Progress on MS, and a somewhat typical genetics story

Multiple sclerosis (MS) is yet another chronic often devastating disease for which cause is not known.  Some epidemiological studies suggest an infectious cause, since cases often clusters geographically, but the fact that prevalence tends to increase with distance from the equator in childhood or adolescence has suggested to other researchers a link with sunlight exposure, and thus perhaps to vitamin D deficiency, because sunlight is important to vitamin D synthesis.  Because causation isn't clear, many also suggest a gene-by-environment interaction, in which some genetic variants react differently to a given environmental factor than other variants do.  And now a new study, reported all over the web, including here, and published in the Annals of Neurology (here, with subscription), reports a genetic link to vitamin D and risk of MS.

MS is an autoimmune disease characterized by degradation of the myelin sheath that surrounds and protects nerve cells.  The sheath is like insulation in electric wires, and protects the nerve signal from dissipating as it travels from the brain to where its action is triggered.  Nerve damage occurs due to the inflammation that happens when the body's immune cells attack the nervous system, interrupting the signals sent along the affected nerves.  Sex and age are related to risk, and among sufferers the symptoms vary widely, depending on which nerves are damaged.  Prognosis also varies widely, and is difficult to predict.  Many studies, including but long before GWAS, have found HLA class II genes, and others with modest effect, but the effect varies by whether cases are sporadic or familial.  This all suggests that the disease is heterogeneous, with varied causation -- not at all unusual for complex chronic diseases (nor even for 'simple' genetic disease).   

The aim of the study just reported, carried out by Oxford researchers in collaboration with colleagues at the University of Ottawa in Canada, was to look for rare genetic variants that might explain the excess of cases in some of the 30,000 families participating in a Canadian study of MS, although they do point out that shared family environment could be important.  They began by sequencing the exomes -- all the gene coding regions -- of a randomly selected affected individual from 43 of the 82 families with four or more members with MS (a fairly rare occurrence given that there seems to be a genetic component to risk).  Using families with multiple affected members is well-known to increase the likelihood of finding relative simple and tractable genetic causation.  They didn't in fact find any shared rare variants in this way, so they then focused on MS genes identified in previous GWA studies they had done, that is, comparing cases with unrelated controls.

This eventually led them to zero in on a single change in the CYP27B1 gene that was shared by at least one unaffected parent in the multiply affected families, and by all the affected members.  This is a candidate gene previously tentatively suggested by a GWA study.  They used data from 3046 additional parent-affected child trios, 422 parent-affected sibling pairs and 1873 healthy individuals (in total 12,579 people) from their study to replicate their results.  

As reported in the story in MedicalExpress, the lead author, George Ebers at Oxford, concluded:

"The odds are very much less probable than being hit by lightning", he said. "Is this gene variant causative in multiple sclerosis? Pretty much! The cornerstone for causation has always been the strength of association."

Further, this mutation is known to be associated with low levels of vitamin D, which implies that MS is somehow linked with vitamin D levels.  In the rare instances when people have 2 copies of this variant, they also have rickets, which is also associated with vitamin D levels.   From the conclusion to the paper:

Most biological effects of vitamin D are mediated by calcitriol acting via the vitamin D receptor (VDR). We have previously shown that vitamin D regulates more than 80% of MS associated genes 25, and thus it is likely that lower levels of calcitriol as a result of CYP27B1 mutations leads to a disruption to critical gene-environment interactions important for the developing immune or nervous system which then predisposes to MS.

Indeed, because there are unaffected family members with the mutation -- it was present in 33% of genotyped unaffected family members -- clearly any genetic cause here is more complex than one-to-one.  Or, in rather imprecise genetic jargon, it's "incompletely penetrant".  And indeed, it's a rare variant, present in only a subset of people with MS.  And, clearly, if there is a vitamin D component to causation, it's also not one-to-one, because while prevalence of MS is higher in higher than lower latitudes, it's still a fairly rare disease, even in people with low levels of vitamin D.  The idea of the latitude effect has long been thought to involve sunlight exposure amounts, but other things are correlated with latitude, including immune exposures.  So, as with most complex chronic diseases, causation doesn't come down to simply one mutation or one environmental factor.

The study does appear to implicate vitamin D biology, though in a curious way since the penetrance even of the clearest alleles is far from complete. There are either many pathways to MS, or there is a specific as yet unspecified subset of the diseases with this causation.  It's not really clear what fraction of risk this new gene explains, but the point is not that the gene 'for' MS has been found, but that this particular mutation is associated with low vitamin D levels, as well as some risk of MS.  The roughly 4-1 female-male sex ratio for MS in general, and its usually adult onset, and highly variable pathology all point to very stochastic (probabilistic) effects and/or cofactors that mean there is still much to learn.   But this may be a case where GWAS have made a somewhat greater than usual contribution to risk, not by identifying genes with strong effects but rather by suggesting a train of thought that may perhaps lead to more systematic understanding of a devastating disease.