Editors' ChoiceHuman Genetics

Genetic study of schizophrenia returns the complement

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Science Translational Medicine  24 Feb 2016:
Vol. 8, Issue 327, pp. 327ec30
DOI: 10.1126/scitranslmed.aaf3851

Schizophrenia is a common psychiatric illness in which patients display varying forms of mental and behavioral dysfunction. The underlying cause of the disease remains unknown. Geneticists have long hoped that large-scale genome-wide association studies (GWAS) would point to specific biological pathways driving observed pathology. To date, GWAS have implicated over one hundred regions of the human genome associated with a possible risk for schizophrenia. However, inferring specific molecular and cellular alterations from these genetic hints has proved a major challenge. Sekar et al. now follow one of these genetic hints to discover a mechanism that may be contributing to brain alterations in patients with schizophrenia.

Variation in the major histocompatibility (MHC) locus is known to contribute to schizophrenia risk. This stretch of chromosome 6 encodes many genes, including human leukocyte antigen (HLA) genes, which are critical for antigen presentation and proper immune regulation, as well genes encoding complement component 4 (C4). Difficulty in pinpointing the nature of the genetic risk in the MHC had previously obscured the associated disease biology. Rather than looking for individual nucleotide variants that cause disease, Sekar et al. set out to examine how complex structural variation in the C4 genes may contribute to schizophrenia risk. Human genomes contain varying numbers of C4A and C4B genes that can be found in either “long” or “short” forms in the population. The authors now report that variation in the configuration of C4 alleles alters gene expression among individuals, and genotypes that increase C4 expression are associated with higher risk of developing schizophrenia.

Decoding the influence of structural variation on C4 gene expression suggested a link between the complement pathway and schizophrenia. The authors followed this lead and showed that C4 is found in human neurons. A mouse model of complement deficiency provided functional validation for a role of C4 in brain development. Mice lacking C4 showed evidence of impaired pruning of synaptic connections. The authors propose that an increase in C4 may be associated with schizophrenia risk in humans by driving excessive pruning of synapses during brain development.

Complex human diseases, especially conditions like schizophrenia that affect cognition, often cannot be easily modeled in rodents and other animals. Human genetics can provide unique clues to disease mechanisms, but experimental and analytical challenges in interpreting genome variation often limit progress. The new study by Sekar et al. provides insights into the effects of complex structural variants in the MHC locus and connects C4 dysregulation to schizophrenia pathology. Future studies will be required to determine whether the implicated complement C4 pathway—or other regulators of synaptic pruning—could be targeted therapeutically to treat schizophrenia.

A. Sekar et al., Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016). [Full Text]

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