PowerPoint PresentationAimIntro to MSSlide 4MS results from progressive destruction of myelinSlide 6Slide 7Slide 8MS - forms of the diseaseMS geneticsEnvironment and GenesSlide 12Slide 13Slide 14Previous genome-wide scans for MS susceptibility genes identify the HLA region1Finding genes associated with Multiple Sclerosis (MS) in Tasmania Lecture 4, Statistics 246January 29, 20042Aim 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.Intro to MS4MS: 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 US5Lack of myelin formation and maintenance causes disruption of nerve impulse conductionMS results from progressive destruction of myelin6• 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 point7Magnetic resonance imaging• Areas of demyelination (plaques) identified by proton-dense signal • High signal observed in periventricular regions in 98% of patients8MS is a condition with a variety of symptoms depending on theareas 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 functionSymptoms of MS9MS - forms of the diseaseTimeSymptomseverityTimeSymptomseverityTimeSymptomseverityRelapsing-remitting Secondary progressivePrimary progressive Progressive-relapsingSymptomseverityTimeMS genetics11Environment 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 MS12Mcleod et al. Med J Aust 1994MS in Australia, 198113Environment 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.pdf14Familial recurrence risks for MSRelation to ProbandMonozygotic twinsDizygotic twinsFull siblingsHalf siblingsCousins% of genomeShared10050502512.5RecurrenceRisk (%)30.84.73.51.50.9308473515615Previous genome-wide scans for MS susceptibility genes identify the HLA regionChromosomal regionswith suggestive linkageStudyAmerican/FrenchBritishCanadianFinnishFamily typesib-pairssib-pairssib-pairsmultiplexfamiliesStage 1Stage 223 (3)98 (46)114 (8)52 (443)129 (311) 61 (261)16 (328) 21 (40)2q, 3q, 4cen, 6p21, 10q, 11tel, 17q, 18tel, 19tel5p, 6p211cen, 5cen, 6p21, 7p, 12p, 14q, 17q22, 19q,
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