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The inheritance of MS susceptibility
D Lord1, A G O'Farrell, H Staunton
1Maynooth College, Co. Kildare, Ireland.
Abstract:
The object of this study was to determine, if possible, the mode of inheritance of the susceptibility to multiple sclerosis (MS). It was known that no single-gene model could fit the observations, so oligogenic models (models involving a small number of genes) were sought. Oligogenic hypotheses were tested against the available population data for MS until a reasonable level of agreement was found. The best-fitting simple hypothesis was this: MS occurs only in people who are homozygous for a recessive gene and carry a dominant X gene, and then only with reduced penetrance. The dangerous allele m- at the autosomal locus appears to be fairly uniformly distributed across England, Ireland and Canada, occurring in 10-30% of the gene pool. There are large variations in the frequency of the allele s- at the X-locus, ranging from 10% up to 72% of the gene pool. The penetrance varies significantly with geographical location, but nowhere approaches unity, so that the environmental factors are of great importance. The hypothesis explains the broad features of the population pattern of the occurrence of MS and it gives an outstanding fit to the best available data on MS in relatives. The result may assist attempts to map the genetic data on MS, opens the way for a reassessment of the attempts to identify the environmental factors, and it makes possible the completion of nonempirical risk tables for various countries. Similar techniques may be applied to other disorders with a genetic component in their aetiology.
Insights
This study suggests multiple sclerosis (MS) susceptibility involves a recessive gene and a dominant X gene, with environmental factors significantly influencing disease risk. This oligogenic model fits population data and family studies.
Area of Science:
- Genetics
- Epidemiology
- Neurology
Background:
- Multiple sclerosis (MS) inheritance patterns are complex and not explained by single-gene models.
- Oligogenic models, involving a few genes, are explored to understand MS susceptibility.
- Previous research indicated a genetic component but lacked a definitive inheritance model.
Purpose of the Study:
- To determine the mode of inheritance for multiple sclerosis (MS) susceptibility.
- To test oligogenic hypotheses against population and family data for MS.
- To identify genetic factors and their interaction with environmental influences in MS.
Main Methods:
- Testing of oligogenic inheritance models against population data for MS.
- Analysis of allele frequencies for autosomal (m-) and X-linked (s-) loci.
- Evaluation of model fit using data on MS occurrence in relatives and geographical variations.
Main Results:
- The best-fitting hypothesis proposes MS occurs in individuals homozygous for a recessive gene and carrying a dominant X gene, with reduced penetrance.
- The frequency of the autosomal allele (m-) is relatively uniform (10-30%) across England, Ireland, and Canada.
- The X-linked allele (s-) frequency varies widely (10-72%), and penetrance is geographically dependent, highlighting environmental importance.
Conclusions:
- The proposed oligogenic model explains key features of MS population patterns and family data.
- This genetic model aids in mapping MS genetic data and reassessing environmental factor research.
- The findings enable the creation of country-specific empirical risk tables for MS and suggest applicability to other complex genetic disorders.