Genome wide association analysis of a founder population identified TAF3 as a gene for MCHC in humans
The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5-10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome...
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| Veröffentlicht in: | PloS one 2013-07, Vol.8 (7), p.e69206-e69206 |
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| creator | Pistis, Giorgio Okonkwo, Shawntel U Traglia, Michela Sala, Cinzia Shin, So-Youn Masciullo, Corrado Buetti, Iwan Massacane, Roberto Mangino, Massimo Thein, Swee-Lay Spector, Timothy D Ganesh, Santhi Pirastu, Nicola Gasparini, Paolo Soranzo, Nicole Camaschella, Clara Hart, Daniel Green, Michael R Toniolo, Daniela |
| description | The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5-10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene. The association was replicated in two cohorts (rs1887582, P = 4.25E-09). TAF3 encodes a transcription cofactor that participates in core promoter recognition complex, and is involved in zebrafish and mouse erythropoiesis. We show here that TAF3 is required for transcription of the SPTA1 gene, encoding alpha spectrin, one of the proteins that link the plasma membrane to the actin cytoskeleton. Mutations in SPTA1 are responsible for hereditary spherocytosis, a monogenic disorder of MCHC, as well as for the normal MCHC level. Based on our results, we propose that TAF3 is required for normal erythropoiesis in human and that it might have a role in controlling the ratio between hemoglobin (Hb) and cell volume and in the dynamics of RBC maturation in healthy individuals. Finally, TAF3 represents a potential candidate or a modifier gene for disorders of red cell membrane. |
| doi_str_mv | 10.1371/journal.pone.0069206 |
| format | Article |
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Only 5-10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene. The association was replicated in two cohorts (rs1887582, P = 4.25E-09). TAF3 encodes a transcription cofactor that participates in core promoter recognition complex, and is involved in zebrafish and mouse erythropoiesis. We show here that TAF3 is required for transcription of the SPTA1 gene, encoding alpha spectrin, one of the proteins that link the plasma membrane to the actin cytoskeleton. Mutations in SPTA1 are responsible for hereditary spherocytosis, a monogenic disorder of MCHC, as well as for the normal MCHC level. Based on our results, we propose that TAF3 is required for normal erythropoiesis in human and that it might have a role in controlling the ratio between hemoglobin (Hb) and cell volume and in the dynamics of RBC maturation in healthy individuals. Finally, TAF3 represents a potential candidate or a modifier gene for disorders of red cell membrane.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0069206</identifier><identifier>PMID: 23935956</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Actin ; Animals ; Association analysis ; Biology ; Blood ; Cell Line, Tumor ; Cell size ; Chromatin Immunoprecipitation ; Cohort Studies ; Consortia ; Cytoskeleton ; Epidemiology ; Erythrocyte Indices - genetics ; Erythrocytes ; Erythrocytes - cytology ; Erythrocytes - metabolism ; Erythropoiesis ; Erythropoiesis - genetics ; Founder Effect ; Gene expression ; Gene Expression Regulation ; Gene loci ; Genetics ; Genome-wide association studies ; Genome-Wide Association Study - methods ; Genomes ; Hematology ; Hemoglobin ; Hemoglobins - metabolism ; Hereditary spherocytosis ; Humans ; Italy ; K562 Cells ; Laboratories ; Maternal & child health ; Medicine ; Mutation ; Older people ; Polymorphism, Single Nucleotide ; Population ; Promoter Regions, Genetic - genetics ; Protein Binding ; Proteins ; Reverse Transcriptase Polymerase Chain Reaction ; RNA Interference ; Spectrin ; Spectrin - genetics ; Spherocytosis ; TATA-Binding Protein Associated Factors ; Transcription ; Transcription Factor TFIID - genetics ; Transcription Factor TFIID - metabolism ; Zebrafish</subject><ispartof>PloS one, 2013-07, Vol.8 (7), p.e69206-e69206</ispartof><rights>2013 Pistis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Pistis et al 2013 Pistis et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-3378f86afdc3d8bf5ec6e49b4f096e85d918e3a72877b8f2bd9cad4dd62555443</citedby><cites>FETCH-LOGICAL-c526t-3378f86afdc3d8bf5ec6e49b4f096e85d918e3a72877b8f2bd9cad4dd62555443</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729833/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729833/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23935956$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pistis, Giorgio</creatorcontrib><creatorcontrib>Okonkwo, Shawntel U</creatorcontrib><creatorcontrib>Traglia, Michela</creatorcontrib><creatorcontrib>Sala, Cinzia</creatorcontrib><creatorcontrib>Shin, So-Youn</creatorcontrib><creatorcontrib>Masciullo, Corrado</creatorcontrib><creatorcontrib>Buetti, Iwan</creatorcontrib><creatorcontrib>Massacane, Roberto</creatorcontrib><creatorcontrib>Mangino, Massimo</creatorcontrib><creatorcontrib>Thein, Swee-Lay</creatorcontrib><creatorcontrib>Spector, Timothy D</creatorcontrib><creatorcontrib>Ganesh, Santhi</creatorcontrib><creatorcontrib>Pirastu, Nicola</creatorcontrib><creatorcontrib>Gasparini, Paolo</creatorcontrib><creatorcontrib>Soranzo, Nicole</creatorcontrib><creatorcontrib>Camaschella, Clara</creatorcontrib><creatorcontrib>Hart, Daniel</creatorcontrib><creatorcontrib>Green, Michael R</creatorcontrib><creatorcontrib>Toniolo, Daniela</creatorcontrib><creatorcontrib>CHARGE Consortium Hematology Working</creatorcontrib><title>Genome wide association analysis of a founder population identified TAF3 as a gene for MCHC in humans</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5-10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene. The association was replicated in two cohorts (rs1887582, P = 4.25E-09). TAF3 encodes a transcription cofactor that participates in core promoter recognition complex, and is involved in zebrafish and mouse erythropoiesis. We show here that TAF3 is required for transcription of the SPTA1 gene, encoding alpha spectrin, one of the proteins that link the plasma membrane to the actin cytoskeleton. Mutations in SPTA1 are responsible for hereditary spherocytosis, a monogenic disorder of MCHC, as well as for the normal MCHC level. Based on our results, we propose that TAF3 is required for normal erythropoiesis in human and that it might have a role in controlling the ratio between hemoglobin (Hb) and cell volume and in the dynamics of RBC maturation in healthy individuals. Finally, TAF3 represents a potential candidate or a modifier gene for disorders of red cell membrane.</description><subject>Actin</subject><subject>Animals</subject><subject>Association analysis</subject><subject>Biology</subject><subject>Blood</subject><subject>Cell Line, Tumor</subject><subject>Cell size</subject><subject>Chromatin Immunoprecipitation</subject><subject>Cohort Studies</subject><subject>Consortia</subject><subject>Cytoskeleton</subject><subject>Epidemiology</subject><subject>Erythrocyte Indices - genetics</subject><subject>Erythrocytes</subject><subject>Erythrocytes - cytology</subject><subject>Erythrocytes - metabolism</subject><subject>Erythropoiesis</subject><subject>Erythropoiesis - genetics</subject><subject>Founder Effect</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Gene loci</subject><subject>Genetics</subject><subject>Genome-wide association studies</subject><subject>Genome-Wide Association Study - methods</subject><subject>Genomes</subject><subject>Hematology</subject><subject>Hemoglobin</subject><subject>Hemoglobins - metabolism</subject><subject>Hereditary spherocytosis</subject><subject>Humans</subject><subject>Italy</subject><subject>K562 Cells</subject><subject>Laboratories</subject><subject>Maternal & child health</subject><subject>Medicine</subject><subject>Mutation</subject><subject>Older people</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Population</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA Interference</subject><subject>Spectrin</subject><subject>Spectrin - genetics</subject><subject>Spherocytosis</subject><subject>TATA-Binding Protein Associated Factors</subject><subject>Transcription</subject><subject>Transcription Factor TFIID - genetics</subject><subject>Transcription Factor TFIID - 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humans</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-07-31</date><risdate>2013</risdate><volume>8</volume><issue>7</issue><spage>e69206</spage><epage>e69206</epage><pages>e69206-e69206</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5-10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene. The association was replicated in two cohorts (rs1887582, P = 4.25E-09). TAF3 encodes a transcription cofactor that participates in core promoter recognition complex, and is involved in zebrafish and mouse erythropoiesis. We show here that TAF3 is required for transcription of the SPTA1 gene, encoding alpha spectrin, one of the proteins that link the plasma membrane to the actin cytoskeleton. Mutations in SPTA1 are responsible for hereditary spherocytosis, a monogenic disorder of MCHC, as well as for the normal MCHC level. Based on our results, we propose that TAF3 is required for normal erythropoiesis in human and that it might have a role in controlling the ratio between hemoglobin (Hb) and cell volume and in the dynamics of RBC maturation in healthy individuals. Finally, TAF3 represents a potential candidate or a modifier gene for disorders of red cell membrane.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23935956</pmid><doi>10.1371/journal.pone.0069206</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-07, Vol.8 (7), p.e69206-e69206 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1440999912 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Actin Animals Association analysis Biology Blood Cell Line, Tumor Cell size Chromatin Immunoprecipitation Cohort Studies Consortia Cytoskeleton Epidemiology Erythrocyte Indices - genetics Erythrocytes Erythrocytes - cytology Erythrocytes - metabolism Erythropoiesis Erythropoiesis - genetics Founder Effect Gene expression Gene Expression Regulation Gene loci Genetics Genome-wide association studies Genome-Wide Association Study - methods Genomes Hematology Hemoglobin Hemoglobins - metabolism Hereditary spherocytosis Humans Italy K562 Cells Laboratories Maternal & child health Medicine Mutation Older people Polymorphism, Single Nucleotide Population Promoter Regions, Genetic - genetics Protein Binding Proteins Reverse Transcriptase Polymerase Chain Reaction RNA Interference Spectrin Spectrin - genetics Spherocytosis TATA-Binding Protein Associated Factors Transcription Transcription Factor TFIID - genetics Transcription Factor TFIID - metabolism Zebrafish |
| title | Genome wide association analysis of a founder population identified TAF3 as a gene for MCHC in humans |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-13T03%3A04%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genome%20wide%20association%20analysis%20of%20a%20founder%20population%20identified%20TAF3%20as%20a%20gene%20for%20MCHC%20in%20humans&rft.jtitle=PloS%20one&rft.au=Pistis,%20Giorgio&rft.aucorp=CHARGE%20Consortium%20Hematology%20Working&rft.date=2013-07-31&rft.volume=8&rft.issue=7&rft.spage=e69206&rft.epage=e69206&rft.pages=e69206-e69206&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0069206&rft_dat=%3Cproquest_plos_%3E1420165233%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1440999912&rft_id=info:pmid/23935956&rft_doaj_id=oai_doaj_org_article_10f20b756ddf47168cadb980f6421b74&rfr_iscdi=true |