Finding genes associated with Multiple Sclerosis MS in Tasmania Lecture 4 Statistics 246 January 29 2004 1 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 2 Intro to MS MS some facts Affects mainly Caucasians N Europe Most common neurodegenerative disease of young adults 50 100 per 100 000 200 000 people with MS in the US Average age at onset 28 f 30 m years Sex bias 2 female to 1 male Chronic illness with cumulative disability Treatment expensive US 10 000 p a 4 MS results from progressive destruction of myelin Lack of myelin formation and maintenance causes disruption of nerve impulse conduction 5 Another schematic illustrating the same point 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 6 Magnetic resonance imaging Areas of demyelination plaques identified by proton dense signal High signal observed in periventricular regions in 98 of patients 7 Symptoms of MS 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 8 Symptom Symptom severity severity T ime T ime Symptom Symptom severity severity T ime T ime MS forms of the disease Relapsing remitting Primary progressive Secondary progressive Progressive relapsing 9 MS genetics 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 11 MS in Australia 1981 Mcleod et al Med J Aust 1994 12 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 wwwgene cimr cam ac uk clayton talks Bristol 2003 segre c pdf 13 Familial recurrence risks for MS Relation to Proband of genome Shared Recurrence Risk Monozygotic twins 100 30 8 308 Dizygotic twins 50 4 7 47 Full siblings 50 3 5 35 Half siblings 25 1 5 15 12 5 0 9 6 Cousins 14 Previous genome wide scans for MS susceptibility genes identify the HLA region Study Family type Stage 1 American sib pairs French British sib pairs Canadian sib pairs Finnish multiplex families Stage 2 52 443 23 3 129 311 98 46 61 261 114 8 16 328 21 40 Chromosomal regions with suggestive linkage 6p21 1cen 5cen 6p21 7p 12p 14q 17q22 19q 22q 5p 6p21 2q 3q 4cen 6p21 10q 11tel 17q 18tel 19tel 15
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