Farmers in the highlands of southern Ethiopia scratch out a subsistence living from the region\'s volcanic red clay. The soil supports the farms, but fine-grained, volcanic rock particles in the dirt threaten the farmers and their families. Continual exposure of bare feet to the volcanic soil causes 1 in 20 people to develop a painful inflammation of the lower extremities that, over time, leads to foot disfigurement. Doctors call it podoconiosis. The locals call it mossy foot. And those affected suffer social stigma as well as debilitating discomfort. Now, researchers think they know why some 4 million people in at least 10 countries worldwide develop this incapacitating condition. One-fifth carry genetic variants that cause their immune system to react to the volcanic dust. This disease-producing response, triggered by exposure from the lack of shoes, provides a dramatic example of the interaction between genes and the environment. Writing in the March 29, 2012 New England Journal of Medicine, an international team that includes researchers from the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, describes the genetic link that turns dirt into a toxin. \"This study draws attention to a neglected tropical disease with a devastating impact on poor people and their communities,\" said NHGRI Scientific Director Dan Kastner, M.D., Ph.D. \"It demonstrates the global reach of genomics research into the lives of people in parts of the world where endemic diseases very often go unchecked.\" Doctors have known for a long time that podoconiosis runs in families and that continual exposure to volcanic soil triggers it. Wearing shoes and socks, or even washing off the dirt, prevents the condition. But doctors have been perplexed that only some people develop the disease, while others with the same environmental exposure are spared. To sort this out, the international collaborators conducted a genome-wide association study - or GWAS - analyzing DNA from 194 volunteers from the Ethiopian highlands affected by podoconiosis, along with DNA from another 203 unaffected individuals from the same region. The researchers collaborated with field workers from the non-profit Mossy Foot Treatment and Prevention Association in southern Ethiopia to collect the data and samples. The researchers generated a dataset from study-participant DNA, screening more than 550,000 single-nucleotide polymorphisms (SNPs), which are sites in an individual\'s DNA that contain a different chemical base when compared to a standard reference human genome sequence. They found significant podoconiosis association for eight SNPs within or nearby a stretch of DNA on chromosome 6, called the HLA class II locus. The researchers performed a second validation step, called a family-based association study, using DNA samples from 202 sets of child-parent trios from affected families. The researchers detected six SNPs that showed significant association - those that mapped to HLA class II region genes and most strongly associated with podoconiosis in the GWAS, validating the GWAS results.