Papers by Maristella Pitzalis
Background:Defective alleles within the <i>PRF1</i> gene, encoding the pore-forming p... more Background:Defective alleles within the <i>PRF1</i> gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines—cytokine storm.Objective:The aim of this study was to determine the function of hypomorph <i>PRF1:p.A91V</i> g.72360387 G > A on multiple sclerosis (MS) and type 1 diabetes (T1D).Methods:We cross-compare the association data for <i>PRF1:p.A91V</i> mutation derived from GWAS on adult MS and pediatric T1D in Sardinians. The novel association with T1D was replicated in metanalysis in 12,584 cases and 17,692 controls from Sardinia, the United Kingdom, and Scotland. To dissect this mutation function, we searched through the coincident association immunophenotypes in additional set of general population Sardinians.Results:We report that <i>...
Background Despite progress in identifying genes associated with breast cancer, many more risk lo... more Background Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. Methods We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. Results Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p
Valeria Orrù§, Maristella Steri§, Carlo Sidore§, Michele Marongiu, Valentina Serra, Stefania Olla... more Valeria Orrù§, Maristella Steri§, Carlo Sidore§, Michele Marongiu, Valentina Serra, Stefania Olla, Gabriella Sole, Sandra Lai, Mariano Dei, Antonella Mulas, Francesca Virdis, Maria Grazia Piras, Monia Lobina, Mara Marongiu, Maristella Pitzalis, Francesca Deidda, Annalisa Loizedda, Stefano Onano, Magdalena Zoledziewska, Marcella Devoto, Matteo Floris, Mauro Pala, David Schlessinger, Edoardo Fiorillo, Francesco Cucca.
Multiple Sclerosis Journal, 2020
Background: Defective alleles within the PRF1 gene, encoding the pore-forming protein perforin, i... more Background: Defective alleles within the PRF1 gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines—cytokine storm. Objective: The aim of this study was to determine the function of hypomorph PRF1:p.A91V g.72360387 G > A on multiple sclerosis (MS) and type 1 diabetes (T1D). Methods: We cross-compare the association data for PRF1:p.A91V mutation derived from GWAS on adult MS and pediatric T1D in Sardinians. The novel association with T1D was replicated in metanalysis in 12,584 cases and 17,692 controls from Sardinia, the United Kingdom, and Scotland. To dissect this mutation function, we searched through the coincident association immunophenotypes in additional set of general population Sardinians. Results: We report that PRF1:p.A91V, is associated with increase of lymphocyte leve...
ObjectivesVaccination against COVID-19 is highly recommended to patients affected by multiple scl... more ObjectivesVaccination against COVID-19 is highly recommended to patients affected by multiple sclerosis (MS); however, the impact of MS disease-modifying therapies (DMTs) on the immune response following vaccination has been only partially investigated. Here, we aimed to elucidate the effect of DMTs on the humoral immune response to mRNA-based anti-SARS-CoV-2 vaccines in MS patients.MethodsWe obtained sera from 912 Sardinian MS patients and 63 healthy controls 30 days after the second dose of BNT162b2 vaccine and tested them for SARS-CoV-2 response using anti-Spike (S) protein-based serology. Previous SARS-CoV-2 infection was assessed by anti-Nucleocapsid (N) serology. Patients were either untreated or undergoing treatment with a total of 13 different DMTs. Differences between treatment groups comprised of at least 10 patients were assessed by generalized linear mixed-effects model. Demographic and clinical data and smoking status were analyzed as additional factors potentially infl...
Nature Genetics, 2020
In the version of this article initially published, in the second sentence of the Abstract, 'inde... more In the version of this article initially published, in the second sentence of the Abstract, 'independent association signals for 459 cell traits at 69 loci (52 of them novel)' should have read 'independent association signals for 459 cell traits at 70 loci (53 of them novel)' to match the correct values in the main text. The error has been corrected in the HTML and PDF versions of the article.
Nature Genetics, 2020
Onano and Mara Marongiu performed RNA data analyses; M.F. and S. Olla carried out bioinformatics ... more Onano and Mara Marongiu performed RNA data analyses; M.F. and S. Olla carried out bioinformatics and drug target analyses; Michele Marongiu managed the SardiNIA project database; S.S. shared genetic data on MS; F.C., G.R.A. and D.S. provided funds and reagents. All authors read the paper and contributed to its final form.
British Journal of Haematology, 2020
TL, et al. 3023 Mayo clinic patients with myeloproliferative neoplasms: risk-stratified compariso... more TL, et al. 3023 Mayo clinic patients with myeloproliferative neoplasms: risk-stratified comparison of survival and outcomes data among disease subgroups.
To investigate the genetic regulation of platelet (PLT) levels we carried out a whole-genome asso... more To investigate the genetic regulation of platelet (PLT) levels we carried out a whole-genome association analysis in 6,528 Sardinians from the general population of the Lanusei valley. We found 6 variants significantly influencing PLT levels, including a novel rare missense mutation (p.Pro27Ser) in the GP1BB protein that is associated with PLT reduction (P=1.17×10−16). This mutation is rare in the SardiNIA population cohort (frequency of 0.45%), even rarer in the rest of the Sardinian island (frequency of 0.16%), and not reported elsewhere. Notably, GP1BB is involved in Bernard-Soulier syndrome (BSS), a rare autosomal recessive bleeding disorder caused by a defect in the platelet GPIb-IX-V protein complex. Consistently, the 57 identified individuals heterozygous for the p.P27S mutation showed mild thrombocytopenia, morphologically enlarged platelets (P=2.13×10−10), and reduced expression of two GPIb-IX-V-complex components: GPIbα (−26.51%, P=3.66×10−8) and GPIX (−24.69%, P=2.66×10−6...
S4d – Reproduction, 2018
(p=0.2), smoking status (p=0.6), high blood pressure (p=0.7), persistent disease activity (p=0.4)... more (p=0.2), smoking status (p=0.6), high blood pressure (p=0.7), persistent disease activity (p=0.4), HCQ (p=0.6) and prednisolone dose >5 g (p=0.2) at the time of scanning. This study shows that the presence of plaque was strongly associated with development of CVD within the next four years in this population of patients. Most CVD events were coronary, so not caused directly by carotid plaque. Vascular ultrasound may be helpful in improving management of CVD risk in patient with SLE.
Nature Genetics, 2018
The population of the Mediterranean island of Sardinia has made important contributions to genome... more The population of the Mediterranean island of Sardinia has made important contributions to genome-wide association studies of complex disease traits and, based on ancient DNA (aDNA) studies of mainland Europe, Sardinia is hypothesized to be a unique refuge for early Neolithic ancestry. To provide new insights on the genetic history of this flagship population, we analyzed 3,514 whole-genome sequenced individuals from Sardinia. We find Sardinian samples show elevated levels of shared ancestry with Basque individuals, especially samples from the more historically isolated regions of Sardinia. Our analysis also uniquely illuminates how levels of Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
The New England journal of medicine, Apr 27, 2017
Background Genomewide association studies of autoimmune diseases have mapped hundreds of suscepti... more 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 al...
Molecular biology and evolution, May 8, 2017
Sardinians are "outliers" in the European genetic landscape and, according to paleogeno... more Sardinians are "outliers" in the European genetic landscape and, according to paleogenomic nuclear data, the closest to early European Neolithic farmers. To learn more about their genetic ancestry, we analyzed 3,491 modern and 21 ancient mitogenomes from Sardinia. We observed that 78.4% of modern mitogenomes cluster into 89 haplogroups that most likely arose in situ. For each Sardinian-specific haplogroup (SSH), we also identified the upstream node in the phylogeny, from which non-Sardinian mitogenomes radiate. This provided minimum and maximum time estimates for the presence of each SSH on the island. In agreement with demographic evidence, almost all SSHs coalesce in the post-Nuragic, Nuragic and Neolithic-Copper Age periods. For some rare SSHs, however, we could not dismiss the possibility that they might have been on the island prior to the Neolithic, a scenario that would be in agreement with archeological evidence of a Mesolithic occupation of Sardinia.
The population of the Mediterranean island of Sardinia has made important contributions to genome... more The population of the Mediterranean island of Sardinia has made important contributions to genome-wide association studies of traits and diseases. The history of the Sardinian population has also been the focus of much research, and in recent ancient DNA (aDNA) studies, Sardinia has provided unique insight into the peopling of Europe and the spread of agriculture. In this study, we analyze whole-genome sequences of 3,514 Sardinians to address hypotheses regarding the founding of Sardinia and its relation to the peopling of Europe, including examining fine-scale substructure, population size history, and signals of admixture. We find the population of the mountainous Gennargentu region shows elevated genetic isolation with higher levels of ancestry associated with mainland Neolithic farmers and depleted ancestry associated with more recent Bronze Age Steppe migrations on the mainland. Notably, the Gennargentu region also has elevated levels of pre-Neolithic hunter-gatherer ancestry a...
Science Advances, 2016
Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms alr... more Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms already known gene loci.
Multiple sclerosis (Houndmills, Basingstoke, England), 2015
Recent studies identified > 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susc... more Recent studies identified > 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored. We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians. We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerke's R(2) and the area under the Receiver Operating Characteristic (ROC) curves. As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predict...
Nature Genetics, 2015
If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.
Nature genetics, Jan 14, 2015
We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% ar... more 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…
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Papers by Maristella Pitzalis