Genetics

The Human Genetics Lab is mainly focused on research projects on the genetics of Autoimmune  and neurodegenerative diseases

1). Genetics of  Autoimmune complex diseases: Multiple sclerosis  (MS)

The research group is focused on a) Genome Wide Association Studies (GWAS) on susceptibility to MS with the identification of 201 non-HLA loci involved in MS susceptibility b) Fine-mapping and in vitro functional studies on the MS loci to identify the primarily functional associated variants within each locus, their functional role and target genes, with a special interest to drug target genes; c) the identification of rare MS associated variants through Next Generation Sequencing and functional studies; d) Association of the genetic factors with several MS clinical features with the identification of genes associated with oligoclonal Immunoglobulin in liquor, presence of sequelae after the first attack , MS progression, and comorbidity with other autoimmune diseases; e) Studies of interaction between genetic and environmental/life-style features to determine their association with MS clinical parameters in MS patients with adult onset as well as patients with the rarer form with pediatric onset; f)  Development of prognostic models and scores to predict MS disease activity and progression, integrating genetic,  clinical, and environment exposure data using machine learning tools. g) Multiomic analysis to compare MS patients with pediatric disease onset vs. adult onset through the integration of GWAS, transcriptomic, methylome and metagenomics data.

The research on MS takes advantage of the group’s coordination of national multicentric networks of clinical and research centers (PROGEMUS consortium -PROgnostic GEnetic factors in

MUltiple Sclerosis, PEDIGREE- (PEDiatric Italian Genetic and enviRonment ExposurE)) as well as the participation to international consortia (IMSGC, International Multiple Sclerosis Genetics Consortium) MultipleMS)

2) Genetics of Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases (Frontotemporal dementia, Parkinson, Spinocerebellar Ataxia)

The research group carries out activities in this field thanks to a close collaboration with the Neurological Clinic at Novara Hospital (AOU Maggiore della Carità) and in particular with the ALS Centre. The group collected biosamples (DNA, Serum and PBMCs) from a large cohort of patients suffering from ALS, ALS/FTD. In recent years we have also been collecting PD patients with juvenile onset or family history and patients with ataxia.

 The research group  activity is focused  to:  a) define the mutational spectrum of ALS patients in Italy; b)  identify new ALS causing genes and test more complex genetic models as digenic inheritance; c) define the role of common variants in the genetic susceptibility of  ALS sporadic cases, d) investigate the role of tandem repeats through the coordination of a multicentric project focused on a genome wide approach and  whole genome sequencing (WGS); e) explore the role of non coding variants from WGS data coupling bioinformatic prioritization tools with in vitro functional assays using massive approach (Massively Parallel Splicing assay and Massively Parallel Reporter Assay) f) to perform functional characterizations of the novel identified variants to test the impact on gene expression or splicing mechanism.

1)  International Multiple Sclerosis Genetics Consortium; MultipleMS Consortium Locus for severity implicates CNS resilience in progression of multiple sclerosis. Nature. 2023 Jul;619(7969):323-331. doi: 10.1038/s41586-023-06250-x. Epub 2023 Jun 28.PMID: 37380766 

2) Chiò A, Moglia C, Canosa A, Manera U, Grassano M, Vasta R, Palumbo F, Gallone S, Brunetti M, Barberis M, De Marchi F, Dalgard C, Chia R, Mora G, Iazzolino B, Peotta L, Traynor BJ, Corrado L, D'Alfonso S, Mazzini L, Calvo A.  Association of Copresence of Pathogenic Variants Related to Amyotrophic Lateral Sclerosis and Prognosis.Neurology. 2023 Jul 4;101(1):e83-e93. doi: 10.1212/WNL.0000000000207367. Epub 2023 May 18.PMID: 37202167 

3)Grassano M, Calvo A, Moglia C, Sbaiz L, Brunetti M, Barberis M, Casale F, Manera U, Vasta R, Canosa A, D'Alfonso S, Corrado L, Mazzini L, Dalgard C, Karra R, Chia R, Traynor B, Chiò A. Systematic evaluation of genetic mutations in ALS: a population-based study. J Neurol Neurosurg Psychiatry. 2022 Jul 27;93(11):1190–3. doi: 10.1136/jnnp-2022-328931. Epub ahead of print. PMID: 35896380; PMCID: PMC9606529.

4) Zuccalà M, Barizzone N, Boggio E, Gigliotti L, Sorosina M, Basagni C, Bordoni R, Clarelli F, Anand S, Mangano E, Vecchio D, Corsetti E, Martire S, Perga S, Ferrante D, Gajofatto A, Ivashynka A, Solaro C, Cantello R, Martinelli V, Comi G, Filippi M, Esposito F, Leone M, De Bellis G, Dianzani U, Martinelli-Boneschi F, D'Alfonso S. Genomic and functional evaluation of TNFSF14 in multiple sclerosis susceptibility. J Genet Genomics. 2021 Jun 20;48(6):497-507. doi: 10.1016/j.jgg.2021.03.017. Epub 2021 May 25. PMID: 34353742.

5) Barizzone N, Zara I, Sorosina M, Lupoli S, Porcu E, Pitzalis M, Zoledziewska M, Esposito F, Leone M, Mulas A, Cocco E, Ferrigno P, Guerini FR, Brambilla P, Farina G, Murru R, Deidda F, Sanna S, Loi A, Barlassina C, Vecchio D, Zauli A, Clarelli F, Braga D, Poddie F, Cantello R, Martinelli V, Comi G, Frau J, Lorefice L, Pugliatti M, Rosati G; PROGEMUS (PROgnostic GEnetic factors in MUltiple Sclerosis) Consortium PROGRESSO (Italian network of Primary Progressive Multiple Sclerosis) Consortium; Melis M, Marrosu MG, Cusi D, Cucca F, Martinelli Boneschi F, Sanna S, D'Alfonso S. The burden of multiple sclerosis variants in continental Italians and Sardinians. Mult Scler. 2015 Oct;21(11):1385-95. doi: 10.1177/1352458515596599. PMID: 26438306.

PROGEMUS, PEDIGREE, IMSGC, MultipleMS, SLAGEN Consortium , Italsgen Consortium, Mine Project

National funding:

1. Arisla 2023 “DIG-ALS - Genome wide investigation of oligogenic inheritance in ALS: searching for digenic disease genes with machine learning in a population-based cohort” SOTTO EMBARGO fino 13 dicembre 2023
2. Progetti di Ricerca d'Interesse Nazionale (PRIN), Ministero dell’Università e della Ricerca 2022 20228N7573 - Genetic and environment interaction in determining phenotype and progression of ALS (GENIALS)
3.  Progetti di Ricerca d'Interesse Nazionale (PRIN), Ministero dell’Università e della Ricerca 202020203P8C3X_003   Unveiling the hidden side of NEUrodevelopmental DIsorder Genetics (NEUDIG): a multidisciplinary pathway to new molecular diagnoses by integrating genomic, transcriptomic, and functional analyses. 
4. Progetti di Ricerca d'Interesse Nazionale (PRIN), Ministero dell’Università e della Ricerca 2017  2017SNW5MB_005  Deconstruct and rebuild phenotypes: a multimodal approach toward personalized medicine in ALS (DECIPHER-ALS)
5. Italian Ministry of Health-PNRR 2022 Predicting multiple sclerosis disease activity and progression: development of a prognostic score and decisional support system. PROMISING study. PNRR-MAD-2022-12376868- (2022-2024) 
6. Italian Ministry of Health (POS) 2022 GENERAGenoma mEdiciNapERsonalizzatAMappatura genomica, medicina predittiva e personalizzata di malattie genetiche complesse (cardiovascolari, neurologiche, oncologiche)- 2022-2027
7. FISM (Fondazione Italiana Sclerosi Multipla) Identification of genetic risk factors and interaction between genetic and non-genetic risk factors in pediatric multiple sclerosis (PEDiatric Italian Genetic and enviRonment ExposurE) (PEDIGREE study), 2022-2024,
8. Piedmont Region (INFRAP2,Finpiemonte) SURVEIL-Development of a genomic surveillance platform to fight the covid-19 pandemic- 2021
9. FISM (Fondazione Italiana Sclerosi Multipla ) SARS-CoV-2 and Multiple Sclerosis: Has the Interplay Started? A Study on the Impact of Infection and Vaccine on the Development of Multiple Sclerosis  (SPECIALS) (2022-2025) 
10. FISM (Fondazione Italiana Sclerosi Multipla) Fine mapping and functional characterization of MS associated loci to dissect the pathogenetic role of drug target genes  (2019/R/33) (2019-2023)
11. FISM (Fondazione Italiana Sclerosi Multipla) Identification of genetic risk factors and interaction between genetic and non-genetic risk factors in pediatric multiple sclerosis (PEDiatric Italian Genetic and enviRonment ExposurE) (PEDIGREE study), (2017/R/15), 2019-2020,
12. FISM (Fondazione Italiana Sclerosi Multipla) Integrating genetic and phenotypic data from the PROGEMUS data-base and the Italian Multiple Sclerosis registry 2022-2023
13. Italian Ministry of Health Exploring genome/phenome interaction in Multiple Sclerosis (Italian Ministry of Health, RF-2016-02361294), (2018-2021)

International funding:

1. European Commission (Horizon 2020) Multiple manifestations of genetic and non-genetic factors in Multiple Sclerosis disentangled with a multi-omics approach to accelerate personalised medicine (MultipleMS). HORIZON 2020, (2016-2022)
2. European Commission (HORIZON-HLTH-2023-TOOL-05-04) Well-being improvement through the integration of healthcare and research data and models without border for chronic immune-mediated diseases - wisdom - 

Prof. Sandra D’Alfonso, Full Professor Medical Genetics,  Group leader

Prof. Lucia Corrado, Associate Professor Medical Genetics

Nadia Barizzone, Assistant Professor Medical Genetics

Nicola Pomella, Post Doc Fellow

Martina Tosi, PhD student Scienze E Biotecnologie Mediche XXXVI cycle

Endri Visha, PhD student Scienze E Biotecnologie Mediche XXXVII cycle

Beatrice Piola, “Food, health and Longevity studies”, XXXVII cycle

Giovanni Papagni, PhD student Scienze E Biotecnologie Mediche XXXIX cycle

Muralidharan Thavamani PhD student Scienze E Biotecnologie Mediche XXXIX cycle

Fjorilda Caushi, Clinical Pathology residents

Marta Allesina, Clinical Pathology residents

Fatima Masoomi Sarvestani, Medical Biotec student

Hesam Aminian, Medical Biotec student

Parsa Khoshgoftar, Medical Biotec student

Alaa Habeeb, Medical Biotec student

Benedetta Bartilomo, Biology student

Alberto Ravanini, Biology student