Research press release


Nature Neuroscience

Rare damaging mutations increase risk for schizophrenia and decrease educational attainment in healthy individuals



今回、Steven McCarroll, Giulio Genoveseたちの研究チームとAndrea Gannaたちの研究チームは、血縁関係のない数千人の被験者(統合失調症と診断された者も含まれている)のエキソーム(タンパク質をコードするDNA塩基配列)を調べた。McCarrollとGenoveseの研究チームは、スウェーデン人12,332人のサンプルでわずか一度しか観察されておらず、精神疾患にかかっていない者の45,000点以上のエキソームからは検出されたことがない遺伝的変異に着目した。その結果、まれな機能障害性遺伝的変異が、統合失調症の患者全体での出現頻度が相対的に高く、変異したタンパク質が脳細胞のシナプスで特異的に発現し、他の種類の細胞や器官では発現しなかったことが明らかになった。



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.

doi: 10.1038/nn.4402

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