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However, identifying the specific variants or genomic regions responsible for disease susceptibility remains a significant challenge. In this study a family-based fine mapping approach was applied to analyze 142 trios, aiming to identify associated genetic variants linked to MS. The targeted genomic region resides within the 17:30,820,506\u201332,483,270\u00a0bp (Ch37\/hg19), which includes the protein-coding gene ASIC2, previously implicated in MS and other neurological conditions, with surrounding genes comprising strongly correlated genetic variants to capture the broader signal from the region. Given the high prevalence of MS in Sardinia and the unique genetic characteristics of the Sardinian population, including reduced heterogeneity and extended linkage disequilibrium, we designed our study specifically within this population and focused on family-based data to enhance the power for detecting genetic signals, avoiding false discoveries. Genotype imputation found 2537 variants, which were then analyzed using the\n                    <jats:italic>knockoff Trio<\/jats:italic>\n                    method to identify loci associated with MS susceptibility. We found rs756787 (3\u2032UTR of MYO1D) increased disease risk (OR 1.57, 95% CI [1.07\u20132.29],\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.02), while rs56175840 (intronic ASIC2) showed a protective effect (OR 0.17, 95% CI [0.04\u20130.74],\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.02), demonstrating the power of knockoff-based fine mapping in family datasets. Integrating LD-based expression and trait analyses helped reveal how rs756787 correlates with variants affecting genes involved in neurodegeneration and the immune response to Epstein\u2013Barr virus, a known environmental factor implicated in MS pathogenesis. Our study highlights the effectiveness of knockoff-based fine mapping combined with expression-trait integration to identify genetic variants influencing MS risk in the Sardinian population.\n                  <\/jats:p>","DOI":"10.1007\/s10528-025-11238-5","type":"journal-article","created":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T09:16:29Z","timestamp":1756545389000},"page":"4130-4146","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Knockoff-Based Fine Mapping of MS-Associated SNPs in Sardinian Trios"],"prefix":"10.1007","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8538-4768","authenticated-orcid":false,"given":"Giulia Nicole","family":"Baldrighi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Nova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claus Thorn","family":"Ekstr\u00f8m","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Luisa","family":"Piras","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Valeria","family":"Saddi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Bernardinelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Fazia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,8,30]]},"reference":[{"key":"11238_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.951202","volume":"16","author":"C Ao","year":"2022","unstructured":"Ao C, Li C, Chen J, Tan J, Zeng L (2022) The role of Cdk5 in neurological disorders. 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Patients were recruited for the project FP7- 305280, as part of the HEALTH-2012-INNOVATION scheme, and by FISM\u2014Fondazione Italiana Sclerosi Multipla (Cod. 2009\/\/R\/\/2) and by Fondazione Cariplo (Grant No. 2009-2528). This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval"}},{"value":"Informed consent was obtained from all subjects involved in the study. Confidential patient data will be handled according to European Union General Data Protection Regulation and maintained in accordance with the privacy guidelines of the hospital.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed Consent"}},{"value":"All the patients gave their consent to disseminate research results also through scientific publications.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Patient Consent for Publication"}}]}}