A High-Density Screen for Linkage in Multiple Sclerosis

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.

Genome‐wide association studies of multiple sclerosis

“…The linkage era culminated in a further collaborative effort by The International Multiple Sclerosis Genetics Consortium (IMSGC) also formed to pool resources and samples to conduct well‐powered studies. The IMSGC typed 4506 single nucleotide polymorphisms (SNPs) in 730 multiplex families and again found no significant linkage peaks outside the MHC, although a handful of suggestive signals were present 24. Although largely negative, these studies strongly supported the notion that MS is not caused by a small amount of mutations of large effect, but is likely to be due to many small risk effects spread across the genome.…”

“…The development of genetic maps covering much of the genome led to linkage analyses in extended MS affected families from a number of countries, primarily of European ancestry 23, 24, 25, 26, 27, 28, 29, 30, 31, 32. These validated the HLA association but showed no significant linkage to loci outside the MHC.…”

HLA-A Confers an HLA-DRB1 Independent Influence on the Risk of Multiple Sclerosis

“…This indicates that genes in the HLA region may confer a larger fraction of the genetic aetiology of MS than previously thought. This notion is further supported by the results of recent MS linkage analyses; in these studies, with increasing power of the analysis, the HLA locus has gradually obtained higher LOD scores, eventually exceeding 11, while all other candidate loci have remained insignificant[18], [19]. Recently, Yeo and co-workers reported an association with several alleles of HLA-DRB1, together with a negative association with the HLA class I allele HLA-C*05 in patients lacking DRB1 risk alleles, a finding which supports the importance of HLA class I genes in MS [9].…”

A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches

“…The HLA class II locus in the major histocompatibility complex (MHC) region on chromosome 6p21 was the only exception, being already identified as a MS risk factor in earlier association studies. Later, linkage to MS was tested for single nucleotide polymorphisms (SNPs) (Sawcer et al 2005), which usually consist of two alleles and are consequently less informative than microsatellites, but are more abundant in the genome. In spite of the higher genome coverage density, the study did not identify any region with statistically significant linkage to MS outside the HLA locus, pointing to a low sensitivity of the method (Cree 2014).…”