Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes

Abstract

Extensive studies are currently being performed to associate disease susceptibility with one form of genetic variation, namely single nucleotide polymorphisms (SNPs). In recent years another type of common genetic variation has been characterised, namely structural variation, including copy number variations (CNVs). To determine the overall contribution of CNVs to complex phenotypes we have performed association analyses of expression levels of 14,925 transcripts with SNPs and CNVs in individuals who are part of the International HapMap project. SNPs and CNVs captured 83.6% and 17.7% of the total detected genetic variation in gene expression, respectively, but the signals from the two types of variation had little overlap. Interrogation of the genome for both types of variants may be an effective way to elucidate the causes of complex phenotypes and disease in humans.Understanding the genetic basis of phenotypic variation in human populations is currently one of the major goals in human genetics. Gene expression (the transcription of DNA into messenger RNA) has been interrogated in a variety of species and experimental scenarios to investigate the genetic basis of variation in gene regulation (1)(2)(3)(4)(5)(6)(7)(8), and to tease apart regulatory networks (9, 10). In some respects, a comprehensive survey of gene expression * Correspondence should be addressed to: Emmanouil T. Dermitzakis (md4@sanger.ac.uk; +44-1223-494866) or Matthew E. Hurles (meh@sanger.ac.uk; +44-1223-495377) (26) and www.sanger.ac.uk/humgen/cnv/data). Log 2 ratios from two sets of clones were analyzed: the whole set of 24,963 autosomal clones (CGH-clones) and the 1322 autosomal clones corresponding to CNVs present in at least two HapMap individuals (CNV clones) (26). We excluded genes on sex chromosomes due to their imbalance in males and females. We performed linear regression (on each of the 4 populations separately) between normalized quantitative gene expression values and SNP genotypes or clone log 2 ratios that were near the gene (SNP position or clone midpoint within 1 Mb and 2Mb, respectively, of the probe midpoint position). We used different window sizes for SNPs and clones because clones are large (median size of ∼170 Kb) and structural variants can exert long-range effects (21), so a 2 Mb window is more appropriate. Statistical significance was evaluated through the use of permutations (27), as previously described (1), and a corrected p-value threshold of 0.001 applied (see Methods). Repeated permutation exercises showed that our permutation thresholds were very stable (see Supplementary Table 4). We test a large number of genes so an additional correction is required. This can either be done by adjusting the threshold to a new corrected threshold above which all genes are expected to be significant (e.g. Bonferoni correction) or by setting the threshold to a value that generates a satisfactory false discovery rate (FDR). We have used the second and we have estimated the FDR based on the number of genes tested and E...

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

“…[35][36][37][38][39][40][41][42][43] Within our associated region, a segmental duplication is reported, 44 which is situated between the two associated regions on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background and caused a 223-kb gap not genotyped in our study. This segmental duplication has, to our knowledge, not been studied regarding human diseases.…”

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

“…In addition to their more direct effect on genes, for example, alteration of gene dosage and gene disruption, CNVs may also affect regulatory regions or other functional regions that influence gene expression, and CNVs have indeed been reported to exert their effect over distances of more than 6 Mb (Stranger et al ., 2007). Only a few of the seven CNVs found to potentially associate with mortality in long‐lived individuals in this study contain known regulatory elements.…”

RNA-Seq and human complex diseases: recent accomplishments and future perspectives

“…In addition, CNVs, insertions/ deletions, short tandem repeats (di-, tri-and tetranucleotide expansion) and large genomic rearrangements can affect gene expression at some specific loci even up to several kb from the breakpoints. 81 Their impact on transcriptome is not limited to a quantitative regulation of the expression levels at some loci, but it also affects the timing of gene expression. 82 Finally, despite our knowledge there are no conclusive studies directly linking epigenetics to complex traits and diseases, the involvement of an epigenetic framework as 'unifying principle' in the etiology of common diseases has been hypothesized.…”