Published: 04-10-2016 13:04 | Updated: 04-10-2016 16:02

Ultra-rare disruptive and damaging mutations influence educational attainment in the general population

(This is the press release from Nature Neuroscience)

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 who 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 genes 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 (observed once in their sample and never in over 65,000 exomes) 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 3 less months of education. When the authors looked at those genes expressed in the brain, then the impact of one of these mutations increased to 6 months fewer 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.

A.G. is supported by the Knut and Alice Wallenberg Foundation (2015.0327) and the Swedish Research Council (2016-00250). M.G.N. is supported by the Royal Netherlands Academy of Science Professor Award (PAH/6635) to Dorret I. Boomsma. V.S. was supported by the Finnish Foundation for Cardiovascular Research. This study was supported by grants from the National Human Genome Research Institute (U54 HG003067 and R01 HG006855); the National Institute of Mental Health (1U01MH105666-01 and 1R01MH101244-02); the National Institute of Diabetes and Digestive and Kidney Disease (1U54DK105566-02); the Stanley Center for Psychiatric Research; the Alexander and Margaret Stewart Trust; the National Institutes of Mental Health (R01 MH077139 and RC2 MH089905); the Sylvan C. Herman Foundation; EU H2020 grants 692145, 676550 and 654248; Estonian Research Council Grant IUT20-60, NIASC, EIT–Health; NIH-BMI Grant No. 2R01DK075787-06A1; and by the EU through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012 GENTRANSMED).


Neuroscience: 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, Published online 03 October 2016 doi:10.1038/nn.4404, and doi:10.1038/nn.4402