these differences largely disappear (Supplementary Fig. 6). Similarly, the distribution of haplotype length across chromosomes is less variable when measured in genetic rather than physical distance. For example, the median length of haplotypes is 54.4 kb on chromosome 1 compared to 34.8 kb on chromosome 21. When measured in genetic distance, however, haplotype length is much more similar: 0.104 cM on chromosome 1 compared to 0.111 cM on chromosome 21 (Supplementary Fig. 9). The exception is again the X chromosome, which has more extensive haplotype structure after accounting for recombination rate (median haplotype length ¼ 0.135 cM). Multiple factors could explain different patterns on the X chromosome: lower SNP density, smaller sample size, restriction of recombination to females and lower effective population size. A view of LD focused on the putative causal SNP Although genealogy and recombination provide insight into why nearby SNPs are often correlated, it is the redundancies among SNPs that are of central importance for the design and analysis of association studies. A truly comprehensive genetic association study must consider all putative causal alleles and test each for its potential role in disease. If a causal variant is not directly tested in the disease sample, its effect can nonetheless be indirectly tested if it is correlated with a SNP or haplotype that has been directly tested. Figure 8 | Comparison of linkage disequilibrium and recombination for two ENCODE regions. For each region (ENr131.2q37.1 and ENm014.7q31.33), D0 plots for the YRI, CEU and CHBþJPT analysis panels are shown: white, D0 , 1 and LOD , 2; blue, D0 ¼ 1 and LOD , 2; pink, D0 , 1 and LOD $ 2; red, D0 ¼ 1 and LOD $ 2. Below each of these plots is shown the intervals where distinct obligate recombination events must have occurred (blue and green indicate adjacent intervals). Stacked intervals represent regions where there are multiple recombination events in the sample history. The bottom plot shows estimated recombination rates, with hotspots shown as red triangles46. NATURE|Vol 437|27 October 2005 ARTICLES 1307