Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans
Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We...
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| Veröffentlicht in: | Human molecular genetics 2012-12, Vol.21 (24), p.5385-5394 |
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| creator | MANGINO, Massimo HWANG, Shih-Jen WEI CHEN SRINIVASAN, Sathanur R KART, Jeremy D BENETOS, Athanase EL SHAMIEH, Said VISVIKIS-SIEST, Sophie CHRISTENSEN, Kaare BERENSON, Gerald S VALDES, Ana M VINUELA, Ana SPECTOR, Timothy D GARCIA, Melissa ARNETT, Donna K BROECKEL, Ulrich PROVINCE, Michael A PANKOW, James S KAMMERER, Candace YONGMEI LIU NALLS, Michael TISHKOFF, Sarah THOMAS, Fridtjof HUNT, Steven C ZIV, Elad PSATY, Bruce M BIS, Joshua C ROTTER, Jerome I TAYLOR, Kent D SMITH, Erin SCHORK, Nicholas J LEVY, Daniel AVIV, Abraham KIMURA, Masayuki FITZPATRICK, Annette L CHRISTIANSEN, Lene PETERSEN, Inge ELBERS, Clara C HARRIS, Tamara |
| description | Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population. |
| doi_str_mv | 10.1093/hmg/dds382 |
| format | Article |
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Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/dds382</identifier><identifier>PMID: 23001564</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Association Studies ; Biological and medical sciences ; Fundamental and applied biological sciences. Psychology ; Genetics of eukaryotes. Biological and molecular evolution ; Genome-Wide Association Study ; Humans ; Kruppel-Like Transcription Factors ; Molecular and cellular biology ; Telomere - metabolism ; Telomere Homeostasis - genetics ; Telomere-Binding Proteins - genetics</subject><ispartof>Human molecular genetics, 2012-12, Vol.21 (24), p.5385-5394</ispartof><rights>2014 INIST-CNRS</rights><rights>The Author 2012. Published by Oxford University Press. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-19424762e461726b0d707a03065e3c230b02bf56e808c3d21da63cf4c58fa1f3</citedby><cites>FETCH-LOGICAL-c474t-19424762e461726b0d707a03065e3c230b02bf56e808c3d21da63cf4c58fa1f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26691852$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23001564$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MANGINO, Massimo</creatorcontrib><creatorcontrib>HWANG, Shih-Jen</creatorcontrib><creatorcontrib>WEI CHEN</creatorcontrib><creatorcontrib>SRINIVASAN, Sathanur R</creatorcontrib><creatorcontrib>KART, Jeremy D</creatorcontrib><creatorcontrib>BENETOS, Athanase</creatorcontrib><creatorcontrib>EL SHAMIEH, Said</creatorcontrib><creatorcontrib>VISVIKIS-SIEST, Sophie</creatorcontrib><creatorcontrib>CHRISTENSEN, Kaare</creatorcontrib><creatorcontrib>BERENSON, Gerald S</creatorcontrib><creatorcontrib>VALDES, Ana M</creatorcontrib><creatorcontrib>VINUELA, Ana</creatorcontrib><creatorcontrib>SPECTOR, Timothy D</creatorcontrib><creatorcontrib>GARCIA, Melissa</creatorcontrib><creatorcontrib>ARNETT, Donna K</creatorcontrib><creatorcontrib>BROECKEL, Ulrich</creatorcontrib><creatorcontrib>PROVINCE, Michael A</creatorcontrib><creatorcontrib>PANKOW, James S</creatorcontrib><creatorcontrib>KAMMERER, Candace</creatorcontrib><creatorcontrib>YONGMEI LIU</creatorcontrib><creatorcontrib>NALLS, Michael</creatorcontrib><creatorcontrib>TISHKOFF, Sarah</creatorcontrib><creatorcontrib>THOMAS, Fridtjof</creatorcontrib><creatorcontrib>HUNT, Steven C</creatorcontrib><creatorcontrib>ZIV, Elad</creatorcontrib><creatorcontrib>PSATY, Bruce M</creatorcontrib><creatorcontrib>BIS, Joshua C</creatorcontrib><creatorcontrib>ROTTER, Jerome I</creatorcontrib><creatorcontrib>TAYLOR, Kent D</creatorcontrib><creatorcontrib>SMITH, Erin</creatorcontrib><creatorcontrib>SCHORK, Nicholas J</creatorcontrib><creatorcontrib>LEVY, Daniel</creatorcontrib><creatorcontrib>AVIV, Abraham</creatorcontrib><creatorcontrib>KIMURA, Masayuki</creatorcontrib><creatorcontrib>FITZPATRICK, Annette L</creatorcontrib><creatorcontrib>CHRISTIANSEN, Lene</creatorcontrib><creatorcontrib>PETERSEN, Inge</creatorcontrib><creatorcontrib>ELBERS, Clara C</creatorcontrib><creatorcontrib>HARRIS, Tamara</creatorcontrib><title>Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.</description><subject>Association Studies</subject><subject>Biological and medical sciences</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>Genome-Wide Association Study</subject><subject>Humans</subject><subject>Kruppel-Like Transcription Factors</subject><subject>Molecular and cellular biology</subject><subject>Telomere - metabolism</subject><subject>Telomere Homeostasis - genetics</subject><subject>Telomere-Binding Proteins - genetics</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU1rFEEQhhtRzCZ68QdIXwQRxvTX9MxcBFlMFIK57CmXpranZrZlpmft6lHy7zPLbqI5VUE9PG_By9g7KT5L0ejL3dhfti3pWr1gK2msKJSo9Uu2Eo01hW2EPWPnRL-EkNbo6jU7U3rZS2tWrLvGOI1Y_A0t8hEzFBBhuKdAfD-FmInnia83a8khtvzu55WtLAfiPUYknrCfB8gh9jzjsHgS8t0yJspwUITId_MIkd6wVx0MhG9P84Jtrr5t1t-Lm9vrH-uvN4U3lcmFbIwylVVorKyU3Yq2EhUILWyJ2i9fb4XadqXFWtRet0q2YLXvjC_rDmSnL9iXo3Y_b0dsPcacYHD7FEZI926C4J5fYti5fvrjdClFVdaL4ONJkKbfM1J2YyCPwwARp5mcVErWpWrsAf10RH2aiBJ2TzFSuEMvbunFHXtZ4Pf_P_aEPhaxAB9OAJCHoUsQfaB_nLXNIVg_AM_alwc</recordid><startdate>20121215</startdate><enddate>20121215</enddate><creator>MANGINO, Massimo</creator><creator>HWANG, Shih-Jen</creator><creator>WEI CHEN</creator><creator>SRINIVASAN, Sathanur R</creator><creator>KART, Jeremy D</creator><creator>BENETOS, Athanase</creator><creator>EL SHAMIEH, Said</creator><creator>VISVIKIS-SIEST, Sophie</creator><creator>CHRISTENSEN, Kaare</creator><creator>BERENSON, Gerald S</creator><creator>VALDES, Ana M</creator><creator>VINUELA, Ana</creator><creator>SPECTOR, Timothy D</creator><creator>GARCIA, Melissa</creator><creator>ARNETT, Donna K</creator><creator>BROECKEL, Ulrich</creator><creator>PROVINCE, Michael A</creator><creator>PANKOW, James S</creator><creator>KAMMERER, Candace</creator><creator>YONGMEI LIU</creator><creator>NALLS, Michael</creator><creator>TISHKOFF, Sarah</creator><creator>THOMAS, Fridtjof</creator><creator>HUNT, Steven C</creator><creator>ZIV, Elad</creator><creator>PSATY, Bruce M</creator><creator>BIS, Joshua C</creator><creator>ROTTER, Jerome I</creator><creator>TAYLOR, Kent D</creator><creator>SMITH, Erin</creator><creator>SCHORK, Nicholas J</creator><creator>LEVY, Daniel</creator><creator>AVIV, Abraham</creator><creator>KIMURA, Masayuki</creator><creator>FITZPATRICK, Annette L</creator><creator>CHRISTIANSEN, Lene</creator><creator>PETERSEN, Inge</creator><creator>ELBERS, Clara C</creator><creator>HARRIS, Tamara</creator><general>Oxford University Press</general><scope>IQODW</scope><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>5PM</scope></search><sort><creationdate>20121215</creationdate><title>Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans</title><author>MANGINO, Massimo ; HWANG, Shih-Jen ; WEI CHEN ; SRINIVASAN, Sathanur R ; KART, Jeremy D ; BENETOS, Athanase ; EL SHAMIEH, Said ; VISVIKIS-SIEST, Sophie ; CHRISTENSEN, Kaare ; BERENSON, Gerald S ; VALDES, Ana M ; VINUELA, Ana ; SPECTOR, Timothy D ; GARCIA, Melissa ; ARNETT, Donna K ; BROECKEL, Ulrich ; PROVINCE, Michael A ; PANKOW, James S ; KAMMERER, Candace ; YONGMEI LIU ; NALLS, Michael ; TISHKOFF, Sarah ; THOMAS, Fridtjof ; HUNT, Steven C ; ZIV, Elad ; PSATY, Bruce M ; BIS, Joshua C ; ROTTER, Jerome I ; TAYLOR, Kent D ; SMITH, Erin ; SCHORK, Nicholas J ; LEVY, Daniel ; AVIV, Abraham ; KIMURA, Masayuki ; FITZPATRICK, Annette L ; CHRISTIANSEN, Lene ; PETERSEN, Inge ; ELBERS, Clara C ; HARRIS, Tamara</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-19424762e461726b0d707a03065e3c230b02bf56e808c3d21da63cf4c58fa1f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Association Studies</topic><topic>Biological and medical sciences</topic><topic>Fundamental and applied biological sciences. 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| fulltext | fulltext |
| identifier | ISSN: 0964-6906 |
| ispartof | Human molecular genetics, 2012-12, Vol.21 (24), p.5385-5394 |
| issn | 0964-6906 1460-2083 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3510758 |
| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Association Studies Biological and medical sciences Fundamental and applied biological sciences. Psychology Genetics of eukaryotes. Biological and molecular evolution Genome-Wide Association Study Humans Kruppel-Like Transcription Factors Molecular and cellular biology Telomere - metabolism Telomere Homeostasis - genetics Telomere-Binding Proteins - genetics |
| title | Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T04%3A51%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genome-wide%20meta-analysis%20points%20to%20CTC1%20and%20ZNF676%20as%20genes%20regulating%20telomere%20homeostasis%20in%20humans&rft.jtitle=Human%20molecular%20genetics&rft.au=MANGINO,%20Massimo&rft.date=2012-12-15&rft.volume=21&rft.issue=24&rft.spage=5385&rft.epage=5394&rft.pages=5385-5394&rft.issn=0964-6906&rft.eissn=1460-2083&rft_id=info:doi/10.1093/hmg/dds382&rft_dat=%3Cproquest_pubme%3E1221852968%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1221852968&rft_id=info:pmid/23001564&rfr_iscdi=true |