Cis and Trans Effects of Human Genomic Variants on Gene Expression

Gene expression is a heritable cellular phenotype that defines the function of a cell and can lead to diseases in case of misregulation. In order to detect genetic variations affecting gene expression, we performed association analysis of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with gene expression measured in 869 lymphoblastoid cell lines of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort in cis and in trans. We discovered that 3,534 genes (false discovery rate (FDR) = 5%) are affected by an expression quantitative trait locus (eQTL) in cis and 48 genes are affected in trans. We observed that CNVs are more likely to be eQTLs than SNPs. In addition, we found that variants associated to complex traits and diseases are enriched for trans-eQTLs and that trans-eQTLs are enriched for cis-eQTLs. As a variant affecting both a gene in cis and in trans suggests that the cis gene is functionally linked to the trans gene expression, we looked specifically for trans effects of cis-eQTLs. We discovered that 26 cis-eQTLs are associated to 92 genes in trans with the cis-eQTLs of the transcriptions factors BATF3 and HMX2 affecting the most genes. We then explored if the variation of the level of expression of the cis genes were causally affecting the level of expression of the trans genes and discovered several causal relationships between variation in the level of expression of the cis gene and variation of the level of expression of the trans gene. This analysis shows that a large sample size allows the discovery of secondary effects of human variations on gene expression that can be used to construct short directed gene regulatory networks.

[1]  Simon C. Potter,et al.  The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study , 2011, PLoS genetics.

[2]  Wei Chen,et al.  Gene Expression in Skin and Lymphoblastoid Cells: Refined Statistical Method Reveals Extensive Overlap in Cis-eqtl Signals , 2022 .

[3]  P. Deloukas,et al.  Common Regulatory Variation Impacts Gene Expression in a Cell Type–Dependent Manner , 2009, Science.

[4]  Pedro G. Ferreira,et al.  Transcriptome and genome sequencing uncovers functional variation in humans , 2013, Nature.

[5]  Tomas W. Fitzgerald,et al.  Origins and functional impact of copy number variation in the human genome , 2010, Nature.

[6]  Elizabeth A. Kruse,et al.  The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells , 2008, Nature Immunology.

[7]  G. Abecasis,et al.  MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes , 2010, Genetic epidemiology.

[8]  E. Unanue,et al.  Batf3 Deficiency Reveals a Critical Role for CD8α+ Dendritic Cells in Cytotoxic T Cell Immunity , 2008, Science.

[9]  S. Ring,et al.  A new human genetic resource: a DNA bank established as part of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC) , 2000, European Journal of Human Genetics.

[10]  Rachel B. Brem,et al.  Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networks , 2008, Nature Genetics.

[11]  R. Guigó,et al.  Transcriptome genetics using second generation sequencing in a Caucasian population , 2010, Nature.

[12]  G. Abecasis,et al.  Genotype imputation. , 2009, Annual review of genomics and human genetics.

[13]  N. Cox,et al.  Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS , 2010, PLoS genetics.

[14]  Gary D. Stormo,et al.  The AP-1 transcription factor Batf controls TH17 differentiation , 2009, Nature.

[15]  S. Mundlos,et al.  Copy-number variations, noncoding sequences, and human phenotypes. , 2011, Annual review of genomics and human genetics.

[16]  He Huang,et al.  Expression of the Wdr9 gene and protein products during mouse development , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[17]  Simon C. Potter,et al.  Mapping cis- and trans-regulatory effects across multiple tissues in twins , 2012, Nature Genetics.

[18]  R. Redon,et al.  Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes , 2007, Science.

[19]  M. Peters,et al.  Systematic identification of trans eQTLs as putative drivers of known disease associations , 2013, Nature Genetics.

[20]  Bin Zhang,et al.  A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. , 2011, Genome research.

[21]  Daniel J. Gaffney,et al.  Global Properties and Functional Complexity of Human Gene Regulatory Variation , 2013, PLoS genetics.

[22]  Joseph E. Powell,et al.  Congruence of Additive and Non-Additive Effects on Gene Expression Estimated from Pedigree and SNP Data , 2013, PLoS genetics.

[23]  Thomas R Insel,et al.  The Challenge of Translation in Social Neuroscience: A Review of Oxytocin, Vasopressin, and Affiliative Behavior , 2010, Neuron.

[24]  F. Collins,et al.  Potential etiologic and functional implications of genome-wide association loci for human diseases and traits , 2009, Proceedings of the National Academy of Sciences.

[25]  Matthew E. Ritchie,et al.  A re-annotation pipeline for Illumina BeadArrays: improving the interpretation of gene expression data , 2009, Nucleic acids research.

[26]  Marco Scutari,et al.  Learning Bayesian Networks with the bnlearn R Package , 2009, 0908.3817.

[27]  Eric E Schadt,et al.  Disentangling molecular relationships with a causal inference test , 2009, BMC Genetics.

[28]  E. Dermitzakis,et al.  Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations , 2010, PLoS genetics.

[29]  J. Castle,et al.  An integrative genomics approach to infer causal associations between gene expression and disease , 2005, Nature Genetics.

[30]  A. Talukder,et al.  CRIPak, a novel endogenous Pak1 inhibitor , 2006, Oncogene.

[31]  E. Dermitzakis,et al.  Passive and active DNA methylation and the interplay with genetic variation in gene regulation , 2013, eLife.

[32]  E. Dermitzakis,et al.  From expression QTLs to personalized transcriptomics , 2011, Nature Reviews Genetics.

[33]  Nathaniel D. Miller,et al.  Molecular (SNP) analyses of overlapping hemizygous deletions of 10q25.3 to 10qter in four patients: Evidence for HMX2 and HMX3 as candidate genes in hearing and vestibular function , 2009, American journal of medical genetics. Part A.

[34]  Joseph K. Pickrell,et al.  Understanding mechanisms underlying human gene expression variation with RNA sequencing , 2010, Nature.

[35]  John A. Todd,et al.  Statistical colocalization of monocyte gene expression and genetic risk variants for type 1 diabetes , 2012, Human molecular genetics.

[36]  T. Lufkin,et al.  Hmx2 and Hmx3 homeobox genes direct development of the murine inner ear and hypothalamus and can be functionally replaced by Drosophila Hmx. , 2004, Developmental cell.

[37]  Luigi Ferrucci,et al.  Allelic heterogeneity and more detailed analyses of known loci explain additional phenotypic variation and reveal complex patterns of association , 2011, Human molecular genetics.

[38]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[39]  D. Lawlor,et al.  Cohort Profile: The ‘Children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children , 2012, International journal of epidemiology.

[40]  Kenny Q. Ye,et al.  An integrated map of genetic variation from 1,092 human genomes , 2012, Nature.