Multiple Sclerosis: Exploring the Limits of Genetic and Environmental Susceptibility
Authors: Goodin DS , Khankhanian P , Gourraud PA , Vince N 
Published: March 2022

AbstractOBJECTIVETo explore the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and to define the limits of this nature based on the statistical uncertainties regarding the various epidemiological observations that have been made.BACKGROUNDCertain parameters of MS-epidemiology are directly observable (e.g., the risk of MS-recurrence in siblings and twins of an MS proband, the proportion ofwomenamong MS patients, the population-prevalence of MS, and the time-dependent changes in the female-to-male (F:M)sex-ratio. By contrast, other parameters can only be inferred from observed parameters (e.g., the proportion of the population that is genetically susceptible, the proportion ofwomenamong susceptible individuals, the probability that a susceptible individual will experience an environment sufficient to cause MS given their genotype, and if they do, the probability that they will develop the disease).DESIGN/METHODSThe “genetically-susceptible” subset (G) of the population (Z) is defined to include everyone withanynon-zero life-time chance of developing MS undersomeenvironmental conditions. For the observed parameters, acceptable ranges are assigned values such that they always include their 95% confidence intervals. By contrast, for the non-observed parameters, the acceptable ranges are assigned such that they cover the entire “plausible” range for each parameter. Using both aCross-sectional Modeland aLongitudinal Model, together with established parameter relationships, we explore, iteratively, trillions of potential parameter combinations and determine those combinations (i.e., solutions) that fall within the acceptable range for the observed and non-observed parameters.RESULTSBothModelsand all analyses are consistent and converge to demonstrate that genetic-susceptibitly is limited to 52% or less of the population and to 30% or less ofwomen. Consequently, most individuals (particularlywomen) have no chance whatsoever of developing MS, regardless of their environmental exposure. Also, currently, the penetrance of MS in susceptiblewomenis greater than it is inmen. Moreover, as expected, the probability that susceptible individuals will develop MS increases with an increased likelihood of these individuals experiencing an environment sufficient to cause MS, given their genotype. Nevertheless, although it is conceivable that these response-curves plateau at 100% for bothwomenandmen, this possibility requires extreme conditions and seems remote. Rather, at leastmen, seem to plateau well below this level and, if so, it is this difference, rather than any differences in the genetic and environmental determinants of disease, that primarily accounts both for the difference in penetrance betweenwomenandmenand for the increasing proportion ofwomenamong of MS patients worldwide.CONCLUSIONSThe development of MS (in an individual) requires both that they have an appropriate genotype (which is uncommon in the population) and that they have an environmental exposure sufficient to cause MS given their individual genotype. Nevertheless, even when the necessary genetic and environmental factors, sufficient for MS pathogenesis, co-occur for an individual, this still insufficient for that person to develop MS. Thus, disease pathogenesis, even in this circumstance, seems not to be deterministic but, rather, to involve an important element of chance.Author SummaryCertain parameters of MS-epidemiology can be directly observed. These parameters include the risk of MS recurrence in siblings and twins of an MS proband, the proportion ofwomenamong MS patients, the population-prevalence of MS, and the time-dependent changes in the female-to-male (F:M)sex-ratio. By contrast, there are other parameters of MS-epidemiology, which can’t be observed, but which must be inferred based on the values of the observable parameters. These parameters include the proportion of the general population (Z) that is genetically susceptible to MS, the proportion ofwomenamong susceptible individuals, the probability that a susceptible individual will experience an environment sufficient to cause MS, and if they do, the likelihood that they will, in fact, develop the MS. We define the subset (G) – i.e., the genetically-susceptible subset – to include everyone in (Z) who hasanynon-zero chance of developing MS over their life-time, under some environmental circumstances. For the observed parameters, plausible ranges are assigned acceptable values such that they always include their 95% confidence interval. By contrast, for the non-observed parameters, the acceptable ranges are assigned such that they cover the entire “plausible” range for each parameter. Then, using both aCross-sectional Modeland aLongitudinal Model, together with established parameter relationships, we explore iteratively trillions of potential parameter combinations and determine those combinations (i.e., solutions) that are allowed by the observed and non-observed parameter ranges. TheCross-sectional Modelmakes two assumptions, commonly made in studies of monozygotic twins, to establish certain relationships between the observed and non-observed parameters. By contrast, theLongitudinal Modelmakes neither of these assumptions but, rather, thisModelutilizes the observed changes in the female-to-male (F:M)sex-ratioand the disease prevalence, which have taken place over the past 4–5 decades, to determine the response curves for susceptible individuals, relating their probability of developing MS to their probability of experiencing an environment sufficient to cause MS. BothModelsand all analyses are consistent with each other and converge to demonstrate that genetic-susceptibitly is limited to 52% or less of the population and 30% or less of women. Consequently, most individuals have no chance whatsoever of developing MS, regardless of their environmental experiences. Thus, MS is a genetic disease in the sense that, if an individual does not have the correct genetic makeup, they can’t develop the disease. However, the probability that susceptible individuals will develop MS increases with an increased likelihood of these individuals experiencing an environment sufficient to cause MS, given their genotype. Thus, MS is also and environmental disease in the sense that the development of MS (in an individual), in addition to their having an appropriate genotype, requires that they experience an environmental exposure sufficient to cause MS given their individual genotype. Nevertheless, there must be another factor involved in disease pathogenesis because, although it is conceivable that these response-curves plateau at 100% for bothwomenandmen, this possibility requires extreme conditions and seems remote. Rather, at leastmen, seem to plateau well below this and, if so, it is this difference, rather than differences in the genetic and environmental determinants of disease, that primarily accounts both for the difference in penetrance betweenwomenandmenand for the increasing proportion ofwomenamong of MS patients worldwide. Consequently, even when the necessary genetic and environmental factors, sufficient for MS pathogenesis, co-occur for an individual, this still seems to be insufficient for that person to develop MS. Thus, disease pathogenesis, even in this circumstance, seems not to be deterministic but, rather, to involve an important element of chance.