A genome screen for linkage in Australian sibling-pairs with multiple sclerosis M Ban 1 , 2 , GJ Stewart 2 , BH Bennetts 3 , R Heard 2 , R Simmons 4 , M Maranian 1 , A Compston 1 and SJ Sawcer 1 1 Neurology Unit, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK; 2 Institute for Immunology and Allergy Research, Westmead Millennium Institute, Westmead Hospital, University of Sydney, NSW, Australia; 3 Department of Paediatrics and Child Health, Children’s Hospital at Westmead, University of Sydney, NSW, Australia; 4 Australian National Register of Multiple Sclerosis Families, Canberra Hospital, ACT, Australia The role of genetic factors in determining susceptibility to multiple sclerosis is well established but, despite the global distribution of the disease, systematic efforts to locate susceptibility genes have concentrated exclusively on populations from the Northern Hemisphere. We performed a genome wide screen of linkage in the Australian population using a panel of 397 microsatellite markers in 54 affected sibling-pairs. Multipoint linkage analysis revealed four regions of suggestive linkage (on chromosomes 2p13, 4q26-28, 6q26 and Xp11) and 18 additional regions of potential linkage (at 1q43-44, 3q13-24, 4q24, 4q31- 34, 5q11-13, 6q27, 7q33-35, 8p23-21, 9q21, 13q31-32, 16p13, 16p11, 16q23-24, 17p13, 18p11, 20p12-11, Xp21-11 and Xq23- 28). Our results contribute to the available data adding new provisional regions of linkage as well as increasing support for areas previously implicated in genetic susceptibility to multiple sclerosis. Genes and Immunity (2002) 3, 464–469. doi:10.1038/sj.gene.6363910 Keywords: multiple sclerosis; linkage genome screen; genetic susceptibility Introduction Multiple sclerosis is a demyelinating disorder of the central nervous system with a complex aetiology in which unknown environmental factors are thought to trigger disease in genetically susceptible individuals. 1 Epidemiological analysis of twins, 2,3 half-sibs 4 and adoptees 5 confirm the involvement of genetic factors while the role of environmental agents is demonstrated by the results of migration studies. 6 In Australia, studies of the prevalence of multiple sclerosis have been particularly influential showing a latitudinal relationship similar to that seen in the Northern Hemisphere with lower rates in northern regions closer to the equator (11/100 000) than in the south (74/ 100 000). 7,8 However, overall, these prevalence rates are lower than those seen in Northern Europe, even though the majority of the Australian population originates from Northern Europe, suggesting that, despite expressing the same susceptibility genes, Australians may be at rela- tively reduced risk of multiple sclerosis through differ- ential exposure to the causative environmental risk factors. To date seven whole genome screens for linkage have been completed in multiple sclerosis, five in Northern European 9–13 and two in Southern European popula- tions. 14,15 None of these screens identified statistically unequivocal evidence for linkage but nearly all found more regions of potential linkage than would be expected to have occurred by chance alone. Several regions show some degree of consistency between screens, including the major histocompatibility complex (MHC) on chromosome 6p21. A systematic search for linkage in multiple sclerosis has not previously been performed in a population from the Southern Hemisphere. Here, we report a genome screen for linkage in 54 Australian affected sibling-pairs with multiple sclerosis using a panel of 397 microsatellite markers. Results Results of the multipoint non-parametric linkage analysis are shown graphically in Figure 1. A Maximum lod score (MLS) value of greater than 1.8, the threshold of suggestive linkage, was seen on chromosomes 2p13, 4q26-28, 6q26 and Xp11. Another 18 regionsFon chromosomes 1q43-44, 3q13-24, 4q24, 4q31-34, 5q11-13, 6q27, 7q33-35, 8p23-21, 9q21, 13q31-32, 16p13, 16p11, 16q23-24, 17p13, 18p11, 20p12-11, Xp21-11 and Xq23-28Fhad MLS values X0.7, indicating poten- tial linkage. The mean genetic information extracted from the 54 families across the genome was 61%, ranging from 16% on chromosome 19pter to 86% on chromosome 4 in a region covered by particularly informative markers. Correspondence: GJ Stewart, Associate Professor, Institute for Immunol- ogy and Allergy Research, Westmead Millennium Institute, Westmead Campus, University of Sydney, Westmead, NSW 2145, Australia. E-mail stewartg@westgate.wh.usyd.edu.au Genes and Immunity (2002) 3, 464–469 & 2002 Nature Publishing Group All rights reserved 1466-4879/02 $25.00 www.nature.com/gene