A genome-wide screen for linkage disequilibrium in Australian HLA-DRB1*1501 positive multiple sclerosis patients

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Abstract

The association of multiple sclerosis with alleles/haplotypes from the HLA region on chromosome 6p21 is well established although the remainder of the genome remains relatively unexplored. We have completed a genome-wide screen for linkage disequilibrium in a cohort of Australian multiple sclerosis patients positive for HLA-DRB1*1501. A total of 4346 microsatellite markers provided through the ā€œGenetic Analysis of Multiple sclerosis in EuropeanSā€ (GAMES) collaborative were analysed in DNA separately pooled from cases (n=217) and controls (n=187). Associations were found in four genomic regions (12q15, 16p13, 18p11 and 19q13) previously identified in linkage genome screens. Three additional regions of novel association were also identified (11q12, 11q23 and 14q21). Further analysis of these regions is required to establish whether the associations observed are due to epistatic interaction with the HLA locus.

Introduction

Multiple sclerosis is an autoimmune disease of the central nervous system with a multi-factorial aetiology involving an interplay of both environmental (Dean et al., 1976) and genetics factors Ebers et al., 1995, Mumford et al., 1994, Sadovnick et al., 1996. The genetic factors are complex with multiple genes involved, probably interacting epistatically.

The only genomic region showing consistent evidence of association with multiple sclerosis is the major histocompatibility complex (MHC) on chromosome 6p21. Multiple sclerosis is associated with the DRB1*1501-DQA1*0102-DQB1*0602 (HLA-DR15) haplotype in northern Europeans Compston et al., 1976, Haines et al., 1998 and predominantly with the DRB1*0301-DQA1*0501-DQB1*0201 (HLA-DR3) haplotype in southern Europeans Coraddu et al., 1998, Marrosu et al., 1998. Given the mainly northern European origin of Australian multiple sclerosis patients, it is not surprising that the association with the HLA-DR15 haplotype has been confirmed in this population (Stewart et al., 1997).

In an effort to identify non-MHC susceptibility genes, eight genome-wide linkage screens Ebers et al., 1996, Haines et al., 1996, Sawcer et al., 1996, Kuokkanen et al., 1997, Broadley et al., 2001, Coraddu et al., 2001, Akesson et al., 2002, Ban et al., 2002 have been completed. Although none of these identified statistically unequivocal linkage, some degree of consistency can be seen (Transatlantic Multiple Sclerosis Genetics Cooperative, 2001) with more regions of potential linkage than would have been expected by chance alone identified in nearly all cases. The greater power of association testing in the search for genes of modest effect (Risch and Merikangas, 1996) has prompted a shift towards such testing and a first pass genome-wide linkage disequilibrium (LD) screen was recently completed in the UK population (Sawcer et al., 2002).

The power of genetic studies is greatly influenced by disease heterogeneity, which is a likely confounding factor in studies of multiple sclerosis. In view of the evidence for the likely interaction of different genes between HLA-DRB1*1501 positive and negative patients Barcellos et al., 2002, Haines et al., 2002, we have attempted to reduce the heterogeneity of a combined cohort by concentrating our screen exclusively on HLA-DRB1*1501 positive cases. This stratification should have no effect on our power to detect loci acting independently of the MHC but should enhance the possibility of identifying those interacting epistatically.

Section snippets

Patients and controls

The patients (n=217) and controls (n=187) included in this study were recruited at the Institute for Immunology and Allergy Research, Westmead Millennium Institute, Australia. All patients satisfied the Poser criteria (Poser et al., 1983) for clinically definite (88%), clinically probable (3%), or laboratory-supported definite (9%) multiple sclerosis. In terms of disease course, 75% were relapsingā€“remitting (RRMS), 19% secondary progressive (SPMS), 5% primary progressive (PPMS) and 1%

Results

From the 6000 markers analysed, usable allele image patterns (AIP) were available from both cases and controls for 4346. Statistical analysis of these data, according to the method used by Sawcer et al. (2002), enabled us to rank markers according to their apparent evidence of association. The raw AIPs for the 81 markers with empirical p-values ā‰¤0.01 were re-examined in order to filter out those markers inappropriately included through genotyping errors or poor data quality. A total of 39 such

Discussion

Our genome-wide linkage disequilibrium screen, involving 217 HLA-DR15 positive multiple sclerosis patients and 187 unrelated controls from the Australian population, has identified seven genomic regions showing potential association with multiple sclerosis. Four of these regions (12q15, 16p13, 18p11 and 19q13) lie in areas previously identified by linkage genome screens, while the remaining three regions (11q12, 11q23 and 14q21) are novel. As there is evidence for the involvement of different

Acknowledgments

We thank all the patients who contributed samples to the study, the Neurologists of Australia and the MS Societies of Australia who assisted in patient recruitment. We also wish to thank N. Hartley, M. Bugeja, and S. Teutsch for preparation of the samples as well as J. Gray and M Maranian for valuable technical support. This work was supported by the National Health and Medical Research Council of Australia (Grant No. 981580 and 153990). This study represents one component of the GAMES project

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