In the animal kingdom, humans are known for our big brains. But not all brains are created equal, and now we have new clues as to why that is. Researchers have uncovered eight genetic variations that help determine the size of key brain regions. These variants may represent “the genetic essence of humanity,” says Stephan Sanders, a geneticist and pediatrician at the University of California, San Francisco, who was not involved in the study.These results are among the first to come out of the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) collaboration, involving some 300 scientists from 33 countries. They contributed MRI scans of more than 30,000 people, along with genetic and other information, most of which had been collected for other reasons. “This paper represents a herculean effort,” Sanders says.Only by pooling their efforts could the researchers track down subtle genetic influences on brain size that would have eluded discovery in smaller studies. “We were surprised we found anything at all,” says Paul Thompson, a neuroscientist at the University of Southern California in Los Angeles. 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One region, the hippocampus, stores memories and helps one learn. Another, called the caudate nucleus, makes it possible to ride a bike, play an instrument, or drive a car without really thinking about it. A third is the putamen, which is involved in running, walking, and moving the body as well as in motivation. The researchers did not try to examine the neocortex, the part of the brain that helps us think and is proportionally much bigger in humans than in other animals. The neocortex has crevices on its surface that look so different from one individual to the next that it’s really hard to measure consistently across labs.There’s a strong link between the sizes of many of these parts of the brain and overall cognitive ability, Thompson says. “Having more brain tissue is better.” Diseases such as Alzheimer’s damage the hippocampus, while Parkinson’s, for example, impairs the putamen.The team discovered eight “letter” differences that can shrink brain tissue by about 1.5%, depending on the letter inherited, Thompson and his colleagues report online today in Nature. Some of the letter variants were inside a gene, while others were near key genes.The most influential gene pinned down, KTN1, helps tell brain cells where to go in the putamen. Two additional variants in the putamen are associated with genes that can cause colon or immune system cancers and seem to regulate the number of cells in that brain region. The remaining five genes do various things, including inhibit programmed cell death, a natural process that can cause brain regions to shrink if it goes unchecked.Many of the eight genes are active during brain development and may play a role in neuropsychiatric disorders such as autism and schizophrenia, Sanders says. He hopes ENIGMA researchers will next look to see if there are links between a particular brain region’s size and one of these disorders. At this point, a genetic test for these variants won’t be much help in the clinic, says Faraneh Vargha-Khadem, a developmental cognitive neuroscientist at University College London who was not involved with the work. To diagnose patients, “you go not by what’s inside the brain or what’s inside the gene, but by what symptoms the patient is showing,” she says. Still, “it’s good to know that these structures have genetic variation,” she says. “It alerts physicians to the relationship between genes, brain structure, and behavior,” a relationship that may one day become useful to clinicians.