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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

Permutation analysis after filtering out regions with low IBD sharing. Blue line indicates genome-wide threshold and black line is the minimal permutation P-value. The full colour version of this figure is available at European Journal of Human Genetics online.
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fig4: Permutation analysis after filtering out regions with low IBD sharing. Blue line indicates genome-wide threshold and black line is the minimal permutation P-value. The full colour version of this figure is available at European Journal of Human Genetics online.

Mentions: After applying the filter, the peaks on chromosomes 5, 9, 14 and 19 remained (Figure 4). The signal on chromosome 19 was the only genome-wide significant hit that was not in a telomeric position. Here, a single marker (RS8092) reached significance in the permutation analysis, whereas the flanking markers did not (RS4806907 and RS1682809). The significant marker was located in the last exome of transcript 001 of gene GNA11.


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)

Permutation analysis after filtering out regions with low IBD sharing. Blue line indicates genome-wide threshold and black line is the minimal permutation P-value. The full colour version of this figure is available at European Journal of Human Genetics online.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Permutation analysis after filtering out regions with low IBD sharing. Blue line indicates genome-wide threshold and black line is the minimal permutation P-value. The full colour version of this figure is available at European Journal of Human Genetics online.
Mentions: After applying the filter, the peaks on chromosomes 5, 9, 14 and 19 remained (Figure 4). The signal on chromosome 19 was the only genome-wide significant hit that was not in a telomeric position. Here, a single marker (RS8092) reached significance in the permutation analysis, whereas the flanking markers did not (RS4806907 and RS1682809). The significant marker was located in the last exome of transcript 001 of gene GNA11.

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