Risk alleles for multiple sclerosis in multiplex families.
OBJECTIVE
We assessed the hypotheses that non-major histocompatibility complex multiple sclerosis (MS) susceptibility loci would be common to sporadic cases and multiplex families, that they would have larger effects in multiplex families, and that the aggregation of susceptibility loci contributes to the increased prevalence of MS in such families.


METHODS
A set of 43 multiplex families comprising 732 individuals and 211 affected subjects was genotyped for 13 MS candidate genes identified by genome-wide association. A control data set of 182 healthy individuals was also genotyped to perform a case-control analysis alongside the family-based pedigree disequilibrium association test, although this may have been underpowered.


RESULTS
An effect of the IL2RA and CD58 loci was shown in multiplex families as in sporadic MS. The aggregate of the IL2RA, IL7R, EVI5, KIAA0350, and CD58 risk genotypes in affected individuals from multiplex families was found to be notably different from controls (chi(2) = 112, p = 1 x 10(-22)).


CONCLUSIONS
Although differences between individual families can only be suggested, the aggregate results in multiplex families demonstrate effect sizes that are increased as compared with those reported in previous studies for sporadic cases. In addition, they imply that concentrations of susceptibility alleles at IL2RA, IL7R, EVI5, KIAA0350, and CD58 are partly responsible for the heightened prevalence of multiple sclerosis within multiplex families.
D'Netto
M J
MJ
Wellcome Trust Centre for Human Genetics, Department of Clinical Neurology, University of Oxford, UK.
Ward
H
H
Morrison
K M
KM
Ramagopalan
S V
SV
Dyment
D A
DA
DeLuca
G C
GC
Handunnetthi
L
L
Sadovnick
A D
AD
Ebers
G C
GC
D000483:Alleles; D018968:CD58 Antigens / Q000235:genetics; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D020690:GTPase-Activating Proteins; D005787:Gene Frequency / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006649:Histocompatibility Antigens / Q000235:genetics; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D037181:Lectins, C-Type / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D017720:Molecular Epidemiology / Q000379:methods; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009103:Multiple Sclerosis / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015995:Prevalence; D020395:Receptors, Interleukin-7 / Q000235:genetics; D012307:Risk Factors
D018968:CD58 Antigens; C522505:CLEC16A protein, human; D018797:Cell Cycle Proteins; C506399:EVI5 protein, human; D020690:GTPase-Activating Proteins; D006649:Histocompatibility Antigens; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D020395:Receptors, Interleukin-7