Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci
Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclea...
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Veröffentlicht in: | Human molecular genetics 2015-08, Vol.24 (16), p.4746-4763 |
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creator | Kirsten, Holger Al-Hasani, Hoor Holdt, Lesca Gross, Arnd Beutner, Frank Krohn, Knut Horn, Katrin Ahnert, Peter Burkhardt, Ralph Reiche, Kristin Hackermüller, Jörg Löffler, Markus Teupser, Daniel Thiery, Joachim Scholz, Markus |
description | Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes. |
doi_str_mv | 10.1093/hmg/ddv194 |
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However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddv194</identifier><identifier>PMID: 26019233</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Association Studies ; Female ; Gene Expression Regulation ; Genome-Wide Association Study ; Humans ; Leukocytes, Mononuclear ; Male ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Regulatory Sequences, Nucleic Acid</subject><ispartof>Human molecular genetics, 2015-08, Vol.24 (16), p.4746-4763</ispartof><rights>The Author 2015. Published by Oxford University Press.</rights><rights>The Author 2015. Published by Oxford University Press. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-e555a451395d3e9631fce762453af990adfb2e47bb5aeb5862a1978f7d7eb33</citedby><cites>FETCH-LOGICAL-c375t-e555a451395d3e9631fce762453af990adfb2e47bb5aeb5862a1978f7d7eb33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26019233$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kirsten, Holger</creatorcontrib><creatorcontrib>Al-Hasani, Hoor</creatorcontrib><creatorcontrib>Holdt, Lesca</creatorcontrib><creatorcontrib>Gross, Arnd</creatorcontrib><creatorcontrib>Beutner, Frank</creatorcontrib><creatorcontrib>Krohn, Knut</creatorcontrib><creatorcontrib>Horn, Katrin</creatorcontrib><creatorcontrib>Ahnert, Peter</creatorcontrib><creatorcontrib>Burkhardt, Ralph</creatorcontrib><creatorcontrib>Reiche, Kristin</creatorcontrib><creatorcontrib>Hackermüller, Jörg</creatorcontrib><creatorcontrib>Löffler, Markus</creatorcontrib><creatorcontrib>Teupser, Daniel</creatorcontrib><creatorcontrib>Thiery, Joachim</creatorcontrib><creatorcontrib>Scholz, Markus</creatorcontrib><title>Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes.</description><subject>Association Studies</subject><subject>Female</subject><subject>Gene Expression Regulation</subject><subject>Genome-Wide Association Study</subject><subject>Humans</subject><subject>Leukocytes, Mononuclear</subject><subject>Male</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Quantitative Trait Loci</subject><subject>Regulatory Sequences, Nucleic Acid</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc-KFDEQxoMo7rh68QGkjyK0m__duQiyq7vCgIh7D-mkuifSnYxJemBfxyc1s7MuevKUCt-vvqriQ-g1we8JVuxit0wXzh2I4k_QhnCJW4p79hRtsJK8lQrLM_Qi5x8YE8lZ9xydUYmJooxt0K8rnzPY4sPUlB00EwQo3uYmjvf_3bqY0JRkQrbJ70tcoPEOQvGjh9yEeID5KPvSJphNAXeCW_h2u82NCa6xMaU4xFTFfO-ZYForGtNdLWc4mGDhOC_E0O5TLOBDbXLHleZo_Uv0bDRzhlcP7zn6_vnT7eVNu_16_eXy47a1rBOlBSGE4YIwJRwDJRkZLXSScsHMqBQ2bhwo8G4YhIFB9JIaorp-7FwHA2Pn6MPJdb8OCzhbT0xm1vvkF5PudDRe_6sEv9NTPOg6kkqGq8HbB4MUf66Qi158tjDPJkBcsyYdoUL2itP_o1L1SkiJeUXfnVCbYs4JxseNCNbH9HVNX5_Sr_Cbv294RP_EzX4DulKxew</recordid><startdate>20150815</startdate><enddate>20150815</enddate><creator>Kirsten, Holger</creator><creator>Al-Hasani, Hoor</creator><creator>Holdt, Lesca</creator><creator>Gross, Arnd</creator><creator>Beutner, Frank</creator><creator>Krohn, Knut</creator><creator>Horn, Katrin</creator><creator>Ahnert, Peter</creator><creator>Burkhardt, Ralph</creator><creator>Reiche, Kristin</creator><creator>Hackermüller, Jörg</creator><creator>Löffler, Markus</creator><creator>Teupser, Daniel</creator><creator>Thiery, Joachim</creator><creator>Scholz, Markus</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20150815</creationdate><title>Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci</title><author>Kirsten, Holger ; Al-Hasani, Hoor ; Holdt, Lesca ; Gross, Arnd ; Beutner, Frank ; Krohn, Knut ; Horn, Katrin ; Ahnert, Peter ; Burkhardt, Ralph ; Reiche, Kristin ; Hackermüller, Jörg ; Löffler, Markus ; Teupser, Daniel ; Thiery, Joachim ; Scholz, Markus</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-e555a451395d3e9631fce762453af990adfb2e47bb5aeb5862a1978f7d7eb33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Association Studies</topic><topic>Female</topic><topic>Gene Expression Regulation</topic><topic>Genome-Wide Association Study</topic><topic>Humans</topic><topic>Leukocytes, Mononuclear</topic><topic>Male</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Quantitative Trait Loci</topic><topic>Regulatory Sequences, Nucleic Acid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kirsten, Holger</creatorcontrib><creatorcontrib>Al-Hasani, Hoor</creatorcontrib><creatorcontrib>Holdt, Lesca</creatorcontrib><creatorcontrib>Gross, Arnd</creatorcontrib><creatorcontrib>Beutner, Frank</creatorcontrib><creatorcontrib>Krohn, Knut</creatorcontrib><creatorcontrib>Horn, Katrin</creatorcontrib><creatorcontrib>Ahnert, Peter</creatorcontrib><creatorcontrib>Burkhardt, Ralph</creatorcontrib><creatorcontrib>Reiche, Kristin</creatorcontrib><creatorcontrib>Hackermüller, Jörg</creatorcontrib><creatorcontrib>Löffler, Markus</creatorcontrib><creatorcontrib>Teupser, Daniel</creatorcontrib><creatorcontrib>Thiery, Joachim</creatorcontrib><creatorcontrib>Scholz, Markus</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kirsten, Holger</au><au>Al-Hasani, Hoor</au><au>Holdt, Lesca</au><au>Gross, Arnd</au><au>Beutner, Frank</au><au>Krohn, Knut</au><au>Horn, Katrin</au><au>Ahnert, Peter</au><au>Burkhardt, Ralph</au><au>Reiche, Kristin</au><au>Hackermüller, Jörg</au><au>Löffler, Markus</au><au>Teupser, Daniel</au><au>Thiery, Joachim</au><au>Scholz, Markus</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2015-08-15</date><risdate>2015</risdate><volume>24</volume><issue>16</issue><spage>4746</spage><epage>4763</epage><pages>4746-4763</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>26019233</pmid><doi>10.1093/hmg/ddv194</doi><tpages>18</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Association Studies Female Gene Expression Regulation Genome-Wide Association Study Humans Leukocytes, Mononuclear Male Polymorphism, Single Nucleotide Quantitative Trait Loci Regulatory Sequences, Nucleic Acid |
title | Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci |
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