GENOME-WIDE ASSOCIATION ANALYSES BASED ON WHOLE-GENOME SEQUENCING IN SARDINIA PROVIDE INSIGHTS INTO REGULATION OF HEMOGLOBIN LEVELS

Danjou, Fabrice; Zoledziewska, Magdalena; Sidore, Carlo; Steri, Maristella; Busonero, Fabio; Maschio, Andrea; Mulas, Antonella; Perseu, Lucia; Barella, Susanna; Porcu, Eleonora; Pistis, Giorgio; Pitzalis, Maristella; Pala, Mauro; Menzel, Stephan; Metrustry, Sarah; Spector, Timothy D.; Leoni, Lidia; Angius, Andrea; Uda, Manuela; Moi, Paolo; Thein, Swee Lay; Galanello, Renzo; Abecasis, Gonçalo R; Schlessinger, David; Sanna, Serena; Cucca, Francesco

doi:10.1038/ng.3307

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GENOME-WIDE ASSOCIATION ANALYSES BASED ON WHOLE-GENOME SEQUENCING IN SARDINIA PROVIDE INSIGHTS INTO REGULATION OF HEMOGLOBIN LEVELS

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Author(s): Fabrice Danjou ¹ , Magdalena Zoledziewska ¹ , Carlo Sidore ¹ ^, ² ^, ³ , Maristella Steri ¹ , Fabio Busonero ¹ ^, ² ^, ⁴ , Andrea Maschio ¹ ^, ² ^, ⁴ , Antonella Mulas ¹ ^, ³ , Lucia Perseu ¹ , Susanna Barella ⁵ , Eleonora Porcu ¹ ^, ² ^, ³ , Giorgio Pistis ¹ ^, ² ^, ³ , Maristella Pitzalis ¹ , Mauro Pala ¹ , Stephan Menzel ⁶ , Sarah Metrustry ⁷ , Timothy D. Spector ⁷ , Lidia Leoni ⁸ , Andrea Angius ¹ ^, ⁸ , Manuela Uda ¹ , Paolo Moi ⁵ ^, ⁹ , Swee Lay Thein ⁶ ^, ¹⁰ , Renzo Galanello ⁵ ^, ⁹ ^, ¹⁴ , Gonçalo R. Abecasis ² , David Schlessinger ¹¹ , Serena Sanna ¹ , Francesco Cucca ¹ ^, ³

Publication date (Electronic): 14 September 2015

Journal: Nature genetics

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Abstract

We report GWAS results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five are due to variants at previously undetected loci: MPHOSPH9, PLTP- PCIF1, FOG1, NFIX, and CCND3. Among those at known loci, 10 are new lead variants and 4 are novel independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and revealed features of coordinated hemoglobin species production.

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Most cited references 51

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Gene Ontology: tool for the unification of biology

Michael Ashburner, Catherine A. Ball, Judith Blake … (2002)

Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.

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Common regulatory variation impacts gene expression in a cell type-dependent manner.

Antigone Dimas, Samuel Deutsch, Barbara Stranger … (2009)

Studies correlating genetic variation to gene expression facilitate the interpretation of common human phenotypes and disease. As functional variants may be operating in a tissue-dependent manner, we performed gene expression profiling and association with genetic variants (single-nucleotide polymorphisms) on three cell types of 75 individuals. We detected cell type-specific genetic effects, with 69 to 80% of regulatory variants operating in a cell type-specific manner, and identified multiple expressive quantitative trait loci (eQTLs) per gene, unique or shared among cell types and positively correlated with the number of transcripts per gene. Cell type-specific eQTLs were found at larger distances from genes and at lower effect size, similar to known enhancers. These data suggest that the complete regulatory variant repertoire can only be uncovered in the context of cell-type specificity.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 28 May 2015

Publication date (Electronic): 14 September 2015

Publication date (Print): November 2015

Publication date PMC-release: 01 May 2016

Volume: 47

Issue: 11

Pages: 1264-1271

Affiliations

[1 ]Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy

[2 ]Center for Statistical Genetics, Ann Arbor, University of Michigan, MI, USA

[3 ]Università degli Studi di Sassari, Sassari, Italy

[4 ]University of Michigan, DNA Sequencing Core, Ann Arbor, MI, USA

[5 ]Ospedale Regionale per le Microcitemie, ASL8, Cagliari, Italy

[6 ]Department of Molecular Hematology, King’s College London, London, UK

[7 ]Department of Twin Research and Genetic Epidemiology, King’s College London, UK

[8 ]Center for Advanced Studies, Research, and Development in Sardinia (CRS4), AGCT Program, Parco Scientifico e tecnologico della Sardegna, Pula, Italy

[9 ]Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy

[10 ]Department of Hematological Medecine, King’s College Hospital NHS Foundation Trust, London, UK

[11 ]Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

[14 ]Renzo Galanello prematurely passed away on May, 13 ^th 2013

Author notes

Correspondence should be addressed to: Fabrice Danjou fabrice.danjou@ 123456irgb.cnr.it Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy Francesco Cucca fcucca@ 123456uniss.it Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy

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Manuscript ID: EMS63149

DOI: 10.1038/ng.3307

PMC ID: 4627580

PubMed ID: 26366553

SO-VID: 91f3e183-41f7-4795-bd9c-08b146376c28

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GENOME-WIDE ASSOCIATION ANALYSES BASED ON WHOLE-GENOME SEQUENCING IN SARDINIA PROVIDE INSIGHTS INTO REGULATION OF HEMOGLOBIN LEVELS

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Abstract

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Genome Integrity

Most cited references 51

Gene Ontology: tool for the unification of biology

R: A language and environment for statistical computing

Common regulatory variation impacts gene expression in a cell type-dependent manner.

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