Genome-Wide Associations of Gene Expression Variation in Humans

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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. With the finished reference sequence of the human genome now available, focus has shifted towards trying to identify all of the functional elements within the sequence. Although quite a lot of progress has been made towards identifying some classes of genomic elements, in particular protein-coding sequences, the characterization of regulatory elements remains a challenge. The authors describe the genetic mapping of regions of the genome that have functional effects on quantitative levels of gene expression. Gene expression of 630 genes was measured in cell lines derived from 60 unrelated human individuals, the same Utah residents of Northern and Western European ancestry that have been genetically well-characterized by The International HapMap Project. This paper reports significant variation among individuals with respect to levels of gene expression, and demonstrates that this quantitative trait has a genetic basis. For some genes, the genetic signal was localized to specific locations in the human genome sequence; in most cases the genomic region associated with expression variation was physically close to the gene whose expression it regulated. The authors demonstrate the feasibility of performing whole-genome association scans to map quantitative traits, and highlight statistical issues that are increasingly important for whole-genome disease mapping studies.