Genetic studies in MS are a vast mountain and not simply a mound, with sample sizes ranging into the thousands.
Climbers and mountaineers seek out free-standing mountains (i.e. mountains that are not part of a mountain range) as their relief from other peaks of equal height makes them an impressive sight to behold.
Do genetic studies have the same power to stand alone in MS?
This is the question that crops up time and again and those working on genetic studies would swear by them.
We have know that certain gene abnormalities in the chromosomal area that deals with immune function in fact increases the risk of MS. But, overall their effect size is small, with bulk of the contribution coming from environmental factors.
The gene with the most evidence is HLA-DRB1*15:01 in the major histocompatibility complex (MHC) region, a very immunologically relevant area. Antibodies in the CSF (oligoclonal bands or OCB) have also been associated with genetic factors over the years, being more prevalent in unaffected siblings of those with MS than healthy controls. And with large population based studies in Scandinavia and Italy demonstrating that HLS-DRB1*15:01 being associated with OCB positivity, whilst HLA-DRB1*04:04 being associated with OCB negativity.
This year in the largest study to date, spanning nine countries, researchers studied genetic factors associated with antibody production in the CSF (see below for abstract). They noted that gender was highly correlated with antibody status, with females having 1.12 fold higher IgG index, and 1.3 fold more likely to be OCB positive than males.
In terms of genetic associations, they found that genetic variants in the immunologically relevant MHC and IGHC (immunoglobulin heavy chain) regions influenced IgG index and OCB status.
It is therefore possible that individuals with and without antibodies are genetically distinct.
And therein lies your heritable risk.
Genetic variants are major determinants of CSF antibody levels in multiple sclerosis
Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index—the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10−16). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10−7). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10−37). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10−22), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10−6). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.