Abstract
Schizophrenia is a complex psychiatric disorder with high genetic heterogeneity, however, the contribution of rare mutations to the disease etiology remains to be further elucidated. We herein performed exome sequencing in a Han Chinese schizophrenia family and identified a missense mutation (c.6724C>T, p.R2242C) in the teneurin transmembrane protein 4 (TENM4) gene in the SCZD2 locus, a region previously linked to schizophrenia at 11q14-21. The mutation was confirmed to co-segregate with the schizophrenia phenotype in the family. Subsequent investigation of TENM4 exons 31, 32, and 33 adjacent to the p.R2242C mutation revealed two additional missense mutations in 120 sporadic schizophrenic patients. Residues mutated in these mutations, which are predicted to be deleterious to protein function, were highly conserved among vertebrates. These rare mutations were not detected in 1000 Genomes, NHLBI Exome Sequencing Project databases, or our in-house 1136 non-schizophrenic control exomes. Analysis of RNA-Seq data showed that TENM4 is expressed in the brain with high abundance and specificity. In line with the important role of TENM4 in central nervous system development, our findings suggested that increased rare variants in TENM4 could be associated with schizophrenia, and thus TENM4 could be a novel candidate gene for schizophrenia in the SCZD2 locus.
Highlights
Schizophrenia (OMIM 181500) is a complex psychiatric disorder, and is a public health problem affecting approximately 1% of the world population, leading to reduced life expectancy by an average of 20–25 years (Tiihonen et al, 2009)
We conducted exome sequencing in a threegeneration family affected by schizophrenia, and identified a novel candidate gene TENM4 in a linkage locus schizophrenia disorder 2 (SCZD2) at 11q1421
One missense mutation cosegregated with the schizophrenia phenotype, and two more missense mutations were detected in unrelated sporadic schizophrenic patients
Summary
Schizophrenia (OMIM 181500) is a complex psychiatric disorder, and is a public health problem affecting approximately 1% of the world population, leading to reduced life expectancy by an average of 20–25 years (Tiihonen et al, 2009). And twin studies have demonstrated a strong genetic component in schizophrenia with heritability estimated to be 60–80% (Sullivan et al, 2003; Shih et al, 2004). High heritability in the disease underlines substantial effects from genetic variants. The frequency of these of alleles ranges from common to extremely rare. Common variants associated with schizophrenia have been widely studied by candidate gene association studies (Stefansson et al, 2002; Chen et al, 2009a, 2) and genome-wide association studies (GWASs) (Bergen and Petryshen, 2012).
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