Proc Natl Acad Sci U S A 100(22): 12877-12882

Twin concordance and sibling recurrence rates in multiple sclerosis

^{Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom;}^{Department of Genetics, Stanford University, M-335A, Stanford, CA 94305-5120;}^{Department of Medical Genetics, and}^{Faculty of Medicine (Neurology), University of British Columbia, Vancouver, BC, Canada V6T 2B5; and}^{Department of Clinical Neurology, Radcliffe Infirmary, Oxford University, Woodstock Road, Oxford OX2 6HE, United Kingdom}

^{To whom correspondence should be sent at the †† address. E-mail:}ku.ca.xo.oruenlc@srebe.egroeg.

Edited by Hilary Koprowski, Thomas Jefferson University, Philadelphia, PA, and approved July 24, 2003

^{Present address: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-0618.}

^{Canadian Collaborative Study Group: D. W. Paty}^{, S. A. Hashimoto}^{, V. Devonshire}^{,J. Hooge}^{, J. Oger}^{, L. Metz}^{, S. Warren}^{, W. Hader}^{, R. Nelson}^{, M. Freedman}^{, D. Brunet}^{, J. Paulseth}^{, G. Rice}^{, P. O'Connor}^{, P. Duquette}^{, Y. Lapierre}^{, J.-P. Bouchard}^{, T. J. Murray}^{, V. Bhan}^{, C. Maxner}^{, W. Pryse-Phillips}^{, and M. Stefanelli}^.

^{University of British Columbia, Vancouver, BC, Canada V6T 1Z4;}^{Foothills Hospital, Calgary, AB, Canada T2N 2T9;}^{Health Sciences Center, University of Alberta, Edmonton, AB, Canada T6G 2E1;}^{Department of Physical Medicine and Rehabilitation, Saskatoon City Hospital, 701 Queen Street, Saskatoon, SK, Canada S7K 0M7;}^{Ottawa General Hospital, Ottawa, ON, Canada KIH 8L6;}^{Kingston General Hospital, Kingston, ON, Canada K7L 2V7;}^{McMaster University Medical Center, Hamilton, ON, Canada L8N 3Z5;}^{London Health Sciences Center, London, ON, Canada N6A 4G5;}^{St. Michael's Hospital, Toronto, ON, Canada M5B 1W8;}^{Notre-Dame Hospital, Montreal, QC, Canada H2L 4MI;}^{Montreal Neurological Institute, Montreal, QC, Canada H3A 2B4;}^{Department des Sciences Neurologiques, Pavillon L'Enfant Jesus-CHA, 1401 18eme Rue, Quebec City, QC, Canada G1J 1Z4;}^{Halifax General Hospital, Halifax, NS, Canada B3H 4H7; and}^{St. John's Memorial Hospital, St. John's, NF, Canada A1B 3V6.}

Edited by Hilary Koprowski, Thomas Jefferson University, Philadelphia, PA, and approved July 24, 2003

Received 2003 May 1

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 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.

Abstract

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).

Table 1.

Previously published MS twin concordance studies

Studies	Female MZ concordance	Male MZ concordance	Pairwise monozygous twin concordance (%)	Pairwise dizygous twin concordance (%)
Ref.
French Research Group (5)	1	0	1/17 (5.9)	1/37 (2.7)
Bammer et al. (6)			1/6 (16.7)	2/7 (28.6)
Bobowick et al. (7)		2^*	2/5 (40)	0/4
Cendrowski (8)				0/3
Currier and Eldridge (9)	8	0	8/22 (36.4)	3/29 (10.3)
Gardner-Thorpe and Foster (11)			0/1
Heltberg and Holm, Danish twin register (12)			4/19 (21.1)	1/28 (3.57)
Kinnunen et al., Finnish twin cohort (13)			1/11 (9.1)	0/10
Kinnunen et al. (14)	1	1	2/7 (28.6)	0/6
Mackay and Myrianthopoulos (15)			6/36 (16.7)	3/26 (11.5)
Mumford et al., British Isles twins (16)	9	2	11/44 (25)	2/61 (3.3)
Thums (18)			0/14	1/36 (2.8)
Williams et al. (19)	6	0	6/12 (50)	2/12 (16.7)
Total (all studies)	25	3	38/175 (21.7)	14/231 (6.1)
Canadian study	22	2	24/133 (18.0)	9/221 (4.1)
Total combined	47	5	62/308 (20.1)	23/452 (5.1)

^{Males-only study.}

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 any potential influence of twinning on MS risk, and previous studies have not examined the difference in concordance rate between DZ twins and sibs. This comparison addresses factors related to intrauterine environment and timing as well as other factors more commonly shared between twins than sibs. Although there has been no indication otherwise, it has not been formally shown that twins with MS carry the same susceptibility alleles as the general population of MS patients. This bears on the generalizability of twin concordance data.

With these considerations in mind, we have attempted over the last two decades to collect all twins with MS in Canada. We aimed to assess whether twinning influences MS risk and whether twins are representative of the patient population for family history of MS and presence of susceptible HLA alleles. We compared the concordance rates for MZ and DZ twins. We also asked whether concordance rates are influenced by the HLA-DR*15 allele or by gender. Finally, we determined the recurrence risk to sibs of twin probands to determine whether DZ twins had any excess risk compared with their nontwin sibs.

Acknowledgments

We thank all the twins who agreed to participate. Ethics approval was obtained at each Canadian MS clinic through the local hospital/ university committee for research on human subjects. The assistance of D. Bucciarelli, H. Armstrong, and S. Noble-Topham (University of Western Ontario, London, ON, Canada) and R. Holmes (University of British Columbia) was invaluable. We thank Dr. Colin Mumford for providing gender-specific data from the British twin series. Statistical assistance from I. Yee (University of British Columbia) and S. Cherney (Wellcome Trust Centre for Human Genetics) is gratefully acknowledged. This research was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation. C.J.W. and D.A.D. are recipients of studentships from the Multiple Sclerosis Society of Canada.

Acknowledgments

Notes

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: MS, multiple sclerosis; DZ, dizygotic; MZ, monozygotic; sib, sibling; CCPGSMS, Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis.

Notes

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: MS, multiple sclerosis; DZ, dizygotic; MZ, monozygotic; sib, sibling; CCPGSMS, Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis.

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