Chunk #20 — Using Results from the GWAS of the International Schizophrenia Consortium as an Example, Are the Results of Dickson et al. Supported by Empirical Observation?
consistent with our results, but all consistent models included common variants as well as rare causal variants. Dickson et al. cites the ISC paper and specifically implied that multiple rare variants could explain the ISC results. Since our only conclusion was that the genetic architecture must include common variants (we specifically stated “our results do not exclude important contributions of rare variants for schizophrenia”), their statement must be interpreted that they believe a model without common variants could explain the ISC results. Within the ISC GWAS analysis we specifically investigated whether a rare variants-only model could fit the observed distribution of the frequencies of associated variants. Those results corroborate the results from the coalescent simulations we have undertaken here, namely that a rare variants-only model predicts a skewed distribution of associations for risk alleles of low frequencies. While, as noted in the ISC paper, we did observe an enrichment of associations with lower-frequency common alleles, we did not observe the substantial excess predicted by a rare variants-only model. Using exactly the same coalescent simulation models and methods as Dickson et al., we repeated the polygenic analysis presented by the ISC. For comparability with the ISC analyses, we sampled variants from
