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Identity-by-descent mapping in a Scandinavian multiple sclerosis cohort.

Westerlind H, Imrell K, Ramanujam R, Myhr KM, Celius EG, Harbo HF, Oturai AB, Hamsten A, Alfredsson L, Olsson T, Kockum I, Koski T, Hillert J - Eur. J. Hum. Genet. (2014)

Bottom Line: Four regions on chromosomes 5, 9, 14 and 19 were found to be significantly associated with the risk for MS.This marker was located within the GNA11 gene, which contains no previous association with MS.We conclude that IBD mapping is not sufficiently powered to identify MS risk loci even in ethnically relatively homogenous populations, or that alternatively rare variants are not adequately present.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
In an attempt to map chromosomal regions carrying rare gene variants contributing to the risk of multiple sclerosis (MS), we identified segments shared identical-by-descent (IBD) using the software BEAGLE 4.0's refined IBD analysis. IBD mapping aims at identifying segments inherited from a common ancestor and shared more frequently in case-case pairs. A total of 2106 MS patients of Nordic origin and 624 matched controls were genotyped on Illumina Human Quad 660 chip and an additional 1352 ethnically matched controls typed on Illumina HumanHap 550 and Illumina 1M were added. The quality control left a total of 441 731 markers for the analysis. After identification of segments shared by descent and significance testing, a filter function for markers with low IBD sharing was applied. Four regions on chromosomes 5, 9, 14 and 19 were found to be significantly associated with the risk for MS. However, all markers but for one were located telomerically, including the very distal markers. For methodological reasons, such segments have a low sharing of IBD signals and are prone to be false positives. One marker on chromosome 19 reached genome-wide significance and was not one of the distal markers. This marker was located within the GNA11 gene, which contains no previous association with MS. We conclude that IBD mapping is not sufficiently powered to identify MS risk loci even in ethnically relatively homogenous populations, or that alternatively rare variants are not adequately present.

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Related in: MedlinePlus

Plot of the distribution of the lengths of the segments.
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Related In: Results  -  Collection

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fig1: Plot of the distribution of the lengths of the segments.

Mentions: A histogram over the frequency of lengths of detected chromosomal segments can be seen in Figure 1. The distribution approximated a Pareto distribution with the mean lengths of segments slightly above 1 cM.


Identity-by-descent mapping in a Scandinavian multiple sclerosis cohort.

Westerlind H, Imrell K, Ramanujam R, Myhr KM, Celius EG, Harbo HF, Oturai AB, Hamsten A, Alfredsson L, Olsson T, Kockum I, Koski T, Hillert J - Eur. J. Hum. Genet. (2014)

Plot of the distribution of the lengths of the segments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402631&req=5

fig1: Plot of the distribution of the lengths of the segments.
Mentions: A histogram over the frequency of lengths of detected chromosomal segments can be seen in Figure 1. The distribution approximated a Pareto distribution with the mean lengths of segments slightly above 1 cM.

Bottom Line: Four regions on chromosomes 5, 9, 14 and 19 were found to be significantly associated with the risk for MS.This marker was located within the GNA11 gene, which contains no previous association with MS.We conclude that IBD mapping is not sufficiently powered to identify MS risk loci even in ethnically relatively homogenous populations, or that alternatively rare variants are not adequately present.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
In an attempt to map chromosomal regions carrying rare gene variants contributing to the risk of multiple sclerosis (MS), we identified segments shared identical-by-descent (IBD) using the software BEAGLE 4.0's refined IBD analysis. IBD mapping aims at identifying segments inherited from a common ancestor and shared more frequently in case-case pairs. A total of 2106 MS patients of Nordic origin and 624 matched controls were genotyped on Illumina Human Quad 660 chip and an additional 1352 ethnically matched controls typed on Illumina HumanHap 550 and Illumina 1M were added. The quality control left a total of 441 731 markers for the analysis. After identification of segments shared by descent and significance testing, a filter function for markers with low IBD sharing was applied. Four regions on chromosomes 5, 9, 14 and 19 were found to be significantly associated with the risk for MS. However, all markers but for one were located telomerically, including the very distal markers. For methodological reasons, such segments have a low sharing of IBD signals and are prone to be false positives. One marker on chromosome 19 reached genome-wide significance and was not one of the distal markers. This marker was located within the GNA11 gene, which contains no previous association with MS. We conclude that IBD mapping is not sufficiently powered to identify MS risk loci even in ethnically relatively homogenous populations, or that alternatively rare variants are not adequately present.

Show MeSH
Related in: MedlinePlus