Epistasis in Schizophrenia

This looks like an interesting new paper. I haven't read it yet but it looks like they carry out an extensive epistasis analysis. Should they have conditioned on main effects? Did they consider epistasis in absence of significant main effects? How much of the genetic architecture for this pathway are they revealing? The follow-up with functional studies looks nice.

Talkowski ME, Kirov G, Bamne M, Georgieva L, Torres G, Mansour H, Chowdari KV, Milanova V, Wood J, McClain L, Prasad K, Shirts B, Zhang J, O'Donovan MC, Owen MJ, Devlin B, Nimgaonkar VL.

Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.

Hum Mol Genet. 2007 Nov 27 [Epub ahead of print]

A network of dopaminergic gene variations implicated as risk factors for schizophrenia.We evaluated the hypothesis that dopaminergic polymorphisms are risk factors for schizophrenia. Stage I (screening): Eighteen dopamine-related genes were analyzed in two independent US Caucasian samples: 150 trios and 328 cases / 501 controls. The most promising associations were detected with SLC6A3 (alias DAT), DRD3, COMT, and SLC18A2 (alias VMAT2). Stage II (SNP coverage and epistasis): To comprehensively evaluate these four genes, 68 SNPs were genotyped in all 478 cases and 501 controls from stage I. Fifteen (23.1%) significant associations were found (p < 0.05). We tested for epistasis between pairs of SNPs providing main effects and observed 17 significant interactions (169 tests); 41.2% of significant interactions involved rs3756450 (5' near promoter) or rs464049 (intron 4) at SLC6A3. Stage III (confirmation): Sixty-five SNPs were genotyped in 659 Bulgarian trios. Both SLC6A3 variants implicated in the US interactions were over-transmitted in this cohort (rs3756450, p = 0.035; rs464049, p = 0.011). Joint analyses from stages II and III identified associations at all four genes (p(joint)< 0.05). We tested 29 putative interactions from stage II and detected replication between 7 locus pairs (p < 0.05). Simulations suggested our stage II and stage III interaction results were unlikely to have occurred by chance (p = 0.008 and 0.001, respectively). Stage IV (function): We tested rs464049 and rs3756450 for functional effects and found significant allele specific differences at rs3756450 using EMSA and dual-luciferase promoter assays. Conclusions: Our data suggest a network of dopaminergic polymorphisms increase risk for schizophrenia.