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Background  To study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes ( CEHs ) of the  MHC  and three non- MHC  “risk-haplotypes” nearby genes  EOMES, ZFP36L1,  and  CLEC16A . Many haplotypes are MS-associated despite having population-frequencies exceeding the percentage of genetically-susceptible individuals. The basis of this frequency-disparity requires explanation.    Methods  The  SNP -data from the WTCCC was phased at the  MHC  and three non- MHC  susceptibility-regions.  CEHs  at the  MHC  were classified into five haplotype - groups: ( HLA-DRB1*15:01  ~  DQB1*06:02  ~  a1 )-containing ( H  +); extended-risk ( ER ); all-protective ( AP ); neutral ( 0 ); and the single- CEH  ( c1 ). MS-associations for different “risk-combinations” at the  MHC  and other non- MHC  “risk-loci” and the appropriateness of additive and multiplicative risk-accumulation models were assessed.    Results  Different combinations of “risk-haplotypes” produce a final MS-risk closer to additive rather than multiplicative risk-models but neither model was consistent. Thus, ( H  +)-haplotypes had greater impact when combined with ( 0 )-haplotypes than with ( H  +)-haplotypes, whereas, ( H  +)-haplotypes had greater impact when combined with a ( c1 )-haplotypes than with ( 0 )-haplotypes. Similarly, risk-genotypes ( 0,H  +), ( c1,H  +), ( H  +  ,H  +) and ( 0,c1 ) were additive with risks from non- MHC  risk-loci, whereas risk-genotypes ( ER,H  +) and ( AP,c1 ) were unaffected.    Conclusions  Genetic-susceptibility to MS is essential for MS to develop but actually developing MS depends heavily upon both an individual’s particular combination of “risk-haplotypes” and how these loci interact.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12920-021-01018-6.

Genetic susceptibility to multiple sclerosis: interactions between conserved extended haplotypes of the MHC and other susceptibility regions