title: Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels.
abstract: We report genome-wide association study 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 signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production.
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
authors.forename: Fabrice
authors.identifier: http://orcid.org/0000-0002-4976-2327
authors.initials: F
authors.lastname: Danjou
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zoledziewska
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.|Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.|Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sidore
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Steri
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.|Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.|DNA Sequencing Core, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Busonero
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.|Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.|DNA Sequencing Core, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Maschio
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.|Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Mulas
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Perseu
authors.affiliation: Ospedale Regionale per le Microcitemie, ASL8, Cagliari, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Barella
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.|Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.|Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Porcu
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.|Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.|Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pistis
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Pitzalis
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Pala
authors.affiliation: Department of Molecular Hematology, King's College London, London, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Menzel
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Metrustry
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Center for Advanced Studies, Research and Development in Sardinia (CRS4), Parco Scientifico e Tecnologico della Sardegna, Pula, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Leoni
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.|Center for Advanced Studies, Research and Development in Sardinia (CRS4), Parco Scientifico e Tecnologico della Sardegna, Pula, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Angius
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Uda
authors.affiliation: Ospedale Regionale per le Microcitemie, ASL8, Cagliari, Italy.|Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Moi
authors.affiliation: Department of Molecular Hematology, King's College London, London, UK.|Department of Hematological Medicine, King's College Hospital National Health Service (NHS) Foundation Trust, London, UK.
authors.forename: Swee Lay
authors.initials: SL
authors.lastname: Thein
authors.affiliation: Ospedale Regionale per le Microcitemie, ASL8, Cagliari, Italy.|Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Galanello
authors.affiliation: Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: Laboratory of Genetics, National Institute on Aging, US National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.|Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
mesh_terms: D000328:Adult; D005260:Female; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D060005:Genotyping Techniques / Q000379:methods*; D006454:Hemoglobins / Q000235:genetics*; D006801:Humans; D062312:Islands; D007558:Italy; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods*; D055542:alpha-Globins / Q000235:genetics; D055544:beta-Globins / Q000235:genetics
chemical_list: D006454:Hemoglobins; D055542:alpha-Globins; D055544:beta-Globins