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Follow-Up Examination of Linkage and Association to Chromosome 1Q43 in Multiple Sclerosis

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Follow-Up Examination of Linkage and Association to Chromosome 1Q43 in Multiple Sclerosis Genes and Immunity (2009) 10, 624–630 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene ORIGINAL ARTICLE Follow-up examination of linkage and association to chromosome 1q43 in multiple sclerosis JL McCauley1, RL Zuvich1, Y Bradford1, SJ Kenealy1, N Schnetz-Boutaud1, SG Gregory2, SL Hauser3, JR Oksenberg3, DP Mortlock1, MA Pericak-Vance4 and JL Haines1 1Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA; 2Center for Human Genetics and Department of Medicine, Duke University Medical Center, Durham, NC, USA; 3Department of Neurology, University of California San Francisco, San Francisco, CA, USA and 4Miami Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disease affecting 44 00 000 individuals in the United States. Population and family-based studies have suggested that there is a strong genetic component. Numerous genomic linkage screens have identified regions of interest for MS loci. Our own second-generation genome-wide linkage study identified a handful of non-major histocompatibility complex regions with suggestive linkage. Several of these regions were further examined using single-nucleotide polymorphisms (SNPs) with average spacing between SNPs of B1.0 Mb in a dataset of 173 multiplex families. The results of that study provided further evidence for the involvement of the chromosome 1q43 region. This region is of particular interest given linkage evidence in studies of other autoimmune and inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus. In this follow-up study, we saturated the region with B700 SNPs (average spacing of 10 kb per SNP) in search of disease-associated variation within this region. We found preliminary evidence to suggest that common variation within the RGS7 locus may be involved in disease susceptibility. Genes and Immunity (2009) 10, 624–630; doi:10.1038/gene.2009.53; published online 23 July 2009 Keywords: multiple sclerosis; linkage; association; 1q43; RGS7 Introduction in MS results in damage to the myelin sheath, producing the pathophysiological phenotype seen in the disease. Multiple sclerosis (MS [MIM 126200]) is a neurodegen- Despite the degenerative nature of the disease, an erative autoimmune disease characterized by demyeli- affected individual’s lifespan is rarely shortened. nation within the central nervous system (CNS). The clinical heterogeneity and complex etiology of MS Demyelination and the resulting formation of scar tissue have been confounding factors for genetic studies of the in the CNS impair the saltatory conduction along axons disease. Yet despite these complexities, it is clear that that is necessary for normal functioning of nerve genes play a vital role in the susceptibility to MS. impulses. Although little is known about the underlying Numerous research groups, including our own, have etiology of the disease, MS is a heterogeneous disorder conducted genomic linkage screens for MS in an attempt with several characteristics common to autoimmune to identify regions that harbor disease loci.2–14 Over 70 disorders—including polygenic inheritance, evidence of genomic regions have been investigated, revealing environmental exposure, and partial susceptibility con- varying levels of support. However, the lack of replica- ferred by a human leukocyte antigen (HLA)-associated tion of results from these studies has been problematic gene.1 There is also a greater prevalence of the disease in for using linkage to detect loci involved in MS. women than in men. This inflammatory disorder results The strongest and most consistent finding for linkage from an autoimmune response directed against CNS to MS is chromosome 6p21.3, the location of the MHC antigens—particularly myelin proteins. Class II major containing HLA. Until just recently, the MHC has been histocompatibility complex (MHC) molecules, such as the only region clearly and consistently demonstrating human leukocyte antigen (HLA), normally function to linkage and association with MS.9,13–15 However, the bind and present peptide antigens to antigen-specific T MHC has been estimated to account for only 10–50% of cells. It is thought that the dysregulation of this process the genetic component of MS susceptibility, at least in the Caucasian populations of northern European descent.6,16 It appears that the association with the HLA-DRB1*1501 Correspondence: Dr JL Haines, Center for Human Genetics allele explains this linkage signal,1,16 although this issue Research, Vanderbilt University Medical Center, 519 Light Hall, has been debated.17 The exact mechanism by which a Nashville, TN, 37232-0700, USA. E-mail: [email protected] gene or genes in the MHC increase disease risk has yet to Received 21 November 2008; revised 3 April 2009; accepted 18 May be determined, although recent work has sought to 2009; published online 23 July 2009 provide the tools needed to explore this region in greater Follow-up examination of chromosome 1q43 in MS JL McCauley et al 625 detail.18,19 Recent work by our group has identified a of evidence. SNPs in the 1q43 region have also demon- strongly associated single-nucleotide polymorphism strated suggestive linkage and/or association in several (SNP) (rs6897932) in the interleukin-7 receptor a gene other MS screens conducted in a variety of study (IL7RA), a gene located on chromosome 5p13. This SNP populations.3,4,29–31 None of these earlier studies, which introduces a coding change (T244I) that alters the ratio of lack the power and marker density of the current soluble to bound protein.20 This result was further generation of genome-wide association studies, demon- replicated in a genome-wide association study (GWAS) strate significant evidence for either linkage or performed by a broader collaborative group of investi- association. However, they do provide support from gators (The International Multiple Sclerosis Genetics independent sample populations of an effect within a Consortium (IMSGC)). The GWAS also identified addi- common region of interest. Another compelling piece of tional replicated associations with variations in other evidence for 1q is linkage to this region in studies for the genes (including CD25/IL2RA and CD58).21 The involve- autoimmune diseases rheumatoid arthritis and systemic ment of these genes plus several others (for example, lupus erythematosus, suggesting the potential presence CLEC16A) are now being tested and confirmed in of a gene common to autoimmune processes in this multiple international studies.22–24 region.32–37 Following these lines of evidence, we set out Although genome-wide association studies have now to test whether common variation within this region is begun, dense SNP follow-up studies of narrowed linkage involved in susceptibility to develop MS. regions are still underway because of their potential for identifying additional disease susceptibility genes. The American-French Multiple Sclerosis Genetics Group published one of the largest MS genomic linkage screens Results conducted.11 Follow-up of candidate regions identified in After quality control procedures, 578 SNPs were this study entailed genotyping SNPs at B1.0 Mb inter- included in our initial analysis. Using the Tagger vals flanking 10 Mb on each side of peak screen SNPs implementation in the Haploview program, we selected in an expanded U.S. dataset.25 The 1q43 region not 268/578 SNPs, with r2o0.2, for inclusion in a multipoint only continued to demonstrate evidence for linkage in linkage analysis of the narrow interval. These results the follow-up analysis (non-parametric multipoint continue to demonstrate considerable evidence for LOD ¼ 2.99), but also generated a narrowed linkage linkage to this region (peak LOD Score 3.42 at interval when using the ordered subset analysis (OSA) B238 Mb) (Figure 2a). As was analyzed in the initial method to condition on the other loci25–28). This follow-up,25 we examined this narrowed interval using narrowed interval is B7.0 Mb for a LOD score cut-off the OSA method to condition on the same loci (namely of 1.8 (corresponding to a –2.0 LOD score confidence HLA-DRB1*1501 and Chr2) in an attempt to further interval from the 3.8 LOD score HLA-based peak) (see resolve this effect (Figure 2a). The goal of this analysis Figure 1). Chromosome 1q43 was selected for further was to determine whether other previously suggested detailed investigation based on several additional lines linkage regions, within our initial dataset, have a 5 4.5 4 3.5 3 2.5 2 LOD Score 1.5 1 0.5 0 228 230 232 234 236 238 240 242 244 246 248 Mb Location (Build 36.2) Original (173 families) HLA Lod Lo-Hi (134 families, p=0.46) Chr2 Lod Hi-Lo (119 families, p=0.11) Figure 1 Region of interest on chromosome 1q. Original multipoint calculations are represented by the solid curve. Multipoint calculations for an OSA subset identified by ranking families for ‘HLA LOD’ scores (that is, ranking families for inclusion in the multipoint analysis based on their LOD scores at the peak linkage position from the HLA locus on chromosome 6) are represented by the dashed curve. Multipoint calculations for an OSA subset identified by ranking families for linkage to chromosome 2q35 are represented by the dotted curve. The cut-off corresponding to a -2.0 LOD score confidence interval (from the B3.8 LOD of the HLA peak) is indicated by the horizontal line at B1.8 and bordered by the intersection of this line with the original multipoint scores. This B7 Mb interval is the target of our more detailed examination. Genes and Immunity Follow-up examination of chromosome 1q43 in MS JL McCauley et al 626 5 4.5 4 3.5 3 2.5 2 LOD Score 1.5 1 0.5 0 234 236 238 240 242 244 Mb Location (Build 36.2) Original (173 families) 268 SNPs (173 families) HLA Lod Lo-Hi (153 families, p=0.89) Chr2 Lod Hi-Lo (44 families, p=0.28) 5 4.5 4 3.5 3 2.5 2 LOD Score 1.5 1 0.5 0 234 236 238 240 242 244 Mb Location (Build 36.2) 268 SNPs (173 families) AI=YES (100 families) AI=NO (53 families) Figure 2 Multipoint linkage analyses across 1q43.
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