ABSTRACT
OBJECTIVE: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. METHODS: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. RESULTS: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). INTERPRETATION: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.
Subject(s)
Disease Susceptibility , Genetic Predisposition to Disease , Multiple Sclerosis/genetics , Polymorphism, Single Nucleotide/genetics , Adolescent , Adult , Child , Female , Gene Frequency , Genome-Wide Association Study , Genotype , Humans , Male , Meta-Analysis as Topic , Middle Aged , Multiple Sclerosis/etiology , Odds Ratio , Young AdultABSTRACT
Appropriate inspection protocols and mitigation strategies are a critical component of effective biosecurity measures, enabling implementation of sound management decisions. Statistical models to analyze biosecurity surveillance data are integral to this decision-making process. Our research focuses on analyzing border interception biosecurity data collected from a Class A Nature Reserve, Barrow Island, in Western Australia and the associated covariates describing both spatial and temporal interception patterns. A clustering analysis approach was adopted using a generalization of the popular k-means algorithm appropriate for mixed-type data. The analysis approach compared the efficiency of clustering using only the numerical data, then subsequently including covariates to the clustering. Based on numerical data only, three clusters gave an acceptable fit and provided information about the underlying data characteristics. Incorporation of covariates into the model suggested four distinct clusters dominated by physical location and type of detection. Clustering increases interpretability of complex models and is useful in data mining to highlight patterns to describe underlying processes in biosecurity and other research areas. Availability of more relevant data would greatly improve the model. Based on outcomes from our research we recommend broader use of cluster models in biosecurity data, with testing of these models on more datasets to validate the model choice and identify important explanatory variables.
Subject(s)
Algorithms , Biosecurity , Cluster Analysis , Western AustraliaABSTRACT
Multiple sclerosis (MS) is a genetically complex autoimmune disease. To dissect further the involvement of four recent identified MS susceptibility genes (KIAA0350, IL2RA, RPL5 and CD58) in disease pathogenesis, we genotyped 94 haplotype-tagging single nucleotide polymorphisms (SNPs) from these loci in 1146 MS cases and 1309 controls. Seven newly-typed SNP variants were nominally associated with risk of MS, and one SNP (rs791589) in the first intron of the IL2RA gene remained associated after adjustment for rs2104286 genotype, a previously reported SNP association. These data provide further evidence of allelic heterogeneity at the IL2RA locus and point to the existence of at least two independent MS susceptibility alleles.