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A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility

Abstract

Multiple sclerosis is a common disease with proven heritability, but, despite large-scale attempts, no underlying risk genes have been identified. Traditional linkage scans have so far identified only one risk haplotype for multiple sclerosis (at HLA on chromosome 6), which explains only a fraction of the increased risk to siblings. Association scans such as admixture mapping have much more power, in principle, to find the weak factors that must explain most of the disease risk. We describe here the first high-powered admixture scan, focusing on 605 African American cases and 1,043 African American controls, and report a locus on chromosome 1 that is significantly associated with multiple sclerosis.

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Acknowledgements

We thank the individuals with multiple sclerosis, their families and friends and others for permission to use their DNA in these studies; M. Williams for his role in building the collection of samples from African Americans; B. Henderson and S. Ingles for permission to use data from the prostate cancer study; D. Goldstein for frequency information from the Italian and Norwegian samples; and D. Goldstein and E. Lander for providing comments throughout the project. This work was supported by grants to D.R. from the Wadsworth Foundation and the US National Institute of Neurological Disorders and Stroke; to D.A.H. from the National Multiple Sclerosis Society; to J.R.O. from the US National Institute of Neurological Disorders and Stroke and the National Multiple Sclerosis Society; and to S.L.H. from the Nancy David and Montel Williams Foundations. D.R. is the recipient of a Burroughs-Wellcome Career Development Award in the Biomedical Sciences; B.A.C.C. is a Sylvia Lawry fellow of the National Multiple Sclerosis Society; N.P. has a US National Institutes of Health career transition award; D.A.H. has a US National Institute of Neurological Disorders and Stroke Javits Investigator Award; and P.L.D.J. is the William C Fowler scholar for MS Research and is supported by US National Institute of Neurological Disorders and Stroke grant and the Clinical Investigator Training program: Harvard-MIT Health Sciences and Technology–Beth Israel Deaconess Medical Center, in collaboration with Pfizer, Inc.

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Competing interests

The authors declare no competing financial interests.

Correspondence to David Reich.

Supplementary information

Supplementary Table 1

Results for the 1,166 SNPs used in the main MCMC analysis (analysis from Run 3). (XLS 435 kb)

Supplementary Table 2

Proof that case-control statistic is normally distributed. (PDF 44 kb)

Supplementary Table 3

Admixture statistics for the populations under study. (PDF 48 kb)

Supplementary Table 4

389 SNPs dropped from main analysis based on the linkage disequilibrium criteria. (XLS 77 kb)

Supplementary Table 5

Results by sample (analysis from run #10). (XLS 435 kb)

Supplementary Methods (PDF 127 kb)

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Further reading

Figure 1: Results of the genome-wide admixture scan (run 3 in Table 1).
Figure 2: The strongest peak of association spans the centromere of chromosome 1.
Figure 3: The 95% credible intervals for increased risk due to European ancestry at the chromosome 1 locus, for all African Americans (n = 605), all Afro-Caribbeans (n = 143) and both cohorts together (n = 748).