Meta-analysis of genome-wide linkage studies for multiple sclerosis, using an extended GSMA method

Abstract

Many genome-wide linkage studies in multiple sclerosis (MS) have been performed, but results are disappointing, with linkage confirmed only in the HLA region. We combined results from all available, nonoverlapping genome-wide linkage studies in MS using the Genome Search Meta-Analysis method (GSMA). The GSMA is a rank-based analysis, which assesses the strongest evidence for linkage within bins of traditionally 30 cM width on the autosomes and X chromosome. Genome-wide evidence for linkage was confirmed on chromosome 6p (HLA region; P ¼ 0.00004). Suggestive evidence for linkage was found on chromosomes 10q (P ¼ 0.0077), 18p (P ¼ 0.0054) and 20p (P ¼ 0.0079). To explore how these results could be affected by bin definition, we analysed the data using different bin widths (20 and 40 cM) and using a shifted 30 cM bin by moving bin boundaries by 15 cM. Consistently significant results were obtained for the 6p region. The regions on 10q and 18p provided suggestive evidence for linkage in some analyses, and, interestingly, a region on 6q, that showed only nominal significance in the original analysis, yielded increased, suggestive significance in two of the additional analyses. These regions may provide targets to focus candidate gene studies or to prioritise results from genome-wide association studies.

European Charcot Foundation Lecture: The natural history of multiple sclerosis and gender

“…These findings as well as results from genome-wide association studies [e.g. [35][36][37] and data on recurrence risks among first-degree relatives (parents, siblings, children) of MS patients provide some support for a polygenic model of inheritance for MS. However, recurrence risks for half-siblings (who share 25% of their genetic material compared to 50% sharing by full siblings) imply that this model does not explain the role of genetics in MS; although the amount of genetic sharing is halved when going from full to halfsiblings, the recurrence risk is not halved.…”

Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy

“…To evaluate the consistency of our results, we repeated the analyses using two additional bin widths of 20 and 40 cM and using a shifted 30-cM bin. 37 Significant results were obtained consistently for regions identified at genome-wide or suggestive significance levels (2p and 6p with asthma, 2q with EOS, 17q with atopic asthma, 3q and 17q regions with SPT and 6p with IgE). These analyses strengthened the evidence of linkage to the 5q region for SPTQ and identified new regions for atopic asthma (1p22-p13, 1q23-q25) and SPT (1p34-p22).…”

“…To explore the manner in which meta-analysis results could be affected by bin definition, we also performed analyses using 20 cM (giving a total of 173 bins) and 40 cM (87 bins) bin widths, and shifted 30-cM bins obtained by moving bin boundaries by 15 cM. 37 Multiple testing of bins was accounted for in the P-value thresholds used, but multiple testing of phenotypes was not corrected for as these phenotypes are correlated. The outcomes of sensitivity analysis according to bin width were only examined in regions detected by the original 30-cM bin-width analysis.…”

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

“…Linkage analyses with several hundreds of highly polymorphic microsatellite repeats showing a relatively uniform distribution through the genome were carried out in more than 30 studies involving families with several MS patients (Ebers et al 1996;Sawcer et al 1996;Ban et al 2002). Genome-wide linkage analyses performed in different ethnic groups, as well as meta-analyses of the pooled data (Hermanowski et al 2007;GAMES and Transatlantic Multiple Sclerosis Genetics Cooperative 2003), yielded inconsistent results in the majority of cases, pointing to potential genetic heterogeneity of MS in different populations. 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.…”