Silvia Naitza

@article{sidore_genome_2015,

title = {Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers},

author = {Carlo Sidore and Fabio Busonero and Andrea Maschio and Eleonora Porcu and Silvia Naitza and Magdalena Zoledziewska and Antonella Mulas and Giorgio Pistis and Maristella Steri and Fabrice Danjou and Alan Kwong and Vicente Diego {Ortega Del Vecchyo} and Charleston W K Chiang and Jennifer Bragg-Gresham and Maristella Pitzalis and Ramaiah Nagaraja and Brendan Tarrier and Christine Brennan and Sergio Uzzau and Christian Fuchsberger and Rossano Atzeni and Frederic Reinier and Riccardo Berutti and Jie Huang and Nicholas J Timpson and Daniela Toniolo and Paolo Gasparini and Giovanni Malerba and George Dedoussis and Eleftheria Zeggini and Nicole Soranzo and Chris Jones and Robert Lyons and Andrea Angius and Hyun M Kang and John Novembre and Serena Sanna and David Schlessinger and Francesco Cucca and Gon{ç}alo R Abecasis},

doi = {10.1038/ng.3368},

issn = {1546-1718},

year  = {2015},

date = {2015-11-01},

journal = {Nature Genetics},

volume = {47},

number = {11},

pages = {1272--1281},

abstract = {We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid24586183,

title = {Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease},

author = { M. Medici and E. Porcu and G. Pistis and A. Teumer and S. J. Brown and R. A. Jensen and R. Rawal and G. L. Roef and T. S. Plantinga and S. H. Vermeulen and J. Lahti and M. J. Simmonds and L. L. Husemoen and R. M. Freathy and B. M. Shields and D. Pietzner and R. Nagy and L. Broer and L. Chaker and T. I. Korevaar and M. G. Plia and C. Sala and U. Völker and J. B. Richards and F. C. Sweep and C. Gieger and T. Corre and E. Kajantie and B. Thuesen and Y. E. Taes and W. E. Visser and A. T. Hattersley and J. Kratzsch and A. Hamilton and W. Li and G. Homuth and M. Lobina and S. Mariotti and N. Soranzo and M. Cocca and M. Nauck and C. Spielhagen and A. Ross and A. Arnold and M. van de Bunt and S. Liyanarachchi and M. Heier and H. J. Grabe and C. Masciullo and T. E. Galesloot and E. M. Lim and E. Reischl and P. J. Leedman and S. Lai and A. Delitala and A. P. Bremner and D. I. Philips and J. P. Beilby and A. Mulas and M. Vocale and G. Abecasis and T. Forsen and A. James and E. Widen and J. Hui and H. Prokisch and E. E. Rietzschel and A. Palotie and P. Feddema and S. J. Fletcher and K. Schramm and J. I. Rotter and A. Kluttig and D. Radke and M. Traglia and G. L. Surdulescu and H. He and J. A. Franklyn and D. Tiller and B. Vaidya and T. de Meyer and T. Jørgensen and J. G. Eriksson and P. C. O'Leary and E. Wichmann and A. R. Hermus and B. M. Psaty and T. Ittermann and A. Hofman and E. Bosi and D. Schlessinger and H. Wallaschofski and N. Pirastu and Y. S. Aulchenko and A. de la Chapelle and R. T. Netea-Maier and S. C. Gough and H. Meyer Zu Schwabedissen and T. M. Frayling and J. M. Kaufman and A. Linneberg and K. Räikkönen and J. W. Smit and L. A. Kiemeney and F. Rivadeneira and A. G. Uitterlinden and J. P. Walsh and C. Meisinger and M. den Heijer and T. J. Visser and T. D. Spector and S. G. Wilson and H. Völzke and A. Cappola and D. Toniolo and S. Sanna and S. Naitza and R. P. Peeters},

year  = {2014},

date = {2014-02-01},

journal = {PLoS Genet},

volume = {10},

number = {2},

pages = {e1004123},

abstract = {Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{orru_genetic_2013,

title = {Genetic variants regulating immune cell levels in health and disease.},

author = {Valeria Orrù and Maristella Steri and Gabriella Sole and Carlo Sidore and Francesca Virdis and Mariano Dei and Sandra Lai and Magdalena Zoledziewska and Fabio Busonero and Antonella Mulas and Matteo Floris and Wieslawa I Mentzen and Silvana A M Urru and Stefania Olla and Michele Marongiu and Maria G Piras and Monia Lobina and Andrea Maschio and Maristella Pitzalis and Maria F Urru and Marco Marcelli and Roberto Cusano and Francesca Deidda and Valentina Serra and Manuela Oppo and Rosella Pilu and Frederic Reinier and Riccardo Berutti and Luca Pireddu and Ilenia Zara and Eleonora Porcu and Alan Kwong and Christine Brennan and Brendan Tarrier and Robert Lyons and Hyun M Kang and Sergio Uzzau and Rossano Atzeni and Maria Valentini and Davide Firinu and Lidia Leoni and Gianluca Rotta and Silvia Naitza and Andrea Angius and Mauro Congia and Michael B Whalen and Chris M Jones and David Schlessinger and Gon{ç}alo R Abecasis and Edoardo Fiorillo and Serena Sanna and Francesco Cucca},

doi = {10.1016/j.cell.2013.08.041},

issn = {1097-4172},

year  = {2013},

date = {2013-09-01},

journal = {Cell},

volume = {155},

number = {1},

pages = {242--56},

abstract = {The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self" result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing ∼8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23969696,

title = {Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease},

author = { M. Sabater-Lleal and J. Huang and D. Chasman and S. Naitza and A. Dehghan and A. D. Johnson and others},

year  = {2013},

date = {2013-09-01},

journal = {Circulation},

volume = {128},

number = {12},

pages = {1310--1324},

abstract = {Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{porcu_meta-analysis_2013,

title = {A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.},

author = {Porcu, Eleonora and Medici, Marco and Pistis, Giorgio and Volpato, Claudia B. and Wilson, Scott G. and Cappola, Anne R. and Bos, Steffan D. and Deelen, Joris and den Heijer, Martin and Freathy, Rachel M. and Lahti, Jari and Liu, Chunyu and Lopez, Lorna M. and Nolte, Ilja M. and O'Connell, Jeffrey R. and Tanaka, Toshiko and Trompet, Stella and Arnold, Alice and Bandinelli, Stefania and Beekman, Marian and Bohringer, Stefan and Brown, Suzanne J. and Buckley, Brendan M. and Camaschella, Clara and de Craen, Anton J. M. and Davies, Gail and de Visser, Marieke C. H. and Ford, Ian and Forsen, Tom and Frayling, Timothy M. and Fugazzola, Laura and Gogele, Martin and Hattersley, Andrew T. and Hermus, Ad R. and Hofman, Albert and Houwing-Duistermaat, Jeanine J. and Jensen, Richard A. and Kajantie, Eero and Kloppenburg, Margreet and Lim, Ee M. and Masciullo, Corrado and Mariotti, Stefano and Minelli, Cosetta and Mitchell, Braxton D. and Nagaraja, Ramaiah and Netea-Maier, Romana T. and Palotie, Aarno and Persani, Luca and Piras, Maria G. and Psaty, Bruce M. and Raikkonen, Katri and Richards, J. Brent and Rivadeneira, Fernando and Sala, Cinzia and Sabra, Mona M. and Sattar, Naveed and Shields, Beverley M. and Soranzo, Nicole and Starr, John M. and Stott, David J. and Sweep, Fred C. G. J. and Usala, Gianluca and van der Klauw, Melanie M. and van Heemst, Diana and van Mullem, Alies and Vermeulen, Sita H. and Visser, W. Edward and Walsh, John P. and Westendorp, Rudi G. J. and Widen, Elisabeth and Zhai, Guangju and Cucca, Francesco and Deary, Ian J. and Eriksson, Johan G. and Ferrucci, Luigi and Fox, Caroline S. and Jukema, J. Wouter and Kiemeney, Lambertus A. and Pramstaller, Peter P. and Schlessinger, David and Shuldiner, Alan R. and Slagboom, Eline P. and Uitterlinden, Andre G. and Vaidya, Bijay and Visser, Theo J. and Wolffenbuttel, Bruce H. R. and Meulenbelt, Ingrid and Rotter, Jerome I. and Spector, Tim D. and Hicks, Andrew A. and Toniolo, Daniela and Sanna, Serena and Peeters, Robin P. and Naitza, Silvia},

doi = {10.1371/journal.pgen.1003266},

issn = {1553-7404 1553-7390},

year  = {2013},

date = {2013-01-01},

journal = {PLoS Genet},

volume = {9},

number = {2},

pages = {e1003266},

abstract = {Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Naitza2012,

title = {A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation.},

author = {Naitza, Silvia and Porcu, Eleonora and Steri, Maristella and Taub, Dennis D and Mulas, Antonella and Xiao, Xiang and Strait, James and Dei, Mariano and Lai, Sandra and Busonero, Fabio and Maschio, Andrea and Usala, Gianluca and Zoledziewska, Magdalena and Sidore, Carlo and Zara, Ilenia and Pitzalis, Maristella and Loi, Alessia and Virdis, Francesca and Piras, Roberta and Deidda, Francesca and Whalen, Michael B and Crisponi, Laura and Concas, Antonio and Podda, Carlo and Uzzau, Sergio and Scheet, Paul and Longo, Dan L and Lakatta, Edward and Abecasis, Gon{ç}alo R and Cao, Antonio and Schlessinger, David and Uda, Manuela and Sanna, Serena and Cucca, Francesco},

editor = {Sabeti, Pardis C.},

url = {http://dx.plos.org/10.1371/journal.pgen.1002480 http://www.ncbi.nlm.nih.gov/pubmed/22291609 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC3266885},

doi = {10.1371/journal.pgen.1002480},

issn = {1553-7404},

year  = {2012},

date = {2012-01-01},

journal = {PLoS genetics},

volume = {8},

number = {1},

pages = {e1002480},

abstract = {Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid18514160,

title = {Phosphodiesterase 8B gene variants are associated with serum ŦSH levels and thyroid function},

author = { },

year  = {2008},

date = {2008-06-01},

volume = {82},

number = {6},

pages = {1270--1280},

abstract = {Thyroid-stimulating hormone (TSH) controls thyroid growth and hormone secretion through binding to its G protein-coupled receptor (TSHR) and production of cyclic AMP (cAMP). Serum TSH is a sensitive indicator of thyroid function, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over a life span. By genotyping 362,129 SNPs in 4,300 Sardinians, we identified a strong association (p = 1.3 x 10(-11)) between alleles of rs4704397 and circulating TSH levels; each additional copy of the minor A allele was associated with an increase of 0.13 muIU/ml in TSH. The single-nucleotide polymorphism (SNP) is located in intron 1 of PDE8B, encoding a high-affinity cAMP-specific phosphodiesterase. The association was replicated in 4,158 individuals, including additional Sardinians and two genetically distant cohorts from Tuscany and the Old Order Amish (overall p value = 1.9 x 10(-20)). In addition to association of TSH levels with SNPs in PDE8B, our genome scan provided evidence for association with PDE10A and several biologically interesting candidates in a focused analysis of 24 genes. In particular, we found evidence for association of TSH levels with SNPs in the THRB (rs1505287},

keywords = {},

pubstate = {published},

tppubtype = {article}

}