title: A genome-wide scan in forty large pedigrees with multiple sclerosis.
abstract: 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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Cristen J
authors.initials: CJ
authors.lastname: Willer
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Dyment
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Stacey
authors.initials: S
authors.lastname: Cherny
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Sreeram V
authors.initials: SV
authors.lastname: Ramagopalan
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Blanca M
authors.initials: BM
authors.lastname: Herrera
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Katie M E
authors.initials: KME
authors.lastname: Morrison
authors.affiliation: Department of Neurology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: A Dessa
authors.initials: AD
authors.lastname: Sadovnick
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Risch
authors.affiliation: 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.
authors.forename: George C
authors.initials: GC
authors.lastname: Ebers
mesh_terms: 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
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains