Genetic influence on brain phenotypes. Implications for disease mechanisms in severe mental disorders

Schizophrenia poses an evolutionary enigma. The disorder has existed throughout recorded human history and persists despite its severe effects on thought and behavior, and its reduced rates of producing offspring. A new study in Biological Psychiatry may help explain why?comparing genetic information of Neanderthals to modern humans, the researchers found evidence for an association between genetic risk for schizophrenia and markers of human evolution. ?This study suggests that schizophrenia is a modern development, one that emerged after humans diverged from Neanderthals,? said John Krystal, Editor of Biological Psychiatry. ?It suggests that early hominids did not have this disorder.? The cause of schizophrenia remains unknown, but researchers know that genetics play a significant role in the development. According to senior author Ole Andreassen from the University of Oslo in Norway and University of California, San Diego, some think that schizophrenia could be a ?side effect? of advantageous gene variants related to the acquisition of human traits, like language and complex cognitive skills, that might have increased our propensity to developing psychoses. Along with Andreassen, first authors Saurabh Srinivasan and Francesco Bettella, both from the University of Oslo, and colleagues looked to the genome of Neanderthals, the closest relative of early humans, to pinpoint specific regions of the genome that could provide insight on the origin of schizophrenia in evolutionary history. They analyzed genetic data from recent genome-wide association studies of people with schizophrenia for overlap with Neanderthal genomic information. The analysis indicates elevated susceptibility for schizophrenia in regions of the genome that likely underwent positive selection sometime after the divergence of humans and Neanderthals. Regions of the human genome associated with schizophrenia, known as risk loci, were more likely to be found in regions that diverge from the Neanderthal genome. An additional analysis to pinpoint loci associated with evolutionary markers suggests that several gene variants that have undergone positive selection are related to cognitive processes. Other such gene loci are known to be associated with schizophrenia and have previously been considered for a causal role in the disorder. ?Our findings suggest that schizophrenia vulnerability rose after the divergence of modern humans from Neanderthals,? said Andreassen, ?and thus support the hypothesis that schizophrenia is a by-product of the complex evolution of the human brain.?

Schizophrenia and bipolar disorder are severe mental disorders and major public health problems with unknown pathophysiology. Recently disease genes were discovered, and more are expected. Brain MR imaging has shown abnormalities in specific brain regions , and cognitive dysfunction is prevalent. We will take advantage of our existing datasets with genetic, brain MRI and neurocognition (TOP study n=800) and use a series of approaches to study brain dysconnectivity as an underlying disease mechanism across schizophrenia and bipolar disorder. We will i) define the connectivity phenotypes by analyzing collected functional MRI data and relate to structural MRI data. These phenotypes will be used to ii) determine behavioral and cognitive correlates to learn mor e about clinical function and disease subgroups, and iii) determine associations to the new disease genes to learn more about genetic architecture. We will develop new statistical methods to fully take advantage of the complex multi-dimensional datasets ( genetic and imaging). This will enable us to identify iv) new genetic mechanisms related to the core neuronal substrates of the disorders, and v) normal gene variants associated with physiological variation in brain phenotypes to identify subtle brain pat hology. We will have a core analytical group, with experts in biostatistics and bioinformatics, working in close collaboration with experts in imaging, cognition, clinical psychiatry and molecular genetics. The TOP sample will form the basis for the appro aches, together with replication samples from large international gene-consortia. We will do follow up studies of the TOP sample, genotype more subjects, and include the HUNT MRI sample (n=1000). Partners include UC San Diego, deCODE, Univ. North Carolina , Oslo Univ. Hosp., SFI Statistics, UIB and NTNU. The project will employ 3 post docs, and junior faculty is involved. The results will provide new understanding of the pathophysiology of severe mental disorders.