Abstract
ObjectivesSchizophrenia (SZ) is a complex psychiatric disorder with high heritability, and genetic components are thought to be pivotal risk factors for this illness. The glutamate decarboxylase 1 gene (GAD1) was hypothesized to be a candidate risk locus for SZ given its crucial role in the GABAergic neurotransmission system, and previous studies have examined the associations of single nucleotide polymorphisms (SNPs) spanning the GAD1 gene with SZ. However, inconsistent results were obtained. We hence examined the associations between GAD1 SNPs and SZ in two independent case-control samples of Han Chinese ancestry.Materials and MethodsTwo Han Chinese SZ case-control samples, referred as the discovery sample and the replication sample, respectively, were recruited for the current study. The discovery sample comprised of 528 paranoid SZ cases (with age of first onset ≥ 18) and 528 healthy controls; the independent replication sample contained 1,256 early onset SZ cases (with age of first onset < 18) and 2,661 healthy controls. Logistic regression analysis was performed to examine the associations between GAD1 SNPs and SZ.ResultsTen SNPs covering GAD1 gene were analyzed in the discovery sample, and two SNPs showed nominal associations with SZ (rs2241165, P = 0.0181, OR = 1.261; rs2241164, P = 0.0225, OR = 1.219). SNP rs2241164 was also nominally significant in the independent replication sample (P = 0.0462, OR = 1.110), and the significance became stronger in a subsequent meta-analysis combining both discovery and replication samples (P = 0.00398, OR = 1.138). Nevertheless, such association could not survive multiple corrections, although the effect size of rs2241164 was comparable with other SZ risk loci identified in genome-wide association studies (GWAS) in Han Chinese population. We also examined the associations between GAD1 SNPs and SZ in published datasets of SZ GWAS in East Asians and Europeans, and no significant associations were observed.ConclusionWe observed weak associations between GAD1 SNPs and risk of SZ in Han Chinese populations. Further analyses in larger Han Chinese samples with more detailed phenotyping are necessary to elucidate the genetic correlation between GAD1 SNPs and SZ.
Highlights
Schizophrenia (SZ) is a severe mental illness that affects approximately 1% of human populations and imposes a high burden on family and society (Huang et al, 2019; McCutcheon et al, 2020)
We examined the same nine single nucleotide polymorphisms (SNPs) within GAD1 in the independent replication sample of 1,256 early onset SZ cases and 2,661 controls
Non-significant associations between GAD1 SNPs and SZ were reported in a previous Japanese case-control sample (Ikeda et al, 2007). To further verify these results in a larger sample, we examined SNPs spanning GAD1 in a large genome-wide association studies (GWAS) of SZ in East Asians (22,778 cases and 35,362 controls primarily recruited from Han Chinese populations), but no significant SNPs surpassing the P-value threshold of 2.75 × 10−4 (Supplementary Figure 1) were identified (Lam et al, 2019)
Summary
Schizophrenia (SZ) is a severe mental illness that affects approximately 1% of human populations and imposes a high burden on family and society (Huang et al, 2019; McCutcheon et al, 2020). In the genetically divergent Han Chinese or East Asian populations, GWAS have reported multiple genome-wide significant loci associated with SZ (Li et al, 2017; Yu et al, 2017; Lam et al, 2019). Overall, these GWAS have provided essential information regarding SZ pathogenesis, and have confirmed some classical pathological hypotheses of the illness, such as the dopamine hypothesis and neurodevelopmental hypothesis
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