A genome-wide scan in forty large pedigrees with multiple sclerosis.
The epidemiology of multiple sclerosis suggests that a complex interaction of genes and environment contribute to susceptibility. To enrich for families with large genetic effects and to potentially reduce genetic heterogeneity, we screened a sample of 18,794 probands and identified forty families with four or more affected individuals. Within these 40 families, HLA DRB1*15 was present in 70% of affected individuals; the transmission disequilibrium test showed a significant excess in transmission of DRB1*15 alleles to affected individuals (47 transmitted, 19 untransmitted, chi (2) = 11.9, p = 0.00057). A 10 cM genome scan was performed and analyzed for linkage under a parametric model with heterogeneity. No excess of significant sharing was observed (HLOD > 3.3) in the parametric multipoint analysis. No region exceeded that for marker GATA8A05 with an HLOD = 1.11. Follow-up genotyping with 17 microsatellites revealed a significant two-point parametric HLOD = 3.99 at marker D4S1597. Transmission disequilibrium tests for markers in this candidate region showed no transmission distortion. A scan for variants in a gene adjacent to D4S1597, PALLD, was negative for synonymous or nonsynonymous changes. A final multipoint scan incorporating all microsatellites in the region provided an HLOD = 1.30. The inability to find significant linkage in these highly penetrant families suggests that linkage is not the optimal tool for dissecting the inheritance of MS.
Willer
Cristen J
CJ
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
Dyment
David A
DA
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Cherny
Stacey
S
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Ramagopalan
Sreeram V
SV
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Herrera
Blanca M
BM
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Morrison
Katie M E
KME
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Sadovnick
A Dessa
AD
Department of Neurology, University of British Columbia, Vancouver, BC, Canada.
Risch
Neil J
NJ
Department of Genetics, Stanford University, Stanford, CA, USA.
Ebers
George C
GC
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. george.ebers@clneuro.oxford.ac.uk.|Department of Clinical Neurology, University of Oxford, Oxford, OX2 6HE, UK. george.ebers@clneuro.oxford.ac.uk.|Department of Clinical Neurology, John Radcliffe Hospital, West Wing, University of Oxford, Oxford, OX3 9DU, UK. george.ebers@clneuro.oxford.ac.uk.
D005192:Family Health; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics / Q000379:methods; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains