Association betweenANKK1(rs1800497) andLTA(rs909253) Genetic Variants and Risk of Schizophrenia

Abstract

Limited research has assessed associations between schizophrenia and genetic variants of the ankyrin repeat and kinase domain containing 1 (ANKK1) and lymphotoxin-alpha (LTA) genes among individuals of Middle Eastern ancestry. Here we present the first association study investigating the ANKK1 rs1800497 (T>C) and LTA rs909253 (A>G) single-nucleotide polymorphisms in an Egyptian population. Among 120 patients with DSM-IV and PANSS (Positive and Negative Syndrome Scale) assessments of schizophrenia and 100 healthy controls, we determined the genotypes for the polymorphisms using endonuclease digestion of amplified genomic DNA. Results confirmed previous findings from different ethnic populations, in that the rs1800497 and rs909253 polymorphisms were both associated with risk of schizophrenia. Differences between the genotypes of cases and controls were strongly significant (P = 0.0005 for rs1800497 and P = 0.001 for rs909253). The relative risk to schizophrenia was 1.2 (P = 0.01) for the C allele and 0.8 (P = 0.04) for the G allele. The CC, GG, and combined CC/AA genotypes were all more frequent in cases than in controls. These results support an association between ANKK1 and LTA genetic markers and vulnerability to schizophrenia and show the potential influence of just one copy of the mutant C or G allele in the Egyptian population.

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

“…Postiron emission tomography (PET) studies with displaceable DA D2/D3 receptor (D2/D3R) radioligands show that low striatal D2/D3R availability may be associated with impulsivity (Clark et al, 2012), addiction to alcohol (Volkow et al, 1996; Martinez et al, 2005), substance abuse (Volkow et al, 1990; Volkow et al, 2001; Martinez et al, 2004; Fehr et al, 2008), and obesity (Wang et al, 2001; Haltia et al, 2007; de Weijer et al, 2011) whereas high D2/D3R availability has been associated with risk for schizophrenia (Laruelle, 1998), although this finding has not been replicated (Howes et al, 2012; Kambeitz et al, 2014). Similarly, the A1 (T) allele of the single nucleotide polymorphism (SNP) TaqIA (rs1800497), located in the ankyrin repeat and kinase domain containing 1 ( ANKK1 ) 10 kb downstream from the DA D2 receptor ( DRD2 ) gene (Grandy et al, 1989), is associated with addictive behavior including gambling (Comings et al, 1996), substance abuse (Noble et al, 1993; Persico et al, 1996; Lawford et al, 2000; Chen et al, 2004; Messas et al, 2005), and binge eating (Davis et al, 2012) and with obesity (Noble et al, 1994; Spitz MR, 2000; Thomas et al, 2001; Stice et al, 2008; Duran-Gonzalez et al, 2011) while the A2 (C) allele is associated with risk for schizophrenia (Parsons et al, 2007; Dubertret et al, 2010; Arab and Elhawary, 2015). …”

Are There Schizophrenia Genetic Markers and Mutations? A Systematic Review and Meta-Analyses

“…The present results suggest that haplotypes VNTR(L)-rs6323(T), VNTR(L)-rs1137070(C), and VNTR-(L)-rs6323(T)-rs1137070(C) may be associated with the increased risk of paranoid schizophrenia in female subjects [7]. Other genes also investigated in susceptibility studies schizophrenia are those encoding proteins the dopaminergic system [4].…”

“…This polymorphism which leads to a substitution glutamic acid to lysine base (E713K) that can high-specificity substrate binding [55] probably modulates the function and expression of DRD2 due to its proximity [56]. Despite the fact that the SNP rs1800497 is located ANKK1 the gene appears to be in linkage disequilibrium with several genetic variants DRD2, which could potentially explain a dopaminergic role in the pathogenesis of schizophrenia [4] [57].…”

“…Genetic factors account for more than 80% of the variance in susceptibility, and risk likely results from multiple loci of small effect [1] [2]. Supporting evidence has linked the high heritability of schizophrenia (SCZ) to a combination of relatively common alleles of small effect and to a few rare alleles with relatively large effects [3] [4]. Genes like GRIK2, GRIA2, [5] ADAMTSL3 [6] and polymorphism present in the MAOA promoter region was associated with schizophrenia [7].…”

“…Some of the most investigated genes in studies of susceptibility to schizophrenia are those that encode proteins of the dopaminergic system [4]. The dysfunction of the dopamine system is believed to be a fundamental component in SCZ development [9].…”