The initial discovery was made in a sample of 289 psychiatric patients and controls from the Norwegian Thematically Organized Psychosis research project (TOP), led by Ole Andreassen from the University of Oslo, principal investigator of the Norwegian branch of the international research team. The most significant findings were then replicated in a sample of 655 healthy and demented patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the largest Alzheimer's disease study ever funded by the National Institutes of Health. The Norwegian sample was ethnically homogenous; the ADNI sample was ethnically diverse. According to the researchers, the fact that reported associations were found across two independent studies, including healthy controls and various patient groups, shows that these effects are likely to be independent of population or disease.

Highly significant associations were found between cortical surface area and polymorphisms in possible regulatory regions near the gene CDK5RAP2. This gene codes for a protein involved in cell-cycle regulation in neuronal progenitor cells - cells that migrate to the cerebral cortex during the second trimester of gestation and eventually become fully functioning neurons. The cerebral cortex is the outer layer of the brain, often referred to as "gray matter." The most highly developed part of the human brain, the cerebral cortex is responsible for higher cognitive functions, such as thinking, perceiving, producing and understanding language, some of which is considered uniquely human.

Similar but less significant findings were made for polymorphisms in two other microcephaly genes, known as MCPH1 and ASPM. All findings were exclusive to either males or females but the functional significance of this sex-segregated effect is unclear.

"One particularly interesting feature of this new discovery is that the strongest links with cortical area were found in regulatory regions, rather than coding regions of the genes," said Andreassen. "One upshot of this may be that in order to further understand the molecular and evolutionary processes that have determined human brain size, we need to focus on regulatory processes rather than further functional characterization of the proteins of these genes. This has huge implications for future research on the link between genetics and brain morphology."