We have evaluated genetic and environmental influences in multiple sclerosis (MS) by comparing age of onset in 99 sibling pairs concordant for the disease. We used three methods of analysis: (1) comparison of mean differences in age of onset and year of onset, (2) linear regression of differences in age or year of onset vs difference in ages, and (3) intraclass correlation of age of onset which is also used for monozygotic twins concordant for MS. Comparison of the mean differences in age of onset or year of onset is found to be inappropriate and potentially misleading. No significant results were found in linear regression of the age of onset or year of onset vs differences in ages, although a trend towards onset at the same age is present. However, nontwin siblings show a significant intraclass correlation for age of onset (P less than 0.01) as is seen in genetic disorders. A stronger intraclass correlation in age of onset in concordant monozygotic twins vs concordant sibling pairs further suggests that age of onset is partly under genetic control, assuming common exposure to an environmental agent. The results give little support for common exposure to an environmental trigger in concordant MS sibling pairs. They are consistent with a mixture of random independent exposures and common exposures leading to the development of the disease, with the former predominating.
Results from studies of twin concordance in multiple sclerosis have not conclusively differentiated between environmental and genetic factors that determine susceptibility to the disease. Published studies that have been based on case finding by public appeal have been characterized by difficulties in ascertainment. The data reported here are from a large population-based study of multiple sclerosis in twins, in which ascertainment has been relatively unbiased and the cooperation of patients nearly complete. A total of 5463 patients attending 10 multiple sclerosis clinics across Canada were surveyed. Twenty-seven monozygotic and 43 dizygotic twin pairs were identified, and the diagnosis of multiple sclerosis was verified by examination and laboratory investigation. Seven of 27 monozygotic pairs (25.9 percent) and 1 of 43 dizygotic pairs (2.3 percent) were concordant for multiple sclerosis. The concordance rate for 4582 nontwin siblings of patients at two multiple sclerosis clinics was 1.9 percent, closely paralleling the concordance rate in dizygotic twins. To the extent that the difference in concordance rates between monozygotic and dizygotic twins indicates genetic susceptibility, the results of this study show a major genetic component in susceptibility to multiple sclerosis.
This study is a 7.5-year follow-up of a population-based series of twins with multiple sclerosis (MS) whose mean age now exceeds 50 years. The twin pairs were identified through the Canadian nationwide system of MS clinics and were drawn from a population of 5,463 patients. After 7.5 years, the monozygotic concordance rate increased from 25.9 to 30.8% and the dizygotic-like sex concordance rate from 2.4 to 4.7%. These results are very similar to those of other population-based studies and to our own modified replication twin data reported here. We interpret the data to mean that MS susceptibility is genetically influenced, and a single dominant or even a single recessive gene is unlikely to account for this effect. The difference in concordance rates suggests that at least two or more genes are operative. These data also have important implications for the nature of the environmental effect(s) in MS susceptibility. Most monozygotic twins are discordant even after a correction for age and magnetic resonance imaging findings. This unambiguously demonstrates the powerful effect of nonheritable factors.
Size and ascertainment constraints often limit twin studies to concordance comparisons between identical and fraternal twins. Here we report the final results of a longitudinal, population-based study of twins with multiple sclerosis (MS) in Canada. Bias was demonstrably minimized, and an estimated 75% of all Canadian MS twin pairs were ascertained, giving a sample sufficiently large (n = 370) to permit additional informative comparisons. Twinning was not found to affect prevalence, and twins with MS did not differ from nontwins for DR15 allele frequency nor for MS risk to their siblings. Probandwise concordance rates of 25.3% (SE +/- 4.4) for monozygotic (MZ), 5.4% (+/-2.8) for dizygotic (DZ), and 2.9% (+/-0.6) for their nontwin siblings were found. MZ twin concordance was in excess of DZ twin concordance. The excess concordance in MZ was derived primarily from like-sexed female pairs with a probandwise concordance rate of 34 of 100 (34 +/- 5.7%) compared with 3 of 79 (3.8 +/- 2.8%) for female DZ pairs. We did not demonstrate an MZ/DZ difference in males, although the sample size was small. We observed a 2-fold increase in risk to DZ twins over nontwin siblings of twins, but the difference was not significant.
Cites: Brain. 2000 Mar;123 Pt 3:641-910686184
Cites: Can J Neurol Sci. 1998 Aug;25(3):216-219706723
Cites: Arch Neurol. 1966 Nov;15(5):449-625955946
Cites: J Med Genet. 1968 Dec;5(4):266-85713636
Cites: J Neurol Sci. 1975 Nov;26(3):361-751237538
Cites: Neurology. 1978 Oct;28(10):978-87570667
Cites: Ann Hum Genet. 1979 May;42(4):507-12475337
Cites: Neurology. 1980 Nov;30(11):1139-477191511
Cites: Arch Neurol. 1982 Mar;39(3):140-47199899
Cites: Can Med Assoc J. 1982 Aug 15;127(4):295-77093869
Cites: Can Med Assoc J. 1982 Dec 15;127(12):11707139466
Cites: Ann Neurol. 1983 Mar;13(3):227-316847134
Cites: N Engl J Med. 1986 Dec 25;315(26):1638-423785335