Abstract Details

Title Genetic Susceptibility to Multiple Sclerosis: Modelling the Risk with Family Data and Exploring the Effects of Latitude

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 129

Objective

Background BACKGROUND: There are well recognized genetic and environmental influences upon disease susceptibility. GWAS have demonstrated >50 loci that confer increased risk, but these are insufficient to explain familial aggregation. The total number of susceptibility loci is not known. Gene-gene and gene-environment interactions are also poorly understood.

Design/Methods DESIGN/METHODS: Conventional meta-analysis methods - published family association studies. Lifetime recurrence risk for family members calculated with novel age-adjustment method. Relative risks ([lambda]) derived from included studies and prevalence data. Heritability estimates used to define the genetic and environmental contributions to susceptibility. Segregation analysis compared 10 models to observed data.

Results RESULTS: The overall recurrence risk for monozygotic twins was 18.2% and for siblings was 2.7%. Recurrence risk [dizygotic (DZ) twins]>risk [siblings]. Recurrence risk [siblings] > risk [offspring] > risk [parents]. Risks for older relatives show a latitudinal trend in line with population risk. Estimate of sibling relative risk ([lambda]s) was 16.7. No latitudinal gradient for relative risk. Best fit model from segregation analysis: one locus moderate risk, with infinite number loci of small effect. Heritability estimates suggest 54% genetic, 17% shared family environment and 29% environmental contributions.

Conclusions CONCLUSIONS: For adult relatives, recurrence risk is influenced by latitude. Disease onset in younger relatives may be more genetically determined. A temporal environmental risk factor acting within the family environment(e.g. infection) and intrauterine risk factors may be relevant in explaining higher risks in DZ twins than siblings, and in siblings compared with other 1st degree relatives. There is little difference in genetic risk across latitude, and genetic risk in the sampled populations appears constant. These findings suggest there is little gene-environment interactions at the population level with regard to latitude. The estimated genetic contribution to susceptibility is >50% with known loci contributing 18-24%.

Authors/Disclosures
Cullen M. O'Gorman, MBBS (Queensland Health) PRESENTER	Dr. O'Gorman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen Australia Pty. An immediate family member of Dr. O'Gorman has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Lundbeck Australia. An immediate family member of Dr. O'Gorman has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Otsuka.
	No disclosure on file
	No disclosure on file
Eric Williamson, MD (UCLA/West Los Angeles Veterans Admin Hospital)	Dr. Williamson has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for TG therapeutics. Dr. Williamson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. The institution of Dr. Williamson has received research support from Biogen. Dr. Williamson has received personal compensation in the range of $100,000-$499,999 for serving as a Employee with Veterans administration.
Simon Broadley, PhD, FRACP (Griffith University School of Medicine)	The institution of Dr. Broadley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. The institution of Dr. Broadley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. The institution of Dr. Broadley has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. Dr. Broadley has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Broadley has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Broadley has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Sage. The institution of Dr. Broadley has received research support from NHMRC. The institution of Dr. Broadley has received research support from ARC. The institution of Dr. Broadley has received research support from GCH Foundation. The institution of Dr. Broadley has received research support from NHMRC.

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