Very rare genetic mutations that disrupt the function of genes are common in patients with schizophrenia and are also associated with fewer months of formal education in healthy individuals, report two independent papers published online this week in Nature Neuroscience. However, since many cognitive, personality and psychological factors also influence educational attainment, it is unknown which of these are affected by this collection of mutations.
Genetic changes that are common in the population contribute to variation in traits such as cognitive function and also risk for psychiatric disorders such as schizophrenia. Damaging genetic changes have been made rare through natural selection, which makes it more difficult to assess their contribution to disease.
To investigate the impact of rare damaging mutations, Steven McCarroll, Giulio Genovese and colleagues and Andrea Ganna and colleagues examined the protein coding sequences of DNA (or exomes) in thousands of unrelated individuals, some of whom have been diagnosed with schizophrenia. McCarroll and Genovese's group focused on mutations that were observed only once in their sample of 12,332 Swedish individuals and never in a large collection of over 45,000 exomes of individuals without psychiatric disorders. They found that rare damaging mutations were more common in patients in schizophrenia overall and that the affected proteins were expressed specifically in the synapses of brain cells and not in other cell types or organs.
Ganna's group assessed the relationship between rare damaging mutations and years of educational attainment among 14,133 individuals from Sweden, Estonia and Finland. They focused on a set of genes that are very sensitive to changes in their DNA and do not have many mutations in the general population. Each damaging mutation in one of these genes was associated with three fewer months of education. When the authors looked at those genes expressed in the brain, the impact of one of these mutations increased to six fewer months of education.
Although the authors investigated thousands of individuals, their sample sizes are still too small to implicate any one gene with a rare mutation contributing to schizophrenia or less education. Larger studies are needed to pinpoint specific genes and specific brain processes as well as to assess the overlap between rare genetic risk for psychiatric disease and typical variation in cognitive function.
Articles: Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia, Giulio Genovese, Menachem Fromer, Eli A Stahl, Douglas M Ruderfer, Kimberly Chambert, Mikael Landén, Jennifer L Moran, Shaun M Purcell, Pamela Sklar, Patrick F Sullivan, Christina M Hultman & Steven A McCarroll, Nature Neuroscience, doi:10.1038/nn.4402, published online 3 October 2016.
Ultra-rare disruptive and damaging mutations influence educational attainment in the general population, Andrea Ganna, Giulio Genovese, Daniel P Howrigan, Andrea Byrnes, Mitja I Kurki, Seyedeh M Zekavat, Christopher W Whelan, Mart Kals, Michel G Nivard, Alex Bloemendal, Jonathan M Bloom, Jacqueline I Goldstein, Timothy Poterba, Cotton Seed, Robert E Handsaker, Pradeep Natarajan, Reedik Mägi, Diane Gage, Elise B Robinson, Andres Metspalu, Veikko Salomaa, Jaana Suvisaari, Shaun M Purcell, Pamela Sklar, Sekar Kathiresan, Mark J Daly, Steven A McCarroll, Patrick F Sullivan, Aarno Palotie, Tõnu Esko, Christina M Hultman & Benjamin M Neale, Nature Neuroscience, doi: 10.1038/nn.4404, published online 3 October 2016.