Finding genes associated with Multiple Sclerosis MS in Tasmania

1
Finding genes associated with Multiple Sclerosis
(MS) in Tasmania

Lecture 4, Statistics 246 January 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.

3
Intro to MS
4
MS some facts

• Affects mainly Caucasians (N. Europe)

• Most common neurodegenerative disease
• of young adults (50-100 per 100,000)

• gt 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 (gtUS10,000 p.a.)

5
MS results from progressive destruction of myelin

• Lack of myelin formation and maintenance causes
  disruption of
  nerve impulse conduction

6
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

7
Magnetic resonance imaging

• Areas of demyelination
• (plaques) identified by
• proton-dense signal

• High signal observed in
• periventricular regions in
• 98 of patients

8
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
9
MS - forms of the disease
Relapsing-remitting
Secondary progressive
Primary progressive
Progressive-relapsing
10
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
MS in Australia, 1981
Mcleod et al. Med J Aust 1994
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_20
  03/segrec.pdf

14
Familial recurrence risks for MS
l
15
Previous genome-wide scans for MS susceptibility
genes identify the HLA region

Stage 1
Chromosomal regions with suggestive linkage
Study
Family type
Stage 2
American /French
sib-pairs
23 (3)
6p21
British
sib-pairs
98 (46)
1cen, 5cen, 6p21, 7p, 12p, 14q, 17q22, 19q, 22q
Canadian
sib-pairs
114 (8)
5p, 6p21
Finnish
multiplex families
21 (40)
2q, 3q, 4cen, 6p21, 10q, 11tel, 17q, 18tel,
19tel