Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system commonly affecting young adults. Pathologically, there are patches of inflammation (plaques) with demyelination of axons and associated loss of oligodendrocytes. Genome-wide association studies have identified over 105 loci of susceptibility, but the total number of possible contributory loci may be considerably higher. Family recurrence risks are available for several northern hemisphere countries, but there are few data for the southern hemisphere and regions at lower latitude such as Australia. The published family data could provide useful recurrence risks if appropriately analysed. Segregation analysis can be used to model the genetic architecture of MS. There is a global latitude gradient in MS prevalence, and the incidence of MS is increasing (particularly in females). These changes suggest a major role for environmental factors in the causation of disease. In the last 20 years there has been increasing evidence for the role of smoking in the aetiology of multiple sclerosis. Cigarette smoking is also associated with increased risk of developing the progressive form of MS. This risk factor has not previously been analysed in Queensland. Furthermore, cigarette smoking represents a possible cause of the changing prevalence of MS over time. Methods The family risks in Australia were measured in three regions at different latitudes. Immediate and extended family pedigrees were collected for three cohorts of MS patients in Queensland, Victoria and Tasmania. Age of onset data from Queensland were utilised to estimate age-adjusted recurrence rates. Meta-analysis of all available family recurrence risk data was performed to define risks to relatives. Standard methods of meta-analysis were combined with novel approaches to age adjustment to provide directly comparable estimates of lifetime risk. Segregation analysis was used to estimate the proportion of the overall genetic risk that can be attributed to identified susceptibility genes. To evaluate risks from smoking in Queensland, a large case-control study was performed, comparing risk of MS (by smoking habit) using regression modelling. The risk of developing progressive disease was measured in a cohort from an MS clinic in Queensland, followed from first clinic attendance until the onset of clinically determined progressive disease. Risk of progression was analysed with gender, age, age of onset, exposure to disease modifying therapy, and smoking status as covariates in a Cox proportional hazards analysis. Finally, a comprehensive meta-analysis was performed of eligible casecontrol and cohort studies that evaluated the risk of MS in smokers and exsmokers. The influence of study design, gender, latitude and year of study were explored with regression modelling. Results Recurrence risks in Australia were significantly lower than in studies from northern hemisphere populations. The age-adjusted risk for siblings across Australia was 2.1% compared with 3.5% for the northern hemisphere. A similar pattern was seen for other relatives. The risks to relatives were proportional to the population risks for each site, and hence the relative risk for siblings (lS) was similar across all sites. From the meta-analysis of family recurrence risks, the overall recurrence risk for monozygotic twins was 18.2% and for siblings 2.7%. The recurrence risk for dizygotic twins was significantly higher than for siblings. The overall estimate of sibling relative risk (lS) was 16.8. Risks for older relatives (parents, siblings, aunts, uncles and cousins) show a latitudinal gradient, in line with population risk. No latitudinal gradient for lS was seen. Segregation analysis supports a multiplicative model of one locus of moderate effect with many loci of small effect. The estimated contribution of the known MS loci is 18–24% of lS. The case-control study in Queensland confirmed an association between increased risk of MS and smoking. The overall adjusted odds ratio was 1.9 (95% confidence interval, CI 1.5–2.5) for ever smokers. There was no statistically significant difference in the risks for males and females. In the progression study, there were significantly higher risks of secondary progressive disease in males (Hazard Ratio, HR 1.83, 95% CI 1.3–2.7) and in ever smokers (HR 1.4, 95% CI 1.0–2.0). Progressive disease occurred approximately 4 years earlier in ever smokers. Smoking did not affect age of onset of primary progressive disease. The meta-analysis of smoking risk included 26 studies representing 8615 cases and 392,352 controls and an additional 792 cases included from a total cohort population of 601,492 individuals, representing more than 9 million person-years. There was a consistent association between smoking and MS with an odds ratio of approximately 1.5, with males at higher risk. This finding was independent of study design. However, latitude and year of study may have unexpected influence. Smoking appeared to confer a greater risk to females living closer to the equator than to females at higher latitudes. Additionally, the effect of cigarette smoke exposure on MS risk may not be fixed over time, but could be increasing. Discussion The familial recurrence risk of MS in Australia is lower than in previously reported studies. This is directly related to the lower population prevalence of MS. The overall genetic susceptibility in Australia as measured by the lS is similar to that seen in the northern hemisphere, suggesting that the difference in population risk is explained largely by environmental factors rather than by genetic admixture. The meta-analysis of family data supports the notion of MS risk being derived from multiple susceptibility genes and environmental factors. Genetic susceptibility appears to be independent of latitude, and the latitudinal gradient of MS prevalence is likely due to environmental factors. The results of the case-control study in Queensland replicate existing work that has shown cigarette smoking increases the risk of MS. Cigarette smoking represents an important modifiable risk factor for the development of MS. Cigarette smoking was also associated with earlier onset of progressive disease in the large clinical cohort studied in Queensland. For patients with relapsing-remitting disease, smoking cessation should be encouraged. The results of the meta-analysis of smoking studies suggest a threshold model of MS risk that includes a fairly constant genetic risk (for Caucasian populations) together with variable environmental risks which are dominated by vitamin D deficiency at higher latitudes and are more significant in women who have an intrinsically lower threshold for development of disease.