Twin concordance and sibling recurrence rates in multiple sclerosis

Abstract

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 MZ͞DZ 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. Multiple sclerosis (MS) is one of the most common neurological diseases affecting young adults (1). In Canada, at least 1 in 1,000 individuals has the disease (2-4), and twice as many women are affected compared with men. It is widely believed that susceptibility to MS is determined by a complex interaction between susceptibility genes and environment. Twin studies have played an important role in current concepts of complex traits including MS and have consistently demonstrated an excess of monozygotic (MZ) over dizygotic (DZ) concordance (refs. 5-19 and Table 1).The magnitude of the MZ-to-DZ difference has implied non-Mendelian inheritance (20). However, in more recent data, it seems that the absolute level of concordance in MZ twins also reflects the background population prevalence. Whereas in Canada and northern Europe concordance rates are high, in southern Europe twin concordance rates mirror the lower prevalence (ref. 5 and L. Ristori, S. Cannoni, and M. Salvetti, unpublished data). Uncertainty has remained about final concordance rates, because twins in previously reported studies retained considerable residual risk based on corrections for age of onset. Corrections can be readily calculated for the general population, but applying it to twins may be inappropriate because the age onset correlations are so much larger for concordant MZ pairs than for siblings (sibs) (21).Twin studies in MS and other putative autoimmune diseases have generally been small. Data have been insufficient in any single study to adequately assess the impact of ascertainment bias, a common confounder of twin studies (22). Questions beyond the comparison of MZ with DZ concordance have been left unanswered, and even this comparison shows wide confidence intervals in published data. Furthermore, it has not been possible to study an...

The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis

“…4,2 The disease shows familial clustering, and about onefifth of affected individuals have a family history of MS. Siblings to MS patients exhibit a 20-40 times higher relative risk of MS than the general population, and twin studies have revealed that a large proportion of family clustering can be attributed to shared genes. 5 Genetic studies in autoimmune diseases have for long supported a model in which the major risk factor resides in the HLA region. 2 However, recent application of genome-wide association studies (GWAS) to large sample sets have provided a convincing support for additional risk loci outside the HLA region, all with low-risk contribution to the disease.…”

Western lifestyle and immunopathology of multiple sclerosis

“…Some studies revealed a higher concordance rate between identical (monozygotic) compared with nonidentical (dizygotic) pairs (approximately 25–30% in monozygotic versus 5% in dizygotic twins) 50, 51. In contrast, other studies showed equivalent concordance rates 52, 53…”

“…Epidemiological studies of families with twins50 and adoptees54 and of migrant individuals who moved between high‐ and low‐risk regions demonstrated that the environment plays an even bigger role in MS than genetic factors. Studies on migrants revealed that individuals moving from an area with high to low MS incidence show a decreased MS risk, while migrants moving in the opposite direction usually maintain the low risk of MS 55, 56.…”

Multiple sclerosis genetics: leaving no stone unturned

“…The use of classic genetics and whole-genome screening in different strains has identified several additional genetic regions that contain QTLs conferring EAE susceptibility, including loci on chromosomes 2,3,7,8,15,16,17 (MHC in the mouse), 17 (distal to MHC) and 18. 99 Other regions have been implicated as containing disease-modifying genes affecting severity, course, duration and CNS pathology.…”

“…Furthermore, twin studies from different populations consistently indicate pairwise concordance (20-40% in identical twin pairs compared to 2-5% in like-sex fraternal twin pairs) providing additional evidence for a genetic etiology in MS. 14,15 Interestingly, twin concordance appears to exhibit, at least in the Canadian series, gender dimorphism. 16 Finally, parent-of-origin effects may also influence both disease susceptibility and outcome, [17][18][19] and concordance in families for early and late clinical features has been observed as well, suggesting that in addition to susceptibility, genes may influence disease severity or other aspects of the clinical phenotype. [20][21][22] Altogether, neither the recurrence familial rate nor the twin concordance supports the presence of a Mendelian trait.…”