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PLOS Genetics  2005 

Genome-Wide Associations of Gene Expression Variation in Humans

DOI: 10.1371/journal.pgen.0010078

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Abstract:

The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12–13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs) with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis-) to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I) HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

References

[1]  Stranger BE, Dermitzakis ET (2005) The genetics of regulatory variation in the human genome. Hum Genomics 2: 126–131.
[2]  Storey JD, Akey JM, Kruglyak L (2005) Multiple locus linkage analysis of genome-wide expression in yeast. PLoS Biol 3: e267.. DOI: 10.1371/journal.pbio.0030267.
[3]  Brem RB, Kruglyak L (2005) The landscape of genetic complexity across 5,700 gene expression traits in yeast. Proc Natl Acad Sci U S A 102: 1572–1577.
[4]  Brem RB, Yvert G, Clinton R, Kruglyak L (2002) Genetic dissection of transcriptional regulation in budding yeast. Science 296: 752–755.
[5]  Yvert G, Brem RB, Whittle J, Akey JM, Foss E, et al. (2003) Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nat Genet 35: 57–64.
[6]  Bystrykh L, Weersing E, Dontje B, Sutton S, Pletcher MT, et al. (2005) Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics'. Nat Genet 37: 225–232.
[7]  Chesler EJ, Lu L, Shou S, Qu Y, Gu J, et al. (2005) Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat Genet 37: 233–242.
[8]  Schadt EE, Monks SA, Drake TA, Lusis AJ, Che N, et al. (2003) Genetics of gene expression surveyed in maize, mouse, and man. Nature 422: 297–302.
[9]  Hubner N, Wallace CA, Zimdahl H, Petretto E, Schulz H, et al. (2005) Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat Genet 37: 243–253.
[10]  Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, et al. (2004) Genetic analysis of genome-wide variation in human gene expression. Nature 430: 743–747.
[11]  Monks SA, Leonardson A, Zhu H, Cundiff P, Pietrusiak P, et al. (2004) Genetic inheritance of gene expression in human cell lines. Am J Hum Genet 75: 1094–1105.
[12]  Cheung VG, Spielman RS, Ewens KG, Weber TM, Morley M, et al. (2005) Mapping determinants of human gene expression by regional and genome-wide association. Nature 437: 1365–1369.
[13]  Ardlie KG, Kruglyak L, Seielstad M (2002) Patterns of linkage disequilibrium in the human genome. Nat Rev Genet 3: 299–309.
[14]  Pastinen T, Sladek R, Gurd S, Sammak A, Ge B, et al. (2004) A survey of genetic and epigenetic variation affecting human gene expression. Physiol Genomics 16: 184–193.
[15]  Yan H, Yuan W, Velculescu VE, Vogelstein B, Kinzler KW (2002) Allelic variation in human gene expression. Science 297: 1143.
[16]  Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273: 1516–1517.
[17]  Wang WY, Barratt BJ, Clayton DG, Todd JA (2005) Genome-wide association studies: Theoretical and practical concerns. Nat Rev Genet 6: 109–118.
[18]  The International HapMap Consortium (2003) The International HapMap Project. Nature 426: 789–796.
[19]  Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, et al. (2005) A haplotype map of the human genome. Nature 437: 1299–1320.
[20]  ENCODE Project Consortium (2004) The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306: 636–640.
[21]  Kuhn K, Baker SC, Chudin E, Lieu MH, Oeser S, et al. (2004) A novel, high-performance random array platform for quantitative gene expression profiling. Genome Res 14: 2347–2356.
[22]  Thomas DC, Haile RW, Duggan D (2005) Recent developments in genome-wide association scans: A workshop summary and review. Am J Hum Genet 77: 337–345.
[23]  Churchill GA, Doerge RW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138: 963–971.
[24]  Storey JD, Tibshirani R (2003) Statistical significance for genome-wide studies. Proc Natl Acad Sci U S A 100: 9440–9445.
[25]  Lettice LA, Heaney SJ, Purdie LA, Li L, de Beer P, et al. (2003) A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 12: 1725–1735.
[26]  Doerge RW, Churchill GA (1996) Permutation tests for multiple loci affecting a quantitative character. Genetics 142: 285–294.
[27]  Beavis WD (1998) QTL analysis: Power, precision, and accuracy. In: Paterson AH, editor. Molecular dissection of complex traits. New York: CRC Press. pp. 145–162. pp.
[28]  Parra G, Reymond A, Dabbouseh N, Dermitzakis ET, Antonarakis SE, et al. (2005) Tandem chimerism as a means to increase protein complexity in the human genome. Genome Research. In press.
[29]  Doss S, Schadt EE, Drake TA, Lusis AJ (2005) Cis-acting expression quantitative trait loci in mice. Genome Res 15: 681–691.
[30]  Beaumont MA, Rannala B (2004) The Bayesian revolution in genetics. Nat Rev Genet 5: 251–261.
[31]  Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, et al. (2004) Detection of large-scale variation in the human genome. Nat Genet 36: 949–951.
[32]  Sebat J, Lakshmi B, Troge J, Alexander J, Young J, et al. (2004) Large-scale copy number polymorphism in the human genome. Science 305: 525–528.
[33]  Rockman MV, Wray GA (2002) Abundant raw material for cis-regulatory evolution in humans. Mol Biol Evol 19: 1991–2004.
[34]  Carroll SB (2005) Endless forms most beautiful: The new science of evo devo and the making of the animal kingdom. (New York): W. W. Norton & Company. 350 p. .
[35]  Park SC, Mathews RA, Zuberbuhler JR, Rowe RD, Neches WH, et al. (1977) Down syndrome with congenital heart malformation. Am J Dis Child 131: 29–33.
[36]  Ghosh S, Watanabe RM, Valle TT, Hauser ER, Magnuson VL, et al. (2000) The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to type 2 diabetes. Am J Hum Genet 67: 1174–1185.
[37]  Cheung VG, Spielman RS (2002) The genetics of variation in gene expression. Nat Genet 32 Suppl: 522–525.
[38]  Bolstad BM, Irizarry RA, Astrand M, Speed TP (2003) A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19: 185–193.
[39]  Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, et al. (2002) The Human Genome Browser at UCSC. Genome Res 12: 996–1006.

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