title: Haplotype-based approach to known MS-associated regions increases the amount of explained risk.
abstract: Genome-wide association studies (GWAS), using single nucleotide polymorphisms (SNPs), have yielded 110 non-human leucocyte antigen genomic regions that are associated with multiple sclerosis (MS). Despite this large number of associations, however, only 28% of MS-heritability can currently be explained. Here we compare the use of multi-SNP-haplotypes to the use of single-SNPs as alternative methods to describe MS genetic risk. SNP-haplotypes (of various lengths from 1 up to 15 contiguous SNPs) were constructed at each of the 110 previously identified, MS-associated, genomic regions. Even after correcting for the larger number of statistical comparisons made when using the haplotype-method, in 32 of the regions, the SNP-haplotype based model was markedly more significant than the single-SNP based model. By contrast, in no region was the single-SNP based model similarly more significant than the SNP-haplotype based model. Moreover, when we included the 932 MS-associated SNP-haplotypes (that we identified from 102 regions) as independent variables into a logistic linear model, the amount of MS-heritability, as assessed by Nagelkerke's R-squared, was 38%, which was considerably better than 29%, which was obtained by using only single-SNPs. This study demonstrates that SNP-haplotypes can be used to fine-map the genetic associations within regions of interest previously identified by single-SNP GWAS. Moreover, the amount of the MS genetic risk explained by the SNP-haplotype associations in the 110 MS-associated genomic regions was considerably greater when using SNP-haplotypes than when using single-SNPs. Also, the use of SNP-haplotypes can lead to the discovery of new regions of interest, which have not been identified by a single-SNP GWAS.
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, USA UCSF MS Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Pouya
authors.initials: P
authors.lastname: Khankhanian
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, USA UCSF MS Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Gourraud
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, USA UCSF MS Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Antoine
authors.initials: A
authors.lastname: Lizee
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, USA UCSF MS Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Goodin
mesh_terms: D002874:Chromosome Mapping; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
keywords: Clinical genetics; Genome-wide; Multiple sclerosis