Elsevier

Neuroscience Letters

Volume 605, 25 September 2015, Pages 49-52
Neuroscience Letters

Research paper
Further evidence supporting the association of NKAPL with schizophrenia

https://doi.org/10.1016/j.neulet.2015.08.023Get rights and content

Highlights

  • NKAPL rs1635 is one of markers identified by a genome-wide association study for schizophrenia in Han Chinese.

  • The rs1635 is a nonsynonymous SNP resulting in Thr152Asn substitution in the encoded protein.

  • We detected the association of NKAPL rs1635 with schizophrenia in Han Chinese, including 1406 cases and 1136 healthy controls.

Abstract

Schizophrenia (SZ) is a severe chronic mental disorder with complex genetic mechanisms. Increasing evidence implicate immune system dysfunction in the pathogenesis of SZ. The non-synonymous single nucleotide polymorphism (SNP) rs1635 in NKAPL, was identified by a genome-wide association study (GWAS) for SZ in Han Chinese from north China. A replication study failed to detect the association of rs1635 with SZ in Han Chinese from central south of China, while another one confirmed the positive association in Han Chinese from Taiwan. To further clarify these findings, we conducted a case–control association study of rs1635 in a cohort of Han Chinese from east China, including 1406 SZ cases and 1136 healthy controls. We detected a positive association of rs1635 with SZ, with the major allele (G) of rs1635 conferring a risk for SZ (P = 0.033, OR = 1.14). Our findings add further evidence for the involvement of NKAPL polymorphisms in the development of SZ.

Introduction

Schizophrenia (SZ) is a severe mental disorder characterized by profound disruption in cognition and emotion, affecting the most fundamental human attributes: language, thought, perception, affect, and sense of self. The neurodevelopmental hypothesis is one of the dominant paradigms for SZ research over the past two decades [12], [18], which posits that SZ has its origins in disturbed development of the nervous system during early brain development, long before the full-blown symptoms.

Immune abnormality may play an important role in SZ by influencing the neurodevelopment process and neurotransmitter functions [8]. Recently, genome-wide association studies (GWASs) for SZ have identified several susceptibility loci within the extended major histocompatibility complex (MHC) region (6p21.2-p22.3), including the single nucleotide polymorphism (SNP) rs1635 in NKAPL (NFKB activating protein-like) [7], [14], [16], [17], [20].

It has been know that the NKAPL mRNA is highly expressed in the cortex, hippocampus, ventral lateral nucleus, locus ceruleus and other areas of the brain of mice [20]. rs1635 is a nonsynonymous SNP located in exon 1 of the NKAPL that results in Thr152Asn substitution in the encoded protein. Since then, follow-up studies have emerged to re-evaluate the association of NKAPL polymorphisms with SZ. Ma et al. failed to replicate the association of rs1635 with SZ in Han Chinese from central south of China [9], while in an association study using re-sequencing, Chen et al. confirmed this association in Han Chinese from Taiwan of China [2]. The samples of the original study by Yue et al. came from north China. Population substructures among Chinese Han populations from different geographic locations have been suggested [1], [19].

To seek further evidence for the association of NKAPL with SZ, we genotyped rs1635 in a cohort of SZ patients and controls in Han Chinese from east China.

Section snippets

Subjects

All participants were unrelated Han Chinese recruited from east China. Drawn from a population of Han descent, our study sample includes 1406 patients (874 men and 532 women, aged 45.9 ± 11.5 years) and 1136 unrelated healthy controls (634 men and 502 women, aged 44.9 ± 10.3 years).

All the patients were recruited from inpatients of several hospitals in Wuxi and Nanjing in Jiangsu province. The diagnosis of SZ was confirmed in interviews with two or more experienced psychiatrists using the

Genetic association

Genotypic distributions of rs1635 did not deviate from Hardy-Weinberg equilibrium (HWE) in either the patient group or the control group (P > 0.05). Allelic distribution of rs1635 was associated with SZ (P = 0.033), with the G-allele conferring risk for SZ (OR = 1.14) (Table 1). Assuming a disease allele frequency of 0.65, and a type I error rate of 0.05, our samples can achieve a power level of 86.5% to detect a variant with an odds ratio of 1.3.

Meta-analysis of rs1635

In the meta-analysis, there existed considerable

Discussion

SZ is one of most disabling mental disorders that affects virtually all brain functions. Although the cause of this disorder remains elusive, by far the vast majority of evidence points to the neurodevelopmental model in which abnormalities of early brain development predisposing to the onset of SZ.

The extended MHC region had been implicated as one of main factors in SZ pathogenesis in different populations [3], [4]. NKAPL is one of GWAS-supported risk genes in the MHC region, and the product

Conflict of interest

The authors declare that they have no competing interests.

Acknowledgements

We would sincerely thank the SZ participants, their families and the healthy volunteers for their participation, and all the medical staff involved in specimen collection. This work was supported by the National Natural Science Foundation of China (81471364).

References (21)

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