Publication Date



Open access

Embargo Period


Degree Type


Degree Name

Doctor of Philosophy (PHD)


Human Genetics and Genomics (Medicine)

Date of Defense


First Committee Member

Jacob L. McCauley

Second Committee Member

William K. Scott

Third Committee Member

Alberto Pugliese

Fourth Committee Member

Margaret A. Pericak-Vance


Multiple Sclerosis (MS) is a demyelinating disease of the central nervous system with autoimmune etiology. It affects approximately 2.3 million people worldwide, but prevalence is distributed unequally with countries closer to the equator manifesting a lower prevalence of MS. The Italian island of Sardinia is an exception, with prevalence rates that are among the highest in the world. Sardinia is inhabited by a unique, isolated population that was founded approximately 10,000 years ago. The reasons for this enrichment of MS cases in Sardinia are unknown. Like most complex diseases, MS has both genetic and environmental components of susceptibility. To date, research has uncovered the identity of 114 Single Nucleotide Polymorphisms (SNPs) which tag loci that explain approximately 27% of the genetic factors that drive MS susceptibility, in populations of Northern European ancestry. With the exception of the effect exerted by polymorphisms in the Human Leukocyte Antigen DRB1gene, these genetic susceptibility alleles have small to moderate effect sizes (Odds Ratio range 1.03 to 1.34) and are largely common in the population (Risk Allele Frequency range 0.09 to 0.95). There are multiple reasons to explore the hypothesis that the Sardinian population may be enriched for the risk alleles that drive MS susceptibility, such as the high prevalence of MS and predictions made by population genetics theory with regard to the genetic landscape of isolated populations. Past studies in the genetics of MS in Sardinia have uncovered regions of the genome with possible roles in MS pathogenesis that display little overlap with regions identified in other populations. In the present study, I examined the presence of established MS-associated SNPs in a dataset of 19 multiplex Sardinian families. Although the Northern European-derived risk variants are present in Sardinians, these are able to differentiate patients from unaffected Sardinian individuals only when considered cumulatively, with the use of a weighted genetic burden score. The presence of multiple MS cases in the same family afforded us the opportunity to search for genetic variation that affected relative pairs may share from a common ancestor. Five regions with suggestive amounts of allele sharing were detected (logarithm of the odds (LOD*) score ≥ 1); fine-mapping underneath these linkage peaks identified four genes that may be relevant in MS pathogenesis in Sardinia (EPHA7 on 6q16.1, JAZF1 on 7p15.1, KLRC2 on 12p13.2 and CD226 on 18q22.2). Interestingly, the chromosome 12 peak spans the natural killer cell gene cluster at that location. I therefore used whole exome sequencing data of the affected individuals from 5 of the Sardinian multiplex families to search for rare, nonsynonymous variants. I identified two variants in IKZF1 at 7p12 and MANBA at 4q24, two genes that are implicated in MS via the established associations. These variants are conserved and predicted to be probably damaging to the protein product. I also found a range of variants in the genes underneath the linkage peaks, highlighting the importance of cumulative assessments of the burden of rare and common variants in disease. In total, these data indicate that the overall MS susceptibility landscape in Sardinia is not markedly different from that of outbred European populations, and likely includes both common and rare risk alleles. However, these data also highlight the utility of multiplex families from an isolated population in the initial identification of possible risk alleles. Replication in large population samples is required to assess the relevance of the identified variants in MS pathogenesis.


multiple sclerosis; exome; Sardinia; isolated population; genetic; family studies