Elsevier

The Lancet Neurology

Volume 13, Issue 7, July 2014, Pages 700-709
The Lancet Neurology

Review
Multiple sclerosis genetics

https://doi.org/10.1016/S1474-4422(14)70041-9Get rights and content

Summary

Genome-wide association studies have revolutionised the genetic analysis of multiple sclerosis. Through international collaborative efforts involving tens of thousands of cases and controls, more than 100 associated common variants have now been identified. These variants consistently implicate genes associated with immunological processes, overwhelmingly lie in regulatory rather than coding regions, and are frequently associated with other autoimmune diseases. The functional implications of these associated variants are mostly unknown; however, early work has shown that several variants have effects on splicing that result in meaningful changes in the balance between different isoforms in relevant tissues. Including the well established risk attributable to variants in genes encoding human leucocyte antigens, only about a quarter of reported heritability can now be accounted for, suggesting that a substantial potential for further discovery remains.

Introduction

Multiple sclerosis is an inflammatory demyelinating disease of the CNS that results in chronic progressive disability for the majority of people with the disorder. Most patients are unemployed within 15 years of diagnosis and rates of depression, suicide, and divorce are substantially increased compared with the healthy population.1 Half of all patients need assistance with mobility within 20 years of diagnosis, and 50% of patients eventually develop substantial cognitive deficits.1 The disease most often starts between 20 and 40 years of age, and affects women more frequently than men.2 According to the Atlas of MS database, worldwide about 2·5 million people have multiple sclerosis, and figures from the Multiple Sclerosis International Federation suggest that in Europe alone the disease costs more than €15 billion each year in terms of direct health-care costs and lost productivity. As is the case for many other autoimmune diseases, evidence suggests that the incidence of multiple sclerosis is increasing.3 Although the precise aetiology of multiple sclerosis remains unknown, in the past few years the identification of genetic variants affecting the development of the disease has grown almost exponentially. In this Review we outline the basic epidemiological foundations underpinning the genetic analysis of multiple sclerosis, describe some of the landmark findings from the past, summarise recent findings, and consider what the future might hold. Like pieces in a jigsaw puzzle, each of these associated variants provides a clue to aetiology. The more pieces we find the more likely it is that they will fit together in meaningful ways to reveal the crucial mechanisms underlying the development of this enigmatic disease.

Section snippets

Epidemiology

Two features have consistently emerged from the extensive epidemiological analysis of multiple sclerosis: first, that the disease clusters in families,4, 5 and second, that the disease varies greatly in frequency worldwide.6, 7 Although neither of these findings necessarily implies an exclusive role for either genetic or environmental factors, supplementary studies in informative subgroups (eg, twins,8 adoptees,9 conjugal pairs,10 and migrant individuals11) suggest that familial clustering is

Linkage

Although segregation analysis has little power to establish the relative importance of the two main allelic models, linkage analysis can be useful.21 Families with multiple sclerosis rarely include more than three or four affected individuals and large, extended families with many cases of the disease are extremely uncommon.22 Furthermore, the absence of any linkage in the few larger-than-average families that have been reported22, 23, 24, 25 suggests that—unlike many other complex traits—rare,

The major histocompatibility complex

Although associations between multiple sclerosis and variation in the genes encoding human leucocyte antigens (HLAs) contained within the major histocompatibility complex have been recognised for several decades,29, 30 the extreme polymorphism and extensive linkage disequilibrium (ie, correlation between linked variants) that characterise this gene-dense region31 make the identification of relevant variants driving these associations difficult. However, in the past few years the advent of

Genome-wide association studies—a new era in complex genetics

Despite decades of candidate-gene-based efforts, little progress was made in the identification of relevant, genuinely associated risk alleles outside the major histocompatibility complex before the advent of genome-wide association studies. The only real progress was the identification of association with the SNP rs6897932 from the IL7R gene, which was suggested by combining information from many data sources (ie, genomic convergence45) and confirmed by typing large numbers of cases and

Immunochip follow-up

The ability of genome-wide association studies to robustly screen most common variation by direct typing of just a few hundred thousand SNPs is crucially dependent on the extensive correlation between tightly linked variants (linkage disequilibrium) that is a characteristic feature of the human genome. Unfortunately, this same feature limits our ability to understand the results of such studies. Rather than individual associated variants, genome-wide association studies necessarily identify

110 established variants associated with multiple sclerosis

Collectively these studies have identified 110 variants outside the major histocompatibility complex that are confidently associated with susceptibility to multiple sclerosis (appendix). According to the Variant Effect Predictor tool71 on Ensembl (release 72), 15 of the 110 SNPs are themselves coding variants and a further 35 are in tight linkage disequilibrium (r2>0·8) with coding variants (appendix). However, among the implicated coding variants, only 14 are missense and just 7 of these are

Secondary phenotypes

Analysis of clinical features in families in which more than one member has multiple sclerosis suggests that genetic factors probably affect the course of the disease.86 In this context, three genome-wide association studies51, 87, 88 have specifically investigated clinical features as their primary endpoint, but unfortunately no genome-wide significant association emerged from these modestly powered efforts. However, genes for calcium and glutamate signalling were enriched among the

Missing heritability

The associated loci identified so far account for only about a quarter of the heritability reported in multiple sclerosis, leaving an obvious question about what determines the remainder. Much of the remainder (perhaps half) is probably so-called phantom heritability—ie, resulting from as-yet-undefined interactions between risk factors.18 The remainder probably relates to risk alleles that are yet to be discovered,70 some of which will be common, and might emerge in larger genome-wide

Conclusions and future directions

Each of the associated genetic variants identified so far has the potential to provide crucial insight into aetiology of multiple sclerosis, and thereby promote the development of a rational therapy that is both safe and effective. The discovery that most, if not all, of these variants seem to exert their effects by affecting tissue-specific gene expression has exposed just how little is known about the way in which regulatory information is encoded in the genome—an information gap that

Search strategy and selection criteria

We searched PubMed for articles published between 1993 and December, 2013, with terms such as “multiple sclerosis”, “gene*”, “genomewide association”, “linkage”, and “association”. We also identified references from relevant articles and the online Catalog of Published Genome-Wide Association Studies. We restricted our search to articles published in English. The final reference list was generated on the basis of relevance to the topics covered in this Review.

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