A multilocus linkage disequilibrium measure based on mutual information theory and its applications.
Evaluating the patterns of linkage disequilibrium (LD) is important for association mapping study as well as for studying the genomic architecture of human genome (e.g., haplotype block structures). Commonly used bi-allelic pairwise measures for assessing LD between two loci, such as r(2) and D', may not make full and efficient use of modern multilocus data. Though extended to multilocus scenarios, their performance is still questionable. Meanwhile, most existing measures for an entire multilocus region, such as normalized entropy difference, do not consider existence of LD heterogeneity across the region under investigation. Additionally, these existing multilocus measures cannot handle distant regions where long-range LD patterns may exist. In this study, we proposed a novel multilocus LD measure developed based on mutual information theory. Our proposed measure described LD pattern between two chromosome regions each of which may consist of multiple loci (including multi-allele loci). As such, the proposed measure can better characterize LD patterns between two arbitrary regions. As potential applications, we developed algorithms on the proposed measure for partitioning haplotype blocks and for selecting haplotype tagging SNPs (htSNPs), which were helpful for follow-up association tests. The results on both simulated and empirical data showed that our LD measure had distinct advantages over pairwise and other multilocus measures. First, our measure was more robust, and can capture comprehensively the LD information between neighboring as well as disjointed regions. Second, haplotype blocks were better described via our proposed measure. Furthermore, association tests with htSNPs from the proposed algorithm had improved power over tests on single markers and on haplotypes.
Zhang
Lei
L
Institute of Molecular Genetics and the Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, 710049, Xi'an, Shaanxi, People's Republic of China. zlbio12@gmail.com
Liu
Jianfeng
J
Deng
Hong-Wen
HW
D000465:Algorithms; D000818:Animals; D002874:Chromosome Mapping / Q000379:methods; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D008962:Models, Theoretical; D020641:Polymorphism, Single Nucleotide
Am J Hum Genet. 2002 Nov;71(5):1227-34
12384857
Science. 2002 Jun 21;296(5576):2225-9
12029063
Nat Rev Genet. 2002 Apr;3(4):299-309
11967554
Am J Hum Genet. 1994 Apr;54(4):705-14
8128969
Mol Biol Evol. 1995 Sep;12(5):921-7
7476138
PLoS Genet. 2006 Jul;2(7):e121
16895449
Nature. 2001 May 10;411(6834):199-204
11346797
Genetics. 2001 Jan;157(1):413-23
11139521
Am J Hum Genet. 2007 Apr;80(4):705-15
17357076
Hum Mol Genet. 2003 Apr 1;12(7):771-6
12651872
Genome Res. 2000 Oct;10(10):1435-44
11042143
Bioinformatics. 2002;18 Suppl 2:S231-40
12386007
Ann Hum Genet. 1999 Mar;63(Pt 2):167-79
10738528
Genetics. 1964 Jan;49(1):49-67
17248194
Genet Epidemiol. 2005 Apr;28(3):193-206
15637716
Am J Hum Genet. 2002 Dec;71(6):1386-94
12439824
Am J Hum Genet. 2006 Apr;78(4):615-28
16532392
Nature. 2005 Oct 27;437(7063):1299-320
16255080
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7335-9
12032283
Am J Hum Genet. 2005 Dec;77(6):988-98
16380910
Am J Hum Genet. 2007 Jan;80(1):112-25
17160899
Genet Epidemiol. 2006 Dec;30(8):703-17
16986163
Bioinformatics. 2005 May 1;21(9):2001-7
15699029
Hum Hered. 2002;54(4):186-98
12771551
Diabetes. 2004 Sep;53(9):2487-91
15331565
Genet Epidemiol. 2005 Dec;29(4):353-64
16173096
Bioinformatics. 2005 Jan 15;21(2):263-5
15297300
Nat Genet. 2001 Oct;29(2):229-32
11586305
Hum Mol Genet. 2000 Mar 22;9(5):725-33
10749979
Genetics. 1987 Oct;117(2):331-41
3666445
Am J Hum Genet. 2003 Sep;73(3):502-15
12916017
Bioinformatics. 2002 Feb;18(2):337-8
11847089
Hum Genet. 2005 Nov;118(2):276-86
16184404