Background
Multiple sclerosis (MS) is an autoimmune disease with central nervous system pathology [
1] and the most common cause of non-traumatic neurological disability in young adults, affecting approximately 2.5 million people worldwide. The global burden of MS has increased over the past century but retains the well-known influence of gender, latitude, and ancestry on risk. This is reflected in the relatively high incidence in some population groups (particularly those of European origin) compared with others (African and Asian groups) [
2,
3]. Likewise, high frequency rates are found in Scandinavia, Iceland, the British Isles and North America (about 1–2 in 1,000), but lower frequencies are observed in the Mediterranean Basin (0.5 in 1000).
There are notable exceptions to the European prevalence gradient, such as in Sardinia where the prevalence of MS is among the highest in the world (1.4/1,000) [
4]. Similarly, Ashkenazi Jews in Israel (and the Diaspora) are at high risk for developing MS [
5]. The distinctive population histories of Sardinians and Ashkenazi Jews include founder effects, admixture, and bottlenecks, suggesting that unique genetic signatures underlie their differential susceptibility. Unraveling these profiles may provide important insights into the genetics of MS and interactions with non-genetic factors.
Extensive empirical evidence confirms that genetic variation is an important determinant of MS risk. Multiple genome-wide association studies (GWAS) have been completed and reported, including a multi-center effort with nearly ten thousand cases [
6]. The classic
HLA-DRB1 risk locus within the MHC, specifically the
HLA-DRB1*15:01 allele stood out in all GWAS with remarkably strong statistical significance. In addition, 110 non-MHC variants were found to be associated with disease susceptibility (Additional file
1: Table S1) [
7]. As expected, each identified variant conferred only modest odds ratios. These studies have focused on datasets ascertained in Europe, Australia and North America and included affected Ashkenazi individuals. Jewish populations in the Diaspora can be grouped into distinct genetic clades shaped by admixture with local populations and social and cultural forces. Nevertheless, they all maintain the ancestral Eastern Mediterranean and Middle Eastern genomic identity, which contrasts significantly with central and northern European populations [
8‐
12]. Here we seek to clarify the genetic characteristics of MS in Ashkenazi Jews.
Previous studies reported the
HLA-DRB1*15:01 association with MS in Ashkenazi Jews living in Israel, albeit with reduced odds ratios compared to Europeans [
13]. The
HLA-DRB1*13:03 allele was the strongest genetic biomarker of risk in a study of non-Ashkenazi Israelis [
13] but was not confirmed in Ashkenazi Israelis [
13]. In our study, we use genomic signatures to identify and extract Ashkenazi Jewish individuals from three SNP-chip-based genome wide studies: a transmission disequilibrium (TD) study and two case control studies. We next illustrate the genetic relationship of the Ashkenazi subsets to the other European sub-populations. We then compare allelic risk at
HLA-DRB1 and polygenic risk across the genome between Ashkenazi Jews and non-Jewish western Europeans, based on previously suggested risk alleles. To identify MS susceptibility alleles that may be specific to the Ashkenazi population, we perform case–control and TD tests for SNPs across the genome and at classical HLA alleles in the Ashkenazi subset.
Discussion
A 2006 survey of MS frequency in Israel reported that the highest disease rates were in Israeli-born Jews and in Jewish immigrants from Europe/America, with prevalence similar to that seen in Europeans [
5]. Jewish immigrants from African/Asian countries and Christian Arabs had intermediate MS rates (significantly lower than in the first two groups but not significantly different from each other) [
5]. Moslem Arabs, Druze, and Bedouins had the lowest rates of MS. Karni and colleagues [
15] highlight an intriguing difference in prevalence between Jewish immigrants from Africa/Asian countries (low prevalence) and their Israeli born children (higher prevalence) suggesting a strong environmental influence acting across a single generation [
15,
16]. The
HLA-DRB1*15:01 allele has been shown to be a risk allele in Ashkenazi [
13], but it is less frequent in Ashkenazi (~5 %) [
11,
16] compared to the general European population (~15-20 %), which is a counterintuitive observation given the high frequency of MS among Ashkenazi.
In this study, we have extracted Ashkenazi individuals using genetic data from three datasets. A key limitation of this study is the sample size, the small number of identified Ashkenazi individuals leaves little power for discovery of new variants, especially at the genome-wide level. Another limitation the small sample size of the well-characterized Ashkenazi controls [
9] used to help define Ashkenazi from within our MS datasets. A larger set of well-characterized controls may allow the identification of more Ashkenazi individuals, and may make the identification more reproducible across future studies.
Despite the power limitation, we have confirmed that the classical MS determinant
HLA-DRB1*15:01 is a risk allele in Ashkenazi. SNP-based
HLA analysis using validated imputed techniques revealed the well-known
HLA-DRB1*15:01- HLA-DQB1*06:02 association with risk was significant in Ashkenazi, but its frequency in Ashkenazi cases is significantly lower than the frequency in other European cases. The linked class I
HLA-B*38:01 and
HLA-C*12:03 alleles showed a nominally significant protective effect, which is in line with a previously described protective effect of
HLA-B*38:01 in a very large European study [
17]. Also relevant, a
HLA-B38 protective effect was detected in an Iranian MS population [
18]. The
HLA-A*68:02 allele showed a nominally significant risk effect. This allele belongs to multiple haplotypes [
19] and is linked to previously described class II risk alleles,
HLA-DRB1*13:01 [
6,
13],
HLA-DRB1*03:01 [
6] and
HLA-DRB1*15:03 in African Americans [
20].
To our knowledge, this is the first study to validate HLA imputation performed on Ashkenazi samples using a European reference population to train the model. We have seen that generally imputation works well for most alleles of most HLA genes, but works very poorly for specific alleles (for example, DRB1*11:01, see Additional file
3 for further examples), which represents a limitation of this study. Other studies using HLA imputation to derive HLA alleles for Ashkenazi would likely benefit from masking those specific alleles, rather than trying to set a single threshold on the confidence metric of imputation. Ideally, an all-Ashkenazi reference population would be used to train the model.
The historical record shows that Jewish people emigrated in mass from their ancestral home in the Eastern Mediterranean, beginning over two and a half millennia ago, establishing Jewish communities in many different regions across the globe. The contemporaneous Jewish population is generally grouped according to the most recent place of origin into two main groups, Ashkenazi (originating from Eastern, Central, and Northern Europe), and Non-Ashkenazi (from North Africa, the Middle East and Asia). Members of each group differ in physiognomy and life style suggesting significant admixture as the force driving Jewish population diversity. However, recent genome-wide assessment of multiple Jewish datasets note their considerable degree of genetic homogeneity and closeness to other populations of the Levant, especially the Druze and Palestinians. Our own data using primarily UK and American Ashkenazi genomes suggests a degree of genome-wide similarity between Ashkenazi and Mediterranean in the context of a primarily northwest European cohort consistent with previous findings. Portions of genetic susceptibility to MS in Ashkenazi are shared with Europeans (
HLA-DRB1*15:01 for example), while others are shared with another middle eastern population (
HLA-B*38 and HLA-C*12 for example), consistent with their previously reported shared ancestry [
9,
12].
'The non-HLA polygenic risk score conferring risk in Ashkenazi was lower in Ashkenazi cases than European cases, and, altogether, the previously described and validated risk alleles (DRB1*15:01 and genome-wide) explain a relatively smaller fraction of the genetic susceptibility to MS in Ashkenazi. Comparable differences were found between Ashkenazi controls and European controls, indicating that underlying differences in the healthy population can explain the apparent genomic differences in cases. The precise reason for the decreased concentration of MS susceptibility alleles in Ashkenazi Jews is unknown, and additional research is necessary to resolve the effects of selection and drift in the context of cultural isolation, admixture and migration. In this study, we also attempted to perform disease association analyses in a small Ashkenazi cohort. We found no evidence of SNP-level association using a genome-wide SNP-based analysis due most likely to lack of power, a rather important limitation of this study. Well-powered GWAS, re-sequencing and epidemiological studies in Ashkenazi datasets may provide a unique opportunity to further decipher the genetic and gene-environment underpinnings of MS.
Acknowledgments
Genetic data were provided by the International Multiple Sclerosis Genetics Consortium, the GeneMSA Consortium, and the Wellcome Trust Case–control Consortium. This study was supported by the National Institutes of Health (RO1NS26799 and R01NS49477). The funding body did not participate in collection, analysis, and interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication.
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Competing interests
The authors have no competing interests to declare.
Authors’ contributions
PK, TM, LM, PAG, SLH, SEB and JRO conceived and designed the study. PK, TM, LM, AL, LD and JM performed data analysis. PK, TM, LM, AL, JM and JRO drafted the manuscript. All authors reviewed and approved the final manuscript.