1 Finding genes associated with Multiple Sclerosis (MS) in Tasmania Lecture 4, Statistics 246 January 29, 2004
1
Finding genes associated with Multiple Sclerosis (MS) in Tasmania
Lecture 4, Statistics 246January 29, 2004
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.
Intro to MS
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
Lack of myelin formation and maintenance causes disruption of nerve impulse conduction
MS results from progressive destruction of myelin
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
Magnetic resonance imaging
• Areas of demyelination (plaques) identified by proton-dense signal
• High signal observed in periventricular regions in 98% of patients
8
MS 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 function
Symptoms of MS
9
MS - forms of the disease
TimeSymptomseverity
TimeSymptomseverity
TimeSymptomseverity
Relapsing-remitting Secondary progressive
Primary progressive Progressive-relapsing
SymptomseverityTime
MS genetics
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
Mcleod et al. Med J Aust 1994
MS in Australia, 1981
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
Familial recurrence risks for MS
Relation to Proband
Monozygotic twins
Dizygotic twins
Full siblings
Half siblings
Cousins
% of genomeShared
100
50
50
25
12.5
RecurrenceRisk (%)
30.8
4.7
3.5
1.5
0.9
308
47
35
15
6
15
Previous genome-wide scans for MS susceptibility genes identify the HLA region
Chromosomal regionswith suggestive linkage
Study
American/French
British
Canadian
Finnish
Family type
sib-pairs
sib-pairs
sib-pairs
multiplexfamilies
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