bioRxiv2020
OBJECTIVETo explore the nature of MS-susceptibility and, by extension, other complex-genetic diseases. BACKGROUNDBasic-epidemiological parameters of MS (e.g., prevalence, recurrence-risks for siblings and twins, time-dependent changes in sex-ratio, etc.) are well-established. Moreover, >200 genetic-loci are unequivocally MS-associated, especially the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype-association. DESIGN/METHODSWe define the "genetically-susceptible" subset-(G) to include everyone with any non-zero life-time chance of developing MS. We analyze, mathematically, the implications that these epidemiological observations have regarding genetic susceptibility. In addition, we use the sex-ratio change (observed over a 35-year interval), to derive the relationship between MS-probability and an increasing likelihood of a suitable environmental-exposure. RESULTSWe demonstrate that genetic-susceptibitly is restricted to less than 4.7% of populations across Europe and North America. Among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, fewer than 20% are even in the subset-(G). Women are less likely to be susceptible than men although their MS-penetrance is considerably greater. Response-curves for MS-probability increase with an increasing likelihood of a suitable environmental-exposure, especially among women. These environmental response-curves plateau at under 50% for women and at a significantly lower level for men. CONCLUSIONSMS is fundamentally a genetic disorder. Despite this, a suitable environmental-exposure is also critical for disease-pathogenesis. Genetic-susceptibility requires specific combinations of non-additive genetic risk-factors. For example, the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, by itself, poses no MS-risk. Moreover, the fact that environmental-response-curves plateau below 50%, indicates that disease-pathogenesis is partly stochastic. By extension, other diseases for which monozygotic-twin recurrence-risks greatly exceed disease-prevalence (e.g., rheumatoid arthritis, diabetes, and celiac disease), must have a similar genetic basis. Author SummaryWe define a "genetic-susceptible" subset (G) of the general population (Z) to include everyone with any non-zero chance of developing MS over their life-time. Using well-established epidemiological data from across Europe and North America, we establish that genetic-susceptibility is confined to less than 4.7% of these populations. Thus, the large majority of individuals have no chance whatsoever of developing MS, irrespective of any environmental conditions that they may experience during their lifetimes. In this sense, MS is fundamentally a genetic disorder. And, indeed, more than 200 genetic-loci, in multiple genomic locations have now been well-established to be associated with MS. Notably, however, the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 or (H+) haplotype, which has, by far, the strongest MS-association of any, has a carrier frequency in the population of 23% in North America and Europe. Therefore, with genetic susceptibility in the population being less than 4.7%, more than 80% of (H+)-haplotype carriers, must not be genetically-susceptible and, thus, have no chance of developing MS. In this circumstance, genetic susceptibility to MS must arise from a combination of this haplotype with "susceptible states" at other genetic loci. By itself, the (H+)-haplotype poses no risk. Indeed, genetic-susceptibility, generally, seems to require specific combinations of non-additive genetic risk-factors. Naturally, the conclusion that MS is fundamentally genetic does not preclude the possibility the environmental events are also critical to disease-pathogenesis. Using epidemiological data about the world-wide increase in the (F:M) sex-ratio for MS to construct (for men and women separately) the response curves relating an increasing likelihood of MS to an increasing likelihood of a sufficient environmental exposure (i.e., an exposure sufficient to cause MS in a susceptible individual). This analysis provides insight to both disease-susceptibility and disease-pathogenesis. First, men are more likely to be susceptible than women although susceptible women are considerably more likely to actually develop MS. Second, men seem to have a lower environmental threshold than women for developing MS. Nevertheless, women are more responsive to changes in the environmental conditions compared to men. Third, even with a maximal environmental exposure, susceptible women never exceed a 50% chance of developing MS. By contrast, susceptible men have a significantly lower likelihood (<10% chance) of developing MS. This indicates that stochastic factors must also be critical in disease pathogenesis. Finally, the nature of genetic susceptibility developed here for MS is applicable to many other complex genetic disorders. Indeed, for any disease, in which the proband-wise MZ-twin concordance rate greatly exceeds the disease-prevalence in the population (e.g., type I diabetes, rheumatoid arthritis, and celiac disease), only a small fraction of the population can possibly be genetically susceptible, as defined.