Genetics’ Contribution To Multiple Sclerosis Risk Among Ashkenazi Jews Investigated

An Open Access research article published in the journal BMC Medical Genetics notes that multiple sclerosis (MS) has a strong genetic component, observing high MS prevalence in European populations including those of Ashkenazi Jewish origin, and low in African and Asian populations also including those of Jewish origin. MS is an autoimmune disease of the central nervous system. The paper’s authors report that more than 100 genetic loci have been implicated in susceptibility to MS among European populations — the most prominent of these being the 15:01 allele of the HLA-DRB1 gene.

The article, entitled “Genetic contribution to multiple sclerosis risk among Ashkenazi Jews” (BMC Medical Genetics 2015, 16:55 doi:10.1186/s12881-015-0201-2 ), is coauthored by Pouya Khankhanian, Lohith Madireddy, Antoine Lize, Lennox Din, Jayaji M. Mor, Pierre-Antoine Gourraud, Stephen L Hauser, Sergio E. Baranzini, and Jorge R. Oksenberg of the University of California at San Francisco’s Department of Neurology, and Takuya Matsushita of the Kyushu University School of Medicine’s Graduate School of Medical Sciences in Fukuoka City, Japan.

Historically Jewish people emigrated en masse from their ancestral home in the Eastern Mediterranean, an exodus known as the Diaspora that began over two and a half millennia ago, and which established diverse Jewish communities in many different regions around the globe. Contemporaneous Jewish populations are 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 (hailing from North Africa, the Middle East and Asia). Members of each group respectively differ in physiognomy and lifestyle, suggesting significant admixture as the force driving Jewish population diversity. However, recent genome-wide assessment of multiple Jewish datasets note a considerable degree of genetic homogeneity and closeness to other populations of the Levant, especially the Druze and Palestinians.

Ashkenazi Jewish origins have been traced to Israelite tribes of Canaan in the Middle East, members of which are believed to have begun settling along Germany’s Rhine River region and Western France during the early Middle Ages. The term “Ashkenazim” is today applied to descendants of that demographic, including those who established communities in Eastern and Central Europe from the 11th through the 19th Centuries, notably in what are now Bohemia, Hungary, Poland, Belarus, Lithuania, Russia, Ukraine, and Romania, and who are thought to account for about 80 percent of the world’s Jews today — down from a peak of about 92 percent in the early 1930s.

The name Ashkenazi derives from the biblical figure Ashkenaz, first son of Gomer, and a Japhetic patriarch in the Table of Nations (Genesis 10), whose kingdom of Ashkenaz was first associated with the Scythian region. Jews living in Eastern Europe identified with Ashkenaz’s kingdom and came to call themselves the Ashkenazi, with Jews from Western and Central Europe later also coming to be called Ashkenazi because the main centers of Jewish learning were located in Germany where they developed Yiddish, a High German language written using the Hebrew alphabet, and heavily influenced by classical Hebrew and Aramaic which during the Middle Ages became the lingua franca among Ashkenazi Jews, and the term “Ashkenaz” came to be identified primarily with German customs and descendants of German Jews.

According to the Encyclopaedia Judaica, during the 10th and 11th Centuries Ashkenazim formed a merchant class in Germany and France, and were treated well because of their trading connections with the Mediterranean and the East. Consequently Jewish communities appeared in many urban centers, where, until Christian guilds were formed, Jews were the craftsmen and artisans, while in France many Jews owned vineyards and made wine. The Medieval Askenazi carried arms and knew how to use them in self-defense, with the Jews of each town constituting an independent, self-governing entity, establishing its own regulations adjudicated by an elected board and judicial courts, who enforced their rulings with the threat of excommunication, with the Ashkenazim generally shying away from outside influences and concentrating on internal Jewish sources, ideas and customs.

Because of their relative genetic homogeneity, Ashkenazi Jews are also more susceptible to roughly 20 to 30 genetic diseases, including multiple sclerosis, than the general population, and many are carriers for at least one illness inherited diseases due to inherited genetic mutations and traits. According to the Philadelphia-Based Victor Center for the Prevention of Jewish Genetic Diseases there are 19 preventable genetic diseases with a 1 in 4 carrier rate among Jews. The Victor Center, which also has offices in Boston, Miami and Pittsburgh, and community partnerships in Atlanta, Birmingham and Dallas provides full service genetic counseling and screening to all interested individuals and couples. Genetic counseling and screening for Jewish genetic diseases is offered both in the office and through the community screenings.

The BMC Medical Genetics researchers identified and extracted data on a total of 213 Ashkenazi MS cases and 546 ethnically matched healthy control individuals from two previous genome-wide case-control association analyses, and 72 trios (affected pro band and two unaffected parents) from a previous genome-wide transmission disequilibrium association study, using genetic data to define Ashkenazi traits. They compared the pattern of genetic risk between Ashkenazi and non-Ashkenazi Europeans, and also sought to identify novel Ashkenazi-specific risk loci by performing association tests on the subset of Ashkenazi cases, controls, probands, and parents from each study.

The investigators found the HLA-DRB1*15:01 allele and the non-HLA risk alleles were present at relatively low frequencies among Ashkenazi and explained a smaller fraction of the population-level risk when compared to non-Ashkenazi Europeans. Alternative HLA susceptibility alleles were identified in an Ashkenazi-only association study, including HLA-A*68:02 and one or both genes in the HLA-B*38:01-HLA-C*12:03haplotype. The genome-wide screen in Ashkenazi did not reveal any loci associated with MS risk.

The paper’s coauthors propose that these results suggest genetic susceptibility to MS in Ashkenazi Jews has not been as well established as that of non-Ashkenazi Europeans, which they maintain implies value in studying large well-characterized Ashkenazi populations in order to accelerate gene discovery in complex genetic diseases.

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Multiple sclerosis (MS), an autoimmune disease with central nervous system pathology, is the most common cause of non-traumatic neurological disability in young adults, estimated to affect approximately 2.5 million people worldwide. The researchers observe that the MS global burden has increased over the past century but retains well-known influences of gender, geographical latitude, and ancestry on risk of developing the disease — factors reflected in the relatively high MS incidence among some population groups (particularly in persons of European origin) compared with others (eg: African and Asian groups). Likewise, high MS frequency rates are found in Scandinavia, Iceland, the British Isles and North America (rates of about 12 in 1,000), but with lower frequencies of MS being observed in the Mediterranean Basin (0.5 in 1000).

However, they note that exceptions to the European prevalence gradient have been documented, such as in the Italian island of Sardinia where MS prevalence of is among the highest in the world (1.4/1,000). Similarly, Ashkenazi Jews in Israel (and the Diaspora) are at high risk for developing MS. The researchers observe that the distinctive population histories of Sardinians and Ashkenazi Jews include founder effects, admixture, and bottlenecks, suggesting that unique genetic signatures underlie their differential susceptibility to the disease, and observe that unraveling these profiles could potentially provide important insights into the genetics of MS and the disorder’s interactions with non-genetic factors, noting an extensive body of empirical evidence confirming genetic variation as a key contributor to and determinant of MS risk.

The coauthors reference a range of genome-wide association studies (GWAS) that have been completed and reported, including a multi-center effort with nearly ten thousand cases, noting that as expected, each identified genetic variant conferred only modest odds ratios, and that these studies have focused on datasets ascertained in Europe, Australia and North America that included affected Ashkenazi individuals. While Jewish populations in the Diaspora can be grouped into distinct genetic clades shaped by admixture with local populations and social and cultural forces, they nevertheless all maintain their ancestral Eastern Mediterranean and Middle Eastern genomic identity, which contrasts significantly with the genetic backgrounds of the majority of central and northern European populations. In this study the investigators seek to clarify the genetic characteristics of MS in Ashkenazi Jews.

Noting that previous studies reported an association of the HLA-DRB1*15:01 gene with MS among Ashkenazi Jews living in Israel, albeit with reduced odds ratios compared to Europeans, the HLA-DRB1*13:03 allele was the strongest genetic biomarker of risk in a study of non-Ashkenazi Israelis, but was not confirmed in Ashkenazi Israelis. In their study, the paper’s coauthors used 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. They next illustrated the genetic relationship of the Ashkenazi subsets to the other European sub-populations, and compared 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, they performed case control and TD tests for SNPs across the genome and at classical HLA alleles in the Ashkenazi subset.

Initially defining Ashkenazi subjects from three previous multiple sclerosis studies: two genome-wide case control association studies (GENEMSA and WTCCC2) and one genome-wide transmission disequilibrium (TD) trio study, they describe the status of Ashkenazi Europeans within the genetic landscape composed of other European populations, comparing selected clinical characteristics of Ashkenazi to non-Ashkenazi Europeans using available data in the GENEMSA dataset. They then proceeded to examine the MS genetic risk burden in Ashkenazi using previously identified MS susceptibility variants. Due to the unique properties of the HLA risk compared to the genome-wide risk, the researchers were able to assess HLA risk before evaluating the genome-wide genetic burden, comparing Ashkenazi MS cases to Ashkenazi controls in order determine whether previously identified risk alleles apply to the Ashkenazi population — and comparing MS risk attributable to previously-identified genetic susceptibility loci between Ashkenazi and non-Ashkenazi Europeans. Finally, they sought to identify Ashkenazi-specific risk loci.

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The coauthors cite some intriguing differences identified in an array of studies referenced, such as significantly lower multiple sclerosis severity score among Ashkenazi, and lower rates of motor weakness and acute transverse myelitis that they say require confirmation in studies with larger datasets. They also reference a 2006 survey of MS frequency in Israel in which highest MS rates were found in Israeli-born Jews and in Jewish immigrants from Europe/America, with prevalence similar to that seen in Europeans. 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), while Moslem Arabs, Druze, and Bedouins had the lowest rates of MS.

In their study, which the researchers say is to their knowledge the first to validate HLA imputation performed on Ashkenazi samples using a European reference population to train the model extracted Ashkenazi individuals using genetic data from three datasets, they note that a key limitation is sample size, with the small number of identified Ashkenazi individuals leaving little latitude for discovery of new variants, especially at the genome-wide level. Another limitation is the small sample size of the well-characterized Ashkenazi controls used to help define Ashkenazi from within their MS datasets. They suggest that a larger set of well-characterized controls may allow identification of more Ashkenazi individuals, and may make the identification more reproducible across future studies.

The investigators report that their 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. Comparable differences were found between Ashkenazi controls and European controls, indicating that underlying differences in the healthy population can explain apparent genomic differences in cases, with the precise reason for the decreased concentration of MS susceptibility alleles in Ashkenazi Jews being unknown, and additional research will be necessary to resolve the effects of selection and drift in the context of cultural isolation, admixture and migration.

The complete electronic version of this Open Access article can be found online at:
https://www.biomedcentral.com/1471-2350/16/55

Genetic data were provided by the International Multiple Sclerosis Genetics Consortium, the GeneMSA Consortium, and the Wellcome Trust Casecontrol 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.

More background on this topic can be found in an article by Alastair Compston entitled “Genetic epidemiology of multiple sclerosis,” which can be accessed online (PDF) here:
https://jnnp.bmj.com/content/62/6/553.full.pdf

Sources:
BMC Medical Genetics
Encyclopaedia Judaica
The Victor Center