We used SMR37 as our primary method to identify SNPs which might mediate association with schizophrenia through effects on gene expression. The significance for SMR is set at the Bonferroni corrected threshold of 0.05/M where M is the number of genes with significant eQTLs tested for a given tissue. Significant SMR associations imply colocalization of the schizophrenia associations with eQTL. We applied the HEIDI test37 to filter out SMR associations (PHEIDI < 0.01) due to linkage disequilibrium between SCZ-associated variants and eQTLs. cis-eQTL summary data were from three studies: fetal brain (N=120)38 , adult brain (n = ~1,500)39 and blood (n = ~32,000)40 . Linkage disequilibrium (LD) data required for the HEIDI test37 were estimated from the Health and Retirement Study (HRS)41 (n = 8,557). We included only genes with at least one cis-eQTL at PeQTL < 5×10−8, excluding those in MHC regions due to the complexity of this region. For blood, we included only genes with eQTLs in brain. This left 7,803 genes in blood, 10,890 genes in prefrontal cortex and 754 genes in fetal brain for analysis (see Supplementary Note for further details). SMR was performed using data from the primary GWAS. The results were then filtered to exclude significant SMR implicated genes where the eQTLs did not map within our definition of an associated locus in the Extended GWAS meta-analysis of our primary GWAS dataset and the dataset provided by deCODE genetics.
For genomic regions where there were multiple genes showing significant SMR associations, we attempted to resolve these with conditional analysis using GCTA-COJO42 ,43 . We selected the top-associated cis-eQTL for one gene (or a set of genes sharing the same cis-eQTL) ran a COJO analysis in the schizophrenia GWAS data and the eQTL data for each of the other genes conditioning on the selected top cis-eQTL. We then re-ran the SMR and HEIDI analyses using these conditional GWAS and eQTL results.
We used FUSION44 and EpiXcan45 as tests of robustness of the SMR results. Details are supplied in the Supplementary Note as are our approaches to prioritising SMR associated genes.
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