Exploring Genetic Links in Multiple Sclerosis: Using IBD Mapping

Multiple sclerosis (MS) is a chronic, demyelinating disease predominantly affecting young adults. Genetic factors play a significant role in MS susceptibility, as evidenced by a heritability estimate of 0.64. Despite identifying over 100 risk genes through large-scale genotyping and case-control analyses, less than one-third of the heritability has been explained. This study aims to explore the potential contribution of rare genetic variants to MS risk by using identity-by-descent (IBD) mapping in a Scandinavian cohort.

The study involved 2106 MS patients of Nordic origin and 624 matched controls, genotyped on the Illumina Human Quad 660 chip. An additional 1352 ethnically matched controls were also included. Quality control measures resulted in the analysis of 441,731 markers. IBD segments were identified using BEAGLE 4.0’s refined IBD analysis, focusing on segments shared more frequently among case-case pairs than controls.

Genotyping was performed using the Illumina Human Quad 660 chip. An initial quality control process excluded 91 individuals due to genotyping errors or close relationships. Additional controls from breast cancer and myocardial infarction studies were included, resulting in a combined dataset of 3953 individuals after outlier removal.

Outliers were removed using the smartPCA algorithm of the EIGENSTRAT package, which involved calculating principal component (PC) vectors and excluding individuals outside the main clusters. This ensured a more homogeneous dataset suitable for IBD analysis. Transformation and IBD Segment Identification The dataset was transformed from PLINK’s format to BEAGLE’s .bgl format and then to .vcf format. A pre-release version of BEAGLE 4.0 was used for segment detection, with the ibdtrim parameter set to 25. The analysis was performed on a computational cluster using scripts for IBD mapping published by Sharon Browning.

The distribution of detected chromosomal segments approximated a Pareto distribution, with mean segment lengths slightly above 1 centimorgan (cM). Significant peaks of IBD sharing were initially found at the ends of chromosomes 5, 9, and 14, and the beginning of chromosomes 1, 7, 15, and 19. However, these peaks were suspected to be artifacts due to low IBD detection at chromosome ends.

After applying a filter to remove regions with low IBD sharing, significant peaks remained on chromosomes 5, 9, 14, and 19. The only genome-wide significant marker not located telomerically was on chromosome 19 within the GNA11 gene, which has no previous association with MS.

Despite the large sample size and homogeneity of the Scandinavian cohort, only one marker reached genome-wide significance. This suggests that IBD mapping may lack sufficient power to identify MS risk loci or that rare variants are not significant contributors to MS risk. The study highlights the challenges of detecting true IBD signals, especially at chromosome ends, and the need for further methodological improvements.

IBD mapping in a Scandinavian MS cohort revealed limited significant findings, with only one marker in the GNA11 gene reaching genome-wide significance. The study underscores the complexity of identifying genetic risk factors for MS and the potential limitations of current IBD mapping techniques. Further research with improved methodologies and larger sample sizes may be necessary to uncover the role of rare variants in MS susceptibility.

Reference:
Westerlind, H., Imrell, K., Ramanujam, R., Myhr, K. M., Celius, E. G., Harbo, H. F., ... & Hillert, J. (2015). Identity-by-descent mapping in a Scandinavian multiple sclerosis cohort. European Journal of Human Genetics, 23(5), 688-692.