1. 1 Finding genes associated with Multiple Sclerosis (MS) in Tasmania Lecture 4, Statistics 246 January 29, 2004

2. 2 Aim To describe some of the statistical methods used in a large project attempting to map genes contributing to multiple sclerosis, making use of data collected from the Australian state of Tasmania.

3. Intro to MS

4. 4 MS: some facts Affects mainly Caucasians (N. Europe) Most common neurodegenerative disease of young adults (50-100 per 100,000) Average age at onset 28(f)/30(m) years. Chronic illness with cumulative disability Treatment expensive (>US$10,000 p.a.) Sex bias: 2 female to 1 male > 200,000 people with MS in the US

5. 5 Lack of myelin formation and maintenance causes disruption of nerve impulse conduction MS results from progressive destruction of myelin

6. 6 As myelin is stripped from axons, transmission of nerve impulses are slowed or blocked This causes the diverse sensory, motor and autonomic symptoms that characterise MS Another schematic illustrating the same point

7. 7 Magnetic resonance imaging Areas of demyelination (plaques) identified by proton-dense signal High signal observed in periventricular regions in 98% of patients

8. 8 MS is a condition with a variety of symptoms depending on the areas of the central nervous system affected by de-myelination The systems commonly affected include: Vision Co-ordination Strength Sensation Speech and swallowing Bladder control Cognitive function Symptoms of MS

9. 9 MS - forms of the disease Relapsing-remittingSecondary progressive Primary progressiveProgressive-relapsing

10. MS genetics

11. 11 Environment and Genes Environment –MS prevalence appears to rise with increasing geographical latitude –Children of immigrants often have same risk of developing MS as new place of residence –Viruses have been implicated in MS pathogenesis Genes –Monozygotic twin concordance rate of ~30% compared to dizygotic twin concordance rate of ~5% –MS is most common in Caucasians –The HLA region (on chromosome 6) has been consistently linked and associated with MS

12. 12 Mcleod et al. Med J Aust 1994 MS in Australia, 1981

13. 13 Environment and Genes Recurrence risks. We are going to digress to go through a talk by David Clayton, one of the world leaders in genetic epidemiology, who also works on genes and MS. The talk is available at www-gene.cimr.cam.ac.uk/clayton/talks/Bristol_2003/segrec.pdf

14. 14 Familial recurrence risks for MS Relation to Proband Monozygotic twins Dizygotic twins Full siblings Half siblings Cousins % of genome Shared 100 50 25 12.5 Recurrence Risk (%) 30.8 4.7 3.5 1.5 0.9 308 47 35 15 6

15. 15 Previous genome-wide scans for MS susceptibility genes identify the HLA region Chromosomal regions with suggestive linkage Study American /French British Canadian Finnish Family type sib-pairs multiplex families Stage 1 Stage 2 23 (3) 98 (46) 114 (8) 52 (443) 129 (311) 61 (261) 16 (328) 21 (40) 2q, 3q, 4cen, 6p21, 10q, 11tel, 17q, 18tel, 19tel 5p, 6p21 1cen, 5cen, 6p21, 7p, 12p, 14q, 17q22, 19q, 22q 6p21