Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder

Abstract

A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P=1.61 × 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 × 10(-9)). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N=18 945, schizophrenia plus bipolar disorder N=21 274 and controls N=38 675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 × 10(-11), odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P=4.1 × 10(-13), OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.

Figure 1. fatSNP1 results for ZNF804A

Armitage trend P-values (−log₁₀) for 176 SNPs genotyped during fatSNP phase 1. Dashed lines represent the boundaries of ZNF804A transcript (NM_194250). Solid lines represent the region targeted by genomic resequencing. rs1344706 was the most significant SNP in the earlier GWAS study (O’Donovan et al 2008). Chromosome position based on NCBI build36.

Figure 2. Forest plot of rs1344706 schizophrenia meta analysis

OR = Odds Ratio for each individual study. Summary = combined OR for all studies. Squares are drawn proportional to the weight of the sample and lines represent 95% Confidence Intervals.

Figure 3. Relative Allelic Expression data for rs4667001

P = results of t-test of mean relative expression. gDNA = relative allelic expression ratio for genomic DNA samples heterozygous for rs4667001. cDNA = relative allelic expression ratio for the corresponding complimentary DNA samples heterozygous for rs4667001. Homo = relative allelic expression ratio for heterozygous rs4667001 cDNA samples stratified for homozygosity at rs1344706. Hetero = relative allelic expression ratio for heterozygous rs4667001 cDNA samples stratified for heterozygosity at rs1344706.