Mara Marongiu

@article{Forabosco2024-jt,

title = {Transcriptome organization of white blood cells through gene  co-expression network analysis in a large RNA-seq dataset},

author = {Paola Forabosco and Mauro Pala and Francesca Crobu and Maria Antonietta Diana and Mara Marongiu and Roberto Cusano and Andrea Angius and Maristella Steri and Valeria Orr`u and David Schlessinger and Edoardo Fiorillo and Marcella Devoto and Francesco Cucca},

doi = {10.3389/fimmu.2024.1350111},

year  = {2024},

date = {2024-04-01},

urldate = {2024-04-01},

journal = {Front. Immunol.},

volume = {15},

pages = {1350111},

abstract = {Gene co-expression network analysis enables identification of 

 biologically meaningful clusters of co-regulated genes (modules) 

 in an unsupervised manner. We present here the largest study 

 conducted thus far of co-expression networks in white blood cells 

 (WBC) based on RNA-seq data from 624 individuals. We identify 41 

 modules, 13 of them related to specific immune-related functions 

 and cell types (e.g. neutrophils, B and T cells, NK cells, and 

 plasmacytoid dendritic cells); we highlight biologically relevant 

 lncRNAs for each annotated module of co-expressed genes. We 

 further characterize with unprecedented resolution the modules in 

 T cell sub-types, through the availability of 95 immune 

 phenotypes obtained by flow cytometry in the same individuals. 

 This study provides novel insights into the transcriptional 

 architecture of human leukocytes, showing how network analysis 

 can advance our understanding of coding and non-coding gene 

 interactions in immune system cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32929287,

title = {Complex genetic signatures in immune cells underlie autoimmunity and inform therapy},

author = {V Orrù and M Steri and C Sidore and M Marongiu and V Serra and S Olla and G Sole and S Lai and M Dei and A Mulas and F Virdis and MG Piras and M Lobina and M Marongiu and M Pitzalis and F Deidda and A Loizedda and S Onano and M Zoledziewska and S Sawcer and M Devoto and M Gorospe and GR Abecasis and M Floris and M Pala and D Schlessinger and E Fiorillo and F Cucca},

doi = {10.1038/s41588-020-0684-4},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Nat Genet},

volume = {52},

number = {10},

pages = {1036--1045},

abstract = {We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (P < 1.28 × 10-11) independent association signals for 459 cell traits at 70 loci (53 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated signals, predominantly for autoimmune disorders, highlighting intermediate phenotypes in pathogenesis. Collectively, our findings illustrate complex genetic regulation of immune cells with highly selective effects on autoimmune disease risk at the cell-subtype level. These results identify drug-targetable pathways informing the design of more specific treatments for autoimmune diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pala_population-_2017,

title = {Population- and individual-specific regulatory variation in Sardinia},

author = {Mauro Pala and Zachary Zappala and Mara Marongiu and Xin Li and Joe R Davis and Roberto Cusano and Francesca Crobu and Kimberly R Kukurba and Michael J Gloudemans and Frederic Reinier and Riccardo Berutti and Maria G Piras and Antonella Mulas and Magdalena Zoledziewska and Michele Marongiu and Elena P Sorokin and Gaelen T Hess and Kevin S Smith and Fabio Busonero and Andrea Maschio and Maristella Steri and Carlo Sidore and Serena Sanna and Edoardo Fiorillo and Michael C Bassik and Stephen J Sawcer and Alexis Battle and John Novembre and Chris Jones and Andrea Angius and Gon{ç}alo R Abecasis and David Schlessinger and Francesco Cucca and Stephen B Montgomery},

doi = {10.1038/ng.3840},

issn = {1546-1718},

year  = {2017},

date = {2017-05-01},

journal = {Nature Genetics},

volume = {49},

number = {5},

pages = {700--707},

abstract = {Genetic studies of complex traits have mainly identified associations with noncoding variants. To further determine the contribution of regulatory variation, we combined whole-genome and transcriptome data for 624 individuals from Sardinia to identify common and rare variants that influence gene expression and splicing. We identified 21,183 expression quantitative trait loci (eQTLs) and 6,768 splicing quantitative trait loci (sQTLs), including 619 new QTLs. We identified high-frequency QTLs and found evidence of selection near genes involved in malarial resistance and increased multiple sclerosis risk, reflecting the epidemiological history of Sardinia. Using family relationships, we identified 809 segregating expression outliers (median z score of 2.97), averaging 13.3 genes per individual. Outlier genes were enriched for proximal rare variants, providing a new approach to study large-effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{steri_overexpression_2017,

title = {Overexpression of the Cytokine BAFF and Autoimmunity Risk},

author = {Maristella Steri and Valeria Orrù and Laura M Idda and Maristella Pitzalis and Mauro Pala and Ilenia Zara and Carlo Sidore and Valeria Faà and Matteo Floris and Manila Deiana and Isadora Asunis and Eleonora Porcu and Antonella Mulas and Maria G Piras and Monia Lobina and Sandra Lai and Mara Marongiu and Valentina Serra and Michele Marongiu and Gabriella Sole and Fabio Busonero and Andrea Maschio and Roberto Cusano and Gianmauro Cuccuru and Francesca Deidda and Fausto Poddie and Gabriele Farina and Mariano Dei and Francesca Virdis and Stefania Olla and Maria A Satta and Mario Pani and Alessandro Delitala and Eleonora Cocco and Jessica Frau and Giancarlo Coghe and Lorena Lorefice and Giuseppe Fenu and Paola Ferrigno and Maria Ban and Nadia Barizzone and Maurizio Leone and Franca R Guerini and Matteo Piga and Davide Firinu and Ingrid Kockum and Izaura {Lima Bomfim} and Tomas Olsson and Lars Alfredsson and Ana Suarez and Patricia E Carreira and Maria J Castillo-Palma and Joseph H Marcus and Mauro Congia and Andrea Angius and Maurizio Melis and Antonio Gonzalez and Marta E {Alarc{ó}n Riquelme} and Berta M da Silva and Maurizio Marchini and Maria G Danieli and Stefano {Del Giacco} and Alessandro Mathieu and Antonello Pani and Stephen B Montgomery and Giulio Rosati and Jan Hillert and Stephen Sawcer and Sandra D'Alfonso and John A Todd and John Novembre and Gon{ç}alo R Abecasis and Michael B Whalen and Maria G Marrosu and Alessandra Meloni and Serena Sanna and Myriam Gorospe and David Schlessinger and Edoardo Fiorillo and Magdalena Zoledziewska and Francesco Cucca},

doi = {10.1056/NEJMoa1610528},

issn = {1533-4406},

year  = {2017},

date = {2017-01-01},

journal = {The New England Journal of Medicine},

volume = {376},

number = {17},

pages = {1615--1626},

abstract = {BACKGROUND: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. 

METHODS: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. 

RESULTS: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. 

CONCLUSIONS: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).},

note = {See Editorials, Korn T, Oukka M. A BAFFling Association between Malaria Resistance and the Risk of Multiple Sclerosis. N Engl J Med. 2017 Apr 27;376(17):1680-1681. doi: 10.1056/NEJMe1700720.; Stohl W., Systemic lupus erythematosus: BAFF emerges from the genetic shadows. Nat Rev Rheumatol. 2017 Jun 15. doi: 10.1038/nrrheum.2017.99; Comabella M. Neuroimmunology: B cells and variant BAFF in autoimmune disease. Nat Rev Neurol. 2017 Jun 16. doi: 10.1038/nrneurol.2017.87.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{marongiu_foxl2_2015,

title = {FOXL2 modulates cartilage, skeletal development and IGF1-dependent growth in mice},

author = {Mara Marongiu and Loredana Marcia and Emanuele Pelosi and Mario Lovicu and Manila Deiana and Yonqing Zhang and Alessandro Puddu and Angela Loi and Manuela Uda and Antonino Forabosco and David Schlessinger and Laura Crisponi},

doi = {10.1186/s12861-015-0072-y},

issn = {1471-213X},

year  = {2015},

date = {2015-07-01},

journal = {BMC developmental biology},

volume = {15},

pages = {27},

abstract = {BACKGROUND: Haploinsufficiency of the FOXL2 transcription factor in humans causes Blepharophimosis/Ptosis/Epicanthus Inversus syndrome (BPES), characterized by eyelid anomalies and premature ovarian failure. Mice lacking Foxl2 recapitulate human eyelid/forehead defects and undergo female gonadal dysgenesis. We report here that mice lacking Foxl2 also show defects in postnatal growth and embryonic bone and cartilage formation. 

METHODS: Foxl2 (-/-) male mice at different stages of development have been characterized and compared to wild type. Body length and weight were measured and growth curves were created. Skeletons were stained with alcian blue and/or alizarin red. Bone and cartilage formation was analyzed by Von Kossa staining and immunofluorescence using anti-FOXL2 and anti-SOX9 antibodies followed by confocal microscopy. Genes differentially expressed in skull vaults were evaluated by microarray analysis. Analysis of the GH/IGF1 pathway was done evaluating the expression of several hypothalamic-pituitary-bone axis markers by RT-qPCR. 

RESULTS: Compared to wild-type, Foxl2 null mice are smaller and show skeletal abnormalities and defects in cartilage and bone mineralization, with down-regulation of the GH/IGF1 axis. Consistent with these effects, we find FOXL2 expressed in embryos at 9.5 dpc in neural tube epithelium, in head mesenchyme near the neural tube, and within the first branchial arch; then, starting at 12.5 dpc, expressed in cartilaginous tissue; and at PO and P7, in hypothalamus. 

CONCLUSIONS: Our results support FOXL2 as a master transcription factor in a spectrum of developmental processes, including growth, cartilage and bone formation. Its action overlaps that of SOX9, though they are antagonistic in female vs male gonadal sex determination but conjoint in cartilage and skeletal development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{stolk_meta-analyses_2012,

title = {Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways},

author = {Stolk, Lisette and Perry, John R B and Chasman, Daniel I and He, Chunyan and Mangino, Massimo and Sulem, Patrick and Barbalic, Maja and Broer, Linda and Byrne, Enda M and ... and Sanna, Serena and Schlessinger, David and Spector, Tim D and Stefansson, Kari and Streeten, Elizabeth A and Thorsteinsdottir, Unnur and Uda, Manuela and Uitterlinden, Andr{é} G and van Duijn, Cornelia M and V{ö}lzke, Henry and Murray, Anna and Murabito, Joanne M and Visser, Jenny A and Lunetta, Kathryn L},

doi = {10.1038/ng.1051},

issn = {1546-1718},

year  = {2012},

date = {2012-01-01},

journal = {Nature Genetics},

volume = {44},

number = {3},

pages = {260--268},

abstract = {To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-$kappa$B signaling and mitochondrial dysfunction as biological processes related to timing of menopause.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{herholz_differential_2011,

title = {Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders},

author = {Jana Herholz and Alessandra Meloni and Mara Marongiu and Francesca Chiappe and Manila Deiana and Carmen Roche Herrero and Giuseppe Zampino and Hanan Hamamy and Yusra Zalloum and Per Erik Waaler and Giangiorgio Crisponi and Laura Crisponi and Frank Rutsch},

doi = {10.1038/ejhg.2010.253},

issn = {1476-5438},

year  = {2011},

date = {2011-05-01},

journal = {European journal of human genetics: EJHG},

volume = {19},

number = {5},

pages = {525--533},

abstract = {Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) are disorders caused by mutations in CRLF1. The two syndromes share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia, associated with death in most cases in the first years of life. To evaluate a potential genotype/phenotype correlation and whether CS and CISS1 represent two allelic diseases or manifestations at different ages of the same disorder, we carried out a detailed clinical analysis of 19 patients carrying mutations in CRLF1. We studied the functional significance of the mutations found in CRLF1, providing evidence that phenotypic severity of the two disorders mainly depends on altered kinetics of secretion of the mutated CRLF1 protein. On the basis of these findings, we believe that the two syndromes, CS and CISS1, represent manifestations of the same disorder, with different degrees of severity. We suggest renaming the two genetic entities CS and CISS1 with the broader term of Sohar-Crisponi syndrome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}