Fan Yang1, Kevin J Gleason2, Jiebiao Wang3, Jubao Duan4,5, Xin He6, Brandon L Pierce2,6, Lin S Chen2. 1. Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, 13001 E. 17th Place, Aurora, Colorado, 80045, USA. 2. Department of Public Health Sciences, University of Chicago, 5841 South Maryland Ave MC2000, Chicago, IL, 60637, USA. 3. Department of Biostatistics, University of Pittsburgh, 7135 Public Health, 130 DeSoto Street, Pittsburgh, PA, 15261, USA. 4. Center for Psychiatric Genetics, NorthShore University HealthSystem, 1001 University Place, Evanston, IL, 60201, USA. 5. Department of Psychiatry and Behavioral Neuroscience, 5841 S Maryland Ave, Chicago MC3077, Chicago, IL, 60637, USA. 6. Heart Center, Turku University Hospital and University of Turku, Turku, Finland.
Abstract
MOTIVATION: Trans-acting expression quantitative trait loci (eQTLs) collectively explain a substantial proportion of expression variation, yet are challenging to detect and replicate since their effects are often individually weak. A large proportion of genetic effects on distal genes are mediated through cisgene expression. Cis-association (between SNP and cis-gene) and gene-gene correlation conditional on SNP genotype could establish trans-association (between SNP and trans-gene). Both cis-association and gene-gene conditional correlation have effects shared across relevant tissues and conditions, and transassociations mediated by cis-gene expression also have effects shared across relevant conditions. RESULTS: . We proposed a Cross-Condition Mediation analysis method (CCmed) for detecting cis-mediated trans-associations with replicable effects in relevant conditions/studies. CCmed integrates cis-association and gene-gene conditional correlation statistics from multiple tissues/studies. Motivated by the bimodal effect-sharing patterns of eQTLs, we proposed two variations of CCmed, CCmedmost and CCmedspec for detecting cross-tissue and tissue-specific trans-associations, respectively. We analyzed data of 13 brain tissues from the Genotype-Tissue Expression (GTEx) project, and identified trios with cis-mediated transassociations across brain tissues, many of which showed evidence of trans-association in two replication studies. We also identified trans-genes associated with schizophrenia loci in at least two brain tissues. AVAILABILITY AND IMPLEMENTATION: CCmed software is available at http://github.com/kjgleason/CCmed. SUPPLEMENTARY INFORMATION: Supplementary Material are available at Bioinformatics online.
MOTIVATION: Trans-acting expression quantitative trait loci (eQTLs) collectively explain a substantial proportion of expression variation, yet are challenging to detect and replicate since their effects are often individually weak. A large proportion of genetic effects on distal genes are mediated through cisgene expression. Cis-association (between SNP and cis-gene) and gene-gene correlation conditional on SNP genotype could establish trans-association (between SNP and trans-gene). Both cis-association and gene-gene conditional correlation have effects shared across relevant tissues and conditions, and transassociations mediated by cis-gene expression also have effects shared across relevant conditions. RESULTS: . We proposed a Cross-Condition Mediation analysis method (CCmed) for detecting cis-mediated trans-associations with replicable effects in relevant conditions/studies. CCmed integrates cis-association and gene-gene conditional correlation statistics from multiple tissues/studies. Motivated by the bimodal effect-sharing patterns of eQTLs, we proposed two variations of CCmed, CCmedmost and CCmedspec for detecting cross-tissue and tissue-specific trans-associations, respectively. We analyzed data of 13 brain tissues from the Genotype-Tissue Expression (GTEx) project, and identified trios with cis-mediated transassociations across brain tissues, many of which showed evidence of trans-association in two replication studies. We also identified trans-genes associated with schizophrenia loci in at least two brain tissues. AVAILABILITY AND IMPLEMENTATION: CCmed software is available at http://github.com/kjgleason/CCmed. SUPPLEMENTARY INFORMATION: Supplementary Material are available at Bioinformatics online.
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