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