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Comparative Study
. 2005 Sep;77(3):454-67.
doi: 10.1086/444547. Epub 2005 Jul 29.

A high-density screen for linkage in multiple sclerosis

Stephen Sawcer  1 , Maria Ban, Mel Maranian, Tai Wai Yeo, Alastair Compston, Andrew Kirby, Mark J Daly, Philip L De Jager, Emily Walsh, Eric S Lander, John D Rioux, David A Hafler, Adrian Ivinson, Jacqueline Rimmler, Simon G Gregory, Silke Schmidt, Margaret A Pericak-Vance, Eva Akesson, Jan Hillert, Pameli Datta, Annette Oturai, Lars P Ryder, Hanne F Harbo, Anne Spurkland, Kjell-Morten Myhr, Mikko Laaksonen, David Booth, Robert Heard, Graeme Stewart, Robin Lincoln, Lisa F Barcellos, Stephen L Hauser, Jorge R Oksenberg, Shannon J Kenealy, Jonathan L Haines; International Multiple Sclerosis Genetics Consortium
Affiliations
Comparative Study

A high-density screen for linkage in multiple sclerosis

Stephen Sawcer et al. Am J Hum Genet. 2005 Sep.

Abstract

To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent. After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis. Multipoint nonparametric linkage analysis revealed highly significant linkage in the major histocompatibility complex (MHC) on chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18). This set of markers achieved a mean information extraction of 79.3% across the genome, with a Mendelian inconsistency rate of only 0.002%. Stratification based on carriage of the multiple sclerosis-associated DRB1*1501 allele failed to identify any other region of linkage with genomewide significance. However, ordered-subset analysis suggested that there may be an additional locus on chromosome 19p13 that acts independent of the main MHC locus. These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for multiple sclerosis will have to involve large sample sizes and an association-based methodology.

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Figures

Figure 1
Figure 1
Multipoint nonparametric linkage analysis performed using MERLIN (Center for Statistical Genetics). The figure includes one graph for each chromosome; the length of the X-axis is proportional to the genetic length of the corresponding chromosome, and the Y-axis scale is 0–3 in each case, except on chromosome 6, where the scale is 0–12.
Figure 1
Figure 1
Multipoint nonparametric linkage analysis performed using MERLIN (Center for Statistical Genetics). The figure includes one graph for each chromosome; the length of the X-axis is proportional to the genetic length of the corresponding chromosome, and the Y-axis scale is 0–3 in each case, except on chromosome 6, where the scale is 0–12.
See this image and copyright information in PMC

References

Web Resources

    1. Center for Statistical Genetics, http://www.sph.umich.edu/csg/abecasis/ (for MERLIN, PEDSTATS, and GRR)
    1. Duke Center for Human Genetics, http://www.chg.duke.edu/software/osa.html (for OSA)
    1. GENEHUNTER++sad, http://www.genome.mcgill.ca/~mlemire/software.html
    1. Haploview, http://www.broad.mit.edu/mpg/haploview/
    1. Illumina, http://www.illumina.com/ (for the BeadLab service facility)

References

    1. Abecasis GR, Cherny SS, Cardon LR (2001a) The impact of genotyping error on family-based analysis of quantitative traits. Eur J Hum Genet 9:130–134 - PubMed
    1. Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2001b) GRR: graphical representation of relationship errors. Bioinformatics 17:742–743 - PubMed
    1. ——— (2002) Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101 - PubMed
    1. Åkesson E, Oturai A, Berg J, Fredrikson S, Andersen O, Harbo HF, Laaksonen M, Myhr KM, Nyland HI, Ryder LP, Sandberg-Wollheim M, Sorensen PS, Spurkland A, Svejgaard A, Holmans P, Compston A, Hillert J, Sawcer S (2002) A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis. Genes Immun 3:279–285 - PubMed
    1. Ban M, Stewart GJ, Bennetts BH, Heard R, Simmons R, Maranian M, Compston A, Sawcer SJ (2002) A genome screen for linkage in Australian sibling-pairs with multiple sclerosis. Genes Immun 3:464–469 - PubMed

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