Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis

Abstract

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.

Figure 1.

GWA trend test scan. Genome-wide association results for 551 642 SNPs in 978 MS cases and 883 controls using a linear trend test for additive allelic effects on disease penetrance (Cochran–Armitage trend test). As expected, the strongest association signal was located in the MHC region in chromosome 6p21.

Figure 2.

Q–Q plot distribution of the GWAS association results. P-values adjusted for HLA-DRB1*1501 and gender (A, trend test; B, genotypic test) are plotted for all SNPs as a function of the null distribution showing an excess in the tail of the distribution at P < 1 × 10⁻⁴. Red line is equal to expectation on H0. Grey/light green, P-values without adjustment for the HLA-DRB1 locus. Black/bright green, P-values with adjustment by including HLA-DRB1 as a covariate in the model. Green (light or bright), SNP loci in HLA region; black/grey, other SNPs.

Figure 3.

Association and logistic regression analyses of the extended MHC region. Results of allelic tests of association (top panel) and results of subsequent logistic regression analyses conditioning upon HLA-DRB1*1501 (bottom panel).