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PMID: 18000641 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A genome-wide scan in forty large pedigrees with multiple sclerosis.

Journal of human genetics ·Vol. 52 ·No. 12 ·2007-00-00 ·Pages 955-962

Willer CJ, Dyment DA, Cherny S, Ramagopalan SV, Herrera BM, Morrison KME, Sadovnick AD, Risch NJ, Ebers GC

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.

MeSH Terms
Family Health Genetic Linkage Genetic Predisposition to Disease Genome, Human/genetics Genomics/methods HLA-DR Antigens/genetics HLA-DRB1 Chains Humans Linkage Disequilibrium Lod Score Multiple Sclerosis/epidemiology,genetics Pedigree Penetrance
Chemicals
HLA-DR Antigens HLA-DRB1 Chains
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Willer Cristen J
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. | Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
Dyment David A
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Cherny Stacey
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Ramagopalan Sreeram V
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Herrera Blanca M
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Morrison Katie M E
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Sadovnick A Dessa
Department of Neurology, University of British Columbia, Vancouver, BC, Canada.
Risch Neil J
Department of Genetics, Stanford University, Stanford, CA, USA.
Ebers George C
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.
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Article Info
Journal
Journal of human genetics
Abbr.
J Hum Genet
ISSN
1434-5161
DOI
10.1007/s10038-007-0194-6
Email
george.ebers@clneuro.oxford.ac.uk
Published
2007-00-00
Epub
2007-00-15
Pages
955-962
Language
English
Region
England
NLM ID
9808008
Subset
IM
External Links
PubMed source DOI: 10.1007/s10038-007-0194-6 View journal details
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