Depressed? Your inner Neandertal may be to blame. Modern humans met and mated with these archaic people in Europe or Asia about 50,000 years ago, and researchers have long suspected that genes picked up in these trysts might be shaping health and well-being today. Now, a study in the current issue of Science details their impact. It uses a powerful new method for scanning the electronic health records of 28,000 Americans to show that some Neandertal gene variants today can raise the risk of depression, skin lesions, blood clots, and other disorders.

Neandertal genes aren’t all bad. “These variants sometimes protect against a disease, sometimes make people more susceptible to disease,” says paleogeneticist Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. Two other new studies identified three archaic genes that boost immune response. And most archaic genes that persist in humans were likely beneficial in prehistoric times. But some now cause disease because modern lifestyles and environments are so different.

Living people carry only trace amounts of Neandertal DNA, which makes its impact on health more striking. “The Neandertal genetic contribution to present-day people seems to have larger physiological effects than I would have naïvely thought,” says Pääbo, who helped launch this avenue of research by sequencing the first ancient genomes but was not involved in these studies. On average, Europeans and Asians have inherited about 1.5% of their genomes from Neandertals. Island Melanesians carry an additional 2% to 3% of DNA inherited from another extinct group, the Denisovans. Most Africans lack this archaic DNA because the interbreeding happened after modern humans left Africa.

By comparing the genomes of a few Neandertals and one Denisovan with people in the 1000 Genomes database, computational biologists have recently uncovered about 12,000 Neandertal gene versions, or haplotypes, in living Europeans and Asians. Researchers had clues to the function of a handful of these haplotypes—some were thought to be involved in the immune system, or the development of skin or hair, for example. But nailing down their precise function has required costly gene expression studies in tissue or animal models.

A breakthrough came when population geneticist Joshua Akey of the University of Washington, Seattle, and evolutionary genomicist Tony Capra of Vanderbilt University in Nashville independently realized that they could fish for Neandertal gene variants in a medical database, the Electronic Medical Records and Genomics (eMERGE) Network. This consortium in nine U.S. cities links patients’ genetic data with their medical data, in the form of specific billing codes that record diagnoses for illnesses and other conditions. Thus eMERGE allows researchers to track correlations between genes and symptoms in tens of thousands of people.

Akey and Capra joined forces and searched for more than 6000 Neandertal haplotypes in genetic data from 28,416 adults of European ancestry. After pinpointing chunks of DNA inherited from Neandertals, the team used statistical analysis to link possession of these archaic variants to a higher risk of the diseases or other traits captured in the billing data, Capra says.

The search netted a dozen Neandertal genes likely to cause significant risk of disease today. For example, one gene variant apparently makes blood more sticky and prone to coagulate. This fast clotting may have spelled the difference between life and death when Neandertals hunted dangerous animals or hemorrhaged after birthing big-brained babies. But it can also increase the risk of blood clots and strokes, which would have been much less common in prehistoric times when most people died young.

The researchers also found a number of Neandertal genes associated with neurological conditions, including depression, which can be triggered by disturbed circadian rhythms. Other variants were linked to precancerous skin lesions called actinic keratoses. Capra speculates that Neandertal brain chemistry and their skin responses to sunlight may both have been attuned to the light conditions and lifestyles of prehistoric Europe. The gene variants responsible may be maladaptive now that most people live by artificial light.

Other Neandertal alleles regulate the transport of thiamine, or vitamin B1, which metabolizes carbohydrates in cells of the gut. Neandertal diets, rich in meat and nuts, may have provided ample thiamine, but people munching processed foods today may not get enough, and having the Neandertal variant may predispose them to malnutrition, Capra speculates.

The study also revealed Neandertal genes associated with incontinence, bladder pain, and urinary tract disorders. And a single base change was associated with nicotine addiction, making it the second Neandertal allele found so far to boost the risk of tobacco addiction.

The Neandertal health legacy isn’t entirely negative. Two studies published in The American Journal of Human Genetics last month identified three archaic genes that boost the innate immune response, which helps defend against fungi and parasites as well as bacteria. All three have been strongly selected for in Europeans and Asians, says computational biologist Janet Kelso of Max Planck, lead author of one study. The three genes work together in subtle ways to regulate the expression of toll-like receptors on the surface of white blood cells, presumably boosting the innate response, says Lluis Quintana-Murci, a population geneticist at the Pasteur Institute and the French National Center for Scientific Research in Paris, lead author of the other study.

Such examples suggest that as modern humans entered new environments that harbored new pathogens, they took an evolutionary shortcut by picking up beneficial genes from other hominins. “You just borrow diversity from another species or population that had lived there longer,” Quintana-Murci says. Neandertals had at least 200,000 years to adapt to life in the Middle East and Europe before moderns got there.

But however beneficial in the Pleistocene and to people living in poor conditions today, even immune-boosting genes may have deleterious effects in the United States and Europe, where people face fewer parasites: Kelso found that the archaic receptor genes were strongly linked to allergies. “The price to pay today is that when you boost the immune response, it can be bad for us in terms of autoimmunity, inflammation, and allergies,” Quintana-Murci says.

Exactly how these genes affected Neandertals themselves is not always clear. “This doesn’t mean that Neandertals were depressed,” or had more skin cancer, cautions computational geneticist Sriram Sankararaman of the University of California, Los Angeles.

These studies are just the beginning, as researchers search for more Neandertal variants passed on in those ancient encounters, and broaden their databases of modern genomes to the hundreds of thousands. “We suspect there are many more Neandertal alleles floating out there,” Capra says.