In 2004, I was an enthusiastic postdoctoral researcher in Eric Lander’s lab at the Broad Institute, with the job I had dreamed of since I was 10 years old. Growing up in Paducah, KY, I read Isaac Asimov’s The Genetic Code. And while I understood nothing of its meaning, I fell in love with the idea of being a human geneticist when I grew up.
I had a particular disease passion that had also been part of the plan since that time: autoimmune genetics. You see, I have a remarkable family. Nearly one-third of my relatives within 3 degrees have an autoimmune disorder. Even at my young age, I somehow knew those weren’t good odds. I knew that “things run in families” and that my family seemed to have autoimmunity in spades. You can imagine my surprise when 20 years afterwards, I realized I was, in fact, a human geneticist in the most renowned tank of genomic thinkers around studying autoimmune disease.
It was a thrilling time to be a geneticist. The human genome sequence was complete. The first thorough map of variation in the genome (single nucleotide polymorphisms or SNPs) was nearly complete. Unconstrained by data to the contrary, it felt like we were turning a corner to truly identify the variation that conferred risk to disease.
But in May of 2004, I began to get very nervous because of an unexpected result we found with one of the most talented teams of autoimmune geneticists in existence: the International Multiple Sclerosis Genetics Consortium. Parenthetically, these folks are absolutely who you want at the front lines of genomic inquiry. They are dogged, thoughtful, and careful about the research they do.
At that time, we were following up on one of the key variants that conferred risk to multiple sclerosis or MS: HLA-DRB1-0201 (or “DR2”). As background, about 40 percent of all patients with MS have the DR2 variation in their genome. By comparison, only 20 percent of the general population has this variant. When you run the statistics, it turns out that this is probably one of the strongest associations in all of autoimmune genetics. So it seemed very reasonable to all of us involved that if we gathered enough patients who had MS and looked separately at the patients with and without DR2, we would expect that we might uncover that there were two types of MS.
To imagine this hypothesis, I visualize genetic “skylines.” While MS may appear to be a “single” disease population based on clinical measures, we hypothesized that the disease resulted from two different genetic skylines. Our experiment was to determine whether
