Mutations in a single gene that increase risk of schizophrenia and other neurodevelopmental disorders are reported in a study published online this week in Nature Neuroscience. Although this is the first study to identify a single risk gene with rare, damaging mutations in schizophrenia, further work is needed to explore how similar changes in the same gene can lead to a variety of related, but distinct, disorders.
Schizophrenia and related disorders arise from a combination of relatively common genetic changes that have small effects on an individual’s disease risk and rarer genetic changes - sometimes only found in single families or patients - that have a larger effect on disease risk. Recent large studies with tens of thousands of participants have identified over one hundred regions in the genome that contain common genetic changes related to schizophrenia. Up until now, however, no study has unequivocally found single genes with rare changes associated with disease risk.
Jeffrey Barrett and colleagues sequenced the protein-coding regions of the genome from 8,534 participants with and without schizophrenia from UK and Finnish populations and combined this with existing data from a Swedish study of 5,074 participants also with and without schizophrenia, as well as 1,078 more participants with schizophrenia from a collection of family studies. They found SETD1A, a gene that regulates changes to chromosomes that control gene expression, was the only gene across the entire genome to statistically have more damaging mutations in people with schizophrenia than in people without. Similar mutations in this gene were rare among another 45,376 participants without schizophrenia, whereas mutations in SETD1A were more frequent among 4,281 other participants with severe developmental disorders that included intellectual disability.