Editors' ChoiceHuman Genomics

Decoding Schizophrenia

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Science Translational Medicine  17 Aug 2011:
Vol. 3, Issue 96, pp. 96ec130
DOI: 10.1126/scitranslmed.3003032

Schizophrenia is a common, highly heritable disease characterized by hallucinations and delusions of grandeur, among many other symptoms. An individual with an affected parent is 10 times more likely to develop the condition than is someone with healthy parents. On the other hand, in genetically identical twins schizophrenia occurs in only one of the pair over 50% of the time, suggesting nongenetic influences on the disease. Further obfuscating the genetic landscape are several recent genome-wide association studies that have failed to explain the missing heritability of this complex trait.

In an effort to help clarify this genetic variability, Girard and colleagues report results from sequencing the exome (the protein coding portion of the genome) of 14 people with sporadic schizophrenia and their unaffected parents. The authors performed exome capture with a commercially available kit and sequencing on the Illumina Genome Analyzer II. They excluded structural genetic variants as contributors to the disease in these patients by also assessing gene copy number variants.

A total of 15 single, de novo mutations were identified in eight of the 14 patients, with none detected in the remaining six. Four of the variants resulted in a nonsense mutation that truncated the protein products of their corresponding genes by 50 to 190 amino acids. Notably, the gene products of these four genes (ZNF480, KPNA1, LRP1, and ALS2CL) regulate biologic processes critical to, among others, autoimmunity, Alzheimer’s disease, amyotrophic lateral sclerosis, and coronary artery disease. The nonsense-to-missense mutation ratio observed in this population (4:15) is far greater than the 1:20 ratio that would be expected to occur by chance. Moreover, the missense mutations in the patients were in otherwise conserved genomic regions, indicating that the de novo mutations probably alter protein function and contribute to disease pathology.

On the basis of these data, it appears that searching for rare, de novo disease-causing mutations may be an effective approach to illuminating the genetic underpinnings of schizophrenia. A recent study of individuals with mental retardation and their parents yielded results analogous to these, with nine de novo variants discovered in seven trios. Going forward, these tantalizing studies need to be augmented with more in-depth mechanistic analyses before a final verdict can be made on the role of de novo mutations in conditions such as schizophrenia and related psychiatric conditions.

S. L. Girard et al., Increased exonic de novo mutation rate in individuals with schizophrenia. Nat. Genet. 7 August 2011 (10.1038/ng.886) [Abstract]

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