Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan

Abstract

The gene that codes for dopamine receptor D2 (DRD2 on chromosome 11q23) has long been a prime functional and positional candidate risk gene for schizophrenia. Collectively, prior case-control studies found a reliable effect of the Ser311Cys DRD2 polymorphism (rs1801028) on risk for schizophrenia, but few other polymorphisms in the gene had ever been evaluated and no adequately powered family-based association study has been performed to date. Our objective was to test 21 haplotype-tagging and all three known nonsynonymous single-nucleotide polymorphisms (SNPs) in DRD2 for association with schizophrenia in a family-based study of 2408 Han Chinese, including 1214 affected individuals from 616 families. We did not find a significant effect of rs1801028, but we did find significant evidence for association of schizophrenia with two multi-marker haplotypes spanning blocks of strong linkage disequilibrium (LD) and nine individual SNPs (Ps<0.05). Importantly, two SNPs (rs1079727 and rs2283265) and both multi-marker haplotypes spanning entire LD blocks (including one that contained rs1801028) remained significant after correcting for multiple testing. These results further add to the body of data implicating DRD2 as a schizophrenia risk gene; however, a causal variant(s) in DRD2 remains to be elucidated by further fine mapping of the gene, with particular attention given to the area surrounding the third through fifth exons.

Figures

Figure 1

Linkage disequilibrium block structure, genomic organization and patterns of association with schizophrenia of dopamine receptor D2 (DRD2) single-nucleotide polymorphisms (SNPs) and haplotypes. (a) The 23 evaluated polymorphisms of DRD2 constituted four blocks (numbered 1–4 from 5′ to 3′) of uninterrupted strong linkage disequilibrium (LD), within which all values of D′ between markers met or exceeded 0.90. Blocks 2–4 also appeared to be subsumed under a larger, higher order block of reasonably strong LD (with interspersed tracks of uninformative markers), which encompassed exons 2–7 and much of the first intron of the gene. (b) Two of four blocks of strong LD were spanned by multi-marker haplotypes that showed nominally significant evidence for association with schizophrenia (*uncorrected Ps < 0.05), and both of these remained significant after corrections for multiple testing were applied to maintain the family-wise type-I error rate (FWER) at 5% (denoted by bold font). Of the 21 SNPs that met the distributional requirements for testing dominance models, nine showed nominally significant evidence for association with schizophrenia in phase I (*Ps < 0.05) and two remained significantly associated with the disorder in phase II after correcting for multiple testing of 12 optimally powered SNPs and maintaining the FWER at 5% using the Nyholt method (Ps < 0.0053, bold).