Genetic Susceptibility to Multiple Sclerosis: Interactions between Conserved Extended Haplotypes of the MHC and other Susceptibility Regions
Authors: Goodin DS , Khankhanian P , Gourraud PA , Vince N 
Published: April 2019

AbstractOBJECTIVETo study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes of the MHC and three non-MHC risk-loci nearby genes EOMES, ZFP36L1, CLEC16A.BACKGROUNDDefining “genetic-susceptibility” as having a non-zero probability of developing MS, both theoretical considerations and epidemiological observations indicate that only 2.2–4.5% of northern-populations can possibly be “genetically-susceptible” to MS. Nevertheless, many haplotypes (both within the MHC and elsewhere) are unequivocally MS-associated and, yet, have population-frequencies of >20%. Such frequency-disparities underscore the complex-interactions that must occur between these “risk-haplotypes” and MS-susceptibility.DESIGN/MEHTODSThe WTCCC dataset was statistically-phased at the MHC and at three other susceptibility-regions. Haplotypes were stratified by their impact on “MS-risk”. MS-associations for different combinations of “risk-haplotypes” were assessed. The appropriateness of both additive and multiplicative risk-accumulation models was determined.RESULTSCombinations of different “risk-haplotypes” produced an MS-risk that was considerably closer to an additive model than a multiplicative model. Nevertheless, neither of these simple probability-models adequately accounted for the accumulation of disease-risk in MS at these four loci.CONCLUSIONS“Genetic-susceptibility” to MS seems to depend upon the exact state at each “risk-locus” and upon specific gene-gene combinations across loci. Moreover, “genetic-susceptibility” is both rare in the population and, yet, is a necessary condition for MS to develop in any individual. In this sense, MS is a “genetic” disease. Nevertheless although, “genetic-susceptibility” is a necessary condition for MS to develop, environmental factors (whatever these may be) and stochastic processes are also necessary determinants of whether a “genetically-susceptible” individual will actually get MS.Author SummaryDefining a “genetically-susceptible” individual to be any person in the population who has any chance of developing multiple sclerosis (MS), we demonstrate that, at a theoretical level and using widely-accepted epidemiological observations, only 2.2-4.5% of individuals in northern populations can possibly be “genetically susceptible” to MS. Thus, more than 95.5% of individuals in these populations have no chance of getting MS, regardless of the environmental circumstances that they may experience.Nevertheless, certain “susceptibility-haplotypes” (e.g., HLA-DRB1*15:01~DQB1*06:02) have a far greater carrier-frequency than 2.2-4.5%. Consequently, most carriers of these “susceptibility-haplotypes” have no chance of getting MS and, therefore, their “susceptibility” must arise from some combination of these haplotypes with other “susceptibility-haplotypes”. By analyzing such combinatorial impacts at four susceptibility-loci, we found significant interactions both within and between the different “susceptibility-haplotypes”, thereby confirming the relationship between “genetic-susceptibility” and specific gene-gene combinations.The nature of “genetic-susceptibility” developed here is applicable to other complex genetic disorders. Indeed, any disease for which the MZ-twin concordance rate is substantially greater than the life-time risk in the general population, only a small fraction of the population can possibly be in the “genetically-susceptible” subset (i.e., have any chance of developing the disease).