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. 2011 Aug;7(8):e1002197.
doi: 10.1371/journal.pgen.1002197. Epub 2011 Aug 4.

Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA

Rudolf S N Fehrmann  1 , Ritsert C Jansen, Jan H Veldink, Harm-Jan Westra, Danny Arends, Marc Jan Bonder, Jingyuan Fu, Patrick Deelen, Harry J M Groen, Asia Smolonska, Rinse K Weersma, Robert M W Hofstra, Wim A Buurman, Sander Rensen, Marcel G M Wolfs, Mathieu Platteel, Alexandra Zhernakova, Clara C Elbers, Eleanora M Festen, Gosia Trynka, Marten H Hofker, Christiaan G J Saris, Roel A Ophoff, Leonard H van den Berg, David A van Heel, Cisca Wijmenga, Gerard J Te Meerman, Lude Franke
Affiliations

Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA

Rudolf S N Fehrmann et al. PLoS Genet. 2011 Aug.

Abstract

For many complex traits, genetic variants have been found associated. However, it is still mostly unclear through which downstream mechanism these variants cause these phenotypes. Knowledge of these intermediate steps is crucial to understand pathogenesis, while also providing leads for potential pharmacological intervention. Here we relied upon natural human genetic variation to identify effects of these variants on trans-gene expression (expression quantitative trait locus mapping, eQTL) in whole peripheral blood from 1,469 unrelated individuals. We looked at 1,167 published trait- or disease-associated SNPs and observed trans-eQTL effects on 113 different genes, of which we replicated 46 in monocytes of 1,490 different individuals and 18 in a smaller dataset that comprised subcutaneous adipose, visceral adipose, liver tissue, and muscle tissue. HLA single-nucleotide polymorphisms (SNPs) were 10-fold enriched for trans-eQTLs: 48% of the trans-acting SNPs map within the HLA, including ulcerative colitis susceptibility variants that affect plausible candidate genes AOAH and TRBV18 in trans. We identified 18 pairs of unlinked SNPs associated with the same phenotype and affecting expression of the same trans-gene (21 times more than expected, P<10(-16)). This was particularly pronounced for mean platelet volume (MPV): Two independent SNPs significantly affect the well-known blood coagulation genes GP9 and F13A1 but also C19orf33, SAMD14, VCL, and GNG11. Several of these SNPs have a substantially higher effect on the downstream trans-genes than on the eventual phenotypes, supporting the concept that the effects of these SNPs on expression seems to be much less multifactorial. Therefore, these trans-eQTLs could well represent some of the intermediate genes that connect genetic variants with their eventual complex phenotypic outcomes.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Disease and trait-associated SNPs are enriched for both cis- and trans-eQTLs.
17% of SNPs, present on common SNP platforms, affect gene expression levels in cis or trans (at FDR of 0.05). This is substantially different from 1,167 SNPs that have been found associated with traits or disease: 40.4% affect gene expression in cis, while 5.7% of these SNPs affect gene expression in trans. These eQTL SNPs significantly more often than expected map within the HLA (13.8% of cis-eQTLs, 47.8% of trans-eQTLs, extreme value distribution p<1.1×10−16).
Figure 2
Figure 2. Type 1 diabetes associated SNPs both affect genes in cis and in trans.
Figure 3
Figure 3. Human leukocyte antigen (HLA) trait-associated SNPs affect gene expression levels in trans.
Thirty-two trait-associated SNPs that map within the HLA are trans-acting on other genes. Trans-genes are indicated in red. Peripheral blood co-expression (Pearson correlation coefficient r≥0.19, p<10−11) between genes is indicated in light grey. Several trans-genes are co-expressed with HLA genes.
Figure 4
Figure 4. Pairs of SNPs that cause the same phenotype more frequently than expected also affect the same downstream genes.
Various pairs of unlinked SNPs cause the same phenotype but also converge on the same downstream genes. a) When using cis- and trans-eQTLs, identified when controlling FDR at 0.05, 7 unique pairs of SNPs cause the same phenotype but also affect the same downstream gene. When controlling the FDR at 0.50 for the trans-eQTLs, 18 unique pairs of SNPs show this convergence. b) This is significantly higher than expected, determined using 100 permutations. c) The SNPs that affect these downstream genes in most instances explain a proportion of the downstream gene expression variation that is substantially higher than what their effect is on the eventual phenotypes.
Figure 5
Figure 5. Trait-associated SNPs show convergence on multiple genes.
For several traits different and unlinked SNPs affect the same genes in cis or trans. For beta thalassemia three different loci affect hemoglobin (HBG2) gene expression (one in cis, indicated with gray arrow, two in trans (at FDR 0.05), indicated with red arrows). For mean corpuscular volume (MCV) the same trans-effects on HBG2 (at FDR 0.05) exist, but convergence is also apparent on ESPN, VWCE, PDKZ1IP1 and RAP1GAP (at FDR 0.50). For mean platelet volume (MPV) numerous trans-effects on genes involved in blood coagulation were identified. Two MPV loci (rs12485738 on 3p26.3 and rs11602954 on 11p15.5) both affect GP9, F13A1 and C19orf33 (at FDR 0.05) and SAMD14, GNG11 and VCL (at FDR 0.50). Peripheral blood co-expression (Pearson correlation coefficient r≥0.19, p<1.0×10−11) between genes is indicated in light grey.
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