Rare compound heterozygous missense SPATA7 variations and risk of schizophrenia; whole-exome sequencing in a consanguineous family with affected siblings, follow-up sequencing and a case-control study

Abstract

Purpose

Whole-exome sequencing (WES) of multiplex families is a promising strategy for identifying causative variations for common diseases. To identify rare recessive risk variations for schizophrenia, we performed a WES study in a consanguineous family with affected siblings. We then performed follow-up sequencing of SPATA7 in schizophrenia-affected families. In addition, we performed a case-control study to investigate association between SPATA7 variations and schizophrenia.

Patients and methods

WES was performed on two affected siblings and their unaffected parents, who were second cousins, of a multiplex schizophrenia family. Subsequently, we sequenced the coding region of SPATA7, a potential risk gene identified by the WES analysis, in 142 affected offspring from 137 families for whom parental DNA samples were available. We further tested rare recessive SPATA7 variations, identified by WES and sequencing, for associations with schizophrenia in 2,756 patients and 2,646 controls.

Results

Our WES analysis identified rare compound heterozygous missense SPATA7 variations, p.Asp134Gly and p.Ile332Thr, in both affected siblings. Sequencing SPATA7 coding regions from 137 families identified no rare recessive variations in affected offspring. In the case-control study, we did not detect the rare compound heterozygous SPATA7 missense variations in patients or controls.

Conclusion

Our data does not support the role of the rare compound heterozygous SPATA7 missense variations p.Asp134Gly and p.Ile332Thr in conferring a substantial risk of schizophrenia.

Keywords:

• Japanese
• multiplex schizophrenia family
• next-generation sequencing
• recessive variations

Supplementary materials

Table S1 Primer sequences for sequencing SPATA7 coding regions

Table S2 Probes used for the TaqMan 5′-exonuclease assay

Table S3 WES quality report summary

Table S4 Coefficient of relatedness from the WES data for each pair of individuals

Table S5 SPATA7 variations identified by sequencing

Table S6 Genotyping of two uncommon missense variations in the case-control study

Acknowledgment

The authors thank the patients, their families, and the healthy volunteers for their participation. We would also like to thank Ms Yamazaki, Ms Aizawa and Ms Nagashima for excellent technical assistance. This work was supported by Grants-in-Aid for Scientific Research (16K19754 to HI) from the Japan Society for the Promotion of Science, by a grant from the Niigata Medical Association (to HI), and by a grant from SENSHIN Medical Research Foundation (to YW). We thank Jeremy Allen, PhD, and Sydney Koke, MFA, from Edanz Group for editing a draft of this manuscript.

Disclosure

The authors report no conflicts of interest in this work.