Our results also provide some guidelines about the use of discovery–replication paradigm to compare eQTL effects between tissues (i.e., detecting eQTLs in one tissue at a stringent P-value threshold and replicating the effects in another tissue after correcting for multiple tests)13,29. Here, we often saw a low to moderate replication rate even if there is no genetic difference between the tissues. This is because the replication rate is a function of the sample size of the validation set (Supplementary Fig. 12) and the sample sizes of eQTL studies in non-blood tissues are often limited. If we apply the discovery–replication paradigm to the GTEx data, only ~10.7% of eQTLs discovered in GTEx-muscle could be replicated in GTEx-hippocampus (although the estimates from the recent methods50,51 based on the discovery–replication paradigm were much higher) (Supplementary Table 7), which could potentially lead to a wrong conclusion that a large proportion of cis-eQTLs are tissue specific (note that the rb estimate between the two tissues was 0.81). We therefore do not recommend the use of the discovery–replication paradigm to quantify the tissue-specific effects especially in small samples.
