Our research interests are to identify genetic variants influencing complex phenotypes and to clarify how these variations affect gene function. The laboratory focuses on genetic studies of some isolated populations located in the Cilento region for which an extensive phenotype characterization as well as whole-genome genotyping and sequence-based data are available. Indeed, because of small number of founders and genetic drift, founder populations represent a powerful strategy for the discovery of low-frequency and rare variants involved in complex traits. Through the use of different isolated populations, deriving from diverse progenitors and sharing well defined environments and life habits, we aim to elucidate the genetics of the complex phenotypes caused by the interaction of multiple genes and the environment. Our work on Cilento populations has also been contributing to international large-scale population-based genetic studies on a broad range of common phenotypes.

Genetic Park of Cilento and Vallo di Diano Project: http://www.igb.cnr.it/cilento

Cilento biobank:  http://www.igb.cnr.it/igb/index.php/centro-risorse-biologiche/

Some ongoing studies:

• Human knockouts study in Cilento isolates

Natural ‘human knockouts’ (HKOs) are referred to people carrying biallelic loss-of-function (LoF) mutations that disrupt both copies of a given gene. Phenotypic analyses of such HKO can provide insight into gene function. LoF variants tend to be significantly enriched in founder populations making these populations particularly adapt for HKO studies. Exome sequencing data and in-depth phenotypic assessment of Cilento populations are used to understand the phenotypic consequences of natural gene KO in humans.

• Clinical Relevance of a Widespread NOTCH3 Mutation for CADASIL Pathogenesis

An inherited blood vessel disease called cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (or otherwise known as CADASIL) can cause impaired blood flow in brain blood vessels.  CADASIL is caused by mutations in NOTCH3 gene, which codes for a transmembrane receptor involved in the protection of  the structure of blood vessel walls. However, abnormal genetic variations of NOTCH3 may generate proteins that do not have the protective abilities and can be associated with blood vessel damage and cognitive impairment. Studying a Cilento population, we have recently discovered that the cysteine-altering p.Arg1231Cys mutation in NOTCH3 is present in a large number of subjects all included in a big pedigree so, making this population an invaluable resource to improve the knowledge of CADASIL pathogenesis. Our study aims to understand how the p.Arg1231Cys mutation may impact the development of CADASIL and whether other genetic factors may be involved in the disease. The study results may provide further insights into the underlying biology of CADASIL, and, ultimately, an increased understanding of the relationship between blood vessel disorders and dementia.

Genetics of PlGF plasma levels highlights a role of its receptors and supports the link between angiogenesis and immunity. Ruggiero D, Nutile T, Nappo S, Tirozzi A, Bellenguez C, Leutenegger AL, Ciullo M. Sci Reports 2021 Aug 19;11(1):16821. doi: 10.1038/s41598-021-96256-0.

The power of genetic diversity in genome-wide association studies of lipids. Graham SE, Clarke SL, Wu KH, Kanoni S, Zajac GJM, Ramdas S, et al  (including Ciullo M) Nature. 2021 Dec;600(7890):675-679. doi: 10.1038/s41586-021-04064-3. Epub 2021 Dec 9.

Whole-Exome Sequencing in the Isolated Populations of Cilento from South Italy. Nutile T, Ruggiero D, Herzig AF, Tirozzi A, Nappo S, Sorice R, Marangio F, Bellenguez C, Leutenegger AL, and Ciullo M. Sci Reports 2019 Mar 11;9(1):4059. doi: 10.1038/s41598-019-41022-6

Associations of autozygosity with a broad range of human phenotypes. Clark DW, Okada Y, Moore KHS, Mason D, Pirastu N, Gandin I, Mattsson H, et al (including Ciullo M). Nat Commun. 2019 Oct 31;10(1):4957. doi: 10.1038/s41467-019-12283-6

Detecting the dominance component of heritability in isolated and outbred human populations. Herzig AF, Nutile T, Ruggiero D, Ciullo M*, Perdry H, Leutenegger AL. Sci Reports 2018 Dec 21;8(1):18048. doi: 10.1038/s41598-018-36050-7.

Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies. Choi SH, Ruggiero D, Sorice R, Song C, Nutile T, Vernon Smith A, Concas MP, Traglia M, Barbieri C, Ndiaye NC, Stathopoulou MG, Lagou V, Maestrale GB, Sala C, Debette S, Kovacs P, Lind L, Lamont J, Fitzgerald P, Tönjes A, Gudnason V, Toniolo D, Pirastu M, Bellenguez C, Vasan RS, Ingelsson E, Leutenegger AL, Johnson AD, DeStefano AL, Visvikis-Siest S, Seshadri S, Ciullo M. PLoS Genetics 2016 Feb 24;12(2):e1005874.

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. Pattaro C, Teumer A, Gorski M, Chu AY, Li M, Mijatovic V, et al. (including Ciullo M). Nat Commun. 2016 Jan 21;7:10023.

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. Kato N, Loh M, Takeuchi F, Verweij N, Wang X, et al. (including Ciullo M). Nat Genetics 2015 Sep 21.

Directional dominance on stature and cognition in diverse human populations. Joshi PK, Esko T, Mattsson H, Eklund N, Gandin I, Nutile T et al. (including Ciullo M) - Nature 2015 July 1.

Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder. Genetics of personality consortium, et al (including Ciullo M). JAMA Psychiatry. 2015 Jul 1;72(7):642-50.

Genetic Variants modulating CRIPTO Serum Levels identified by Genome-Wide Association Study in Cilento Isolates. Ruggiero D, Nappo S, Nutile T, Sorice R, Talotta F, Giorgio E, Bellenguez C, Leutenegger AL, Liguori G L, Ciullo M. PloS Genetics. 2015 Jan 28;11(1):e1004976. doi: 10.1371/journal.pgen.1004976. eCollection 2015 Jan.

Angiogenesis and biomarkers of cardiovascular risk in adults with metabolic syndrome. Siervo M, Ruggiero D, Sorice R, Nutile T, Aversano M, Stephan BC, Ciullo M. J Intern Med. 2010 Oct;268(4):338-47. doi: 10.1111/j.1365-2796.2010.02255.x.

Genome-Wide Association Analyses Identify 18 New Loci Associated With Serum Urate. Köttgen, E. Albrecht, A. Teumer, V. Vitart, J. Krumsiek, C. Hundertmark, G. Pistis, D. Ruggiero, C.M O’Seaghdha, T. Haller et al (including M. Ciullo as co-last author) Nat Genetics 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23

75 genetic loci influencing the human red blood cell. P. van der Harst, W. Zhang, I. V Mateo Leach, J. Sehmi, N. Verweij, D. S Paul, A. Rendon, H. Allayee, X. Li, A. Radhakrishnan, S.-T. Tan, C. A Albers, A. Al-Hussani, F.W Asselbergs, M. Ciullo et al. Nature. 2012 Dec 20;492(7429):369-75. doi: 10.1038/nature11677. Epub 2012 Dec 5.

The complete list of publications is available on Google Scholar (Marina Ciullo profile) and at ORCID ID: orcid.org/0000-0002-9621-9984

Marina Ciullo is Research Director of National Research Council of Italy at Institute of Genetics and Biophysics "A. Buzzati-Traverso" (IGB-CNR) of Naples, Italy. She obtained a degree in Biological Sciences at University "Federico II" of Naples in 1993. She got a PhD in Biology at the University of Paris (Paris XI), France in 2003 working on chromosomal instability in cancer at the Unité de Génomique Fonctionnelle Biologie Systémique pour la Santé-CNRS, in Villejuif. As postdoc at IGB-CNR she acquired expertise in human genetics and molecular genetics. She was visiting Researcher at the Unité Génétique Epidémiologique et Structure des Populations humaines - INSERM, Paris, France between 2004 to 2006. In that period, she expanded her expertise in genetic epidemiology. Since 2007 she is the head of the Genetics of Complex traits laboratory at the IGB-CNR and scientific coordinator of the “Genetic Park of Cilento and Vallo di Diano” project, one of the largest genetic epidemiology studies in Italy on isolated populations. She leads a research group working on population data collection, statistical and molecular analyses. Moreover, she has established strong ties with local communities that have made it possible to recruit and track participants to Cilento project over time (http://www.igb.cnr.it/cilento). She has coordinated and/or participated in many GWAS meta-analysis studies in large population cohorts working together with international groups and in a multidisciplinary context. She is member of the Steering Committee in several International Consortia and is one of the co-founders of the VEGF Consortium. She has attracted several grants from National and International funding Agencies, including EU programmes, Alzheimer’s Association, and Italian Ministry of University and Research (MUR). She serves as reviewer for a number of scientific journals and is author of more than 70 peer-reviewed publications.