VALIDATING GWA ASSOCIATIONS IN PSYCHIATRIC DISORDERS WITH FUNCTIONAL GENOMIC DATA

Genome-wide association studies have been successful at identifying regions of the genome associated with disease. Often, the identified SNPs are in regions of linkage disequilibrium that stretch over large distances, making it difficult to ascertain which gene in the region is functionally relevant to the trait of interest. For disorders of the brain, assessing the functional relevance of SNPs in the same sample in which they were discovered is, of course, difficult. Here we applied the SMR (Summary-data based Mendelian Randomisation) method to the latest GWAS results of psychiatric disorders, to evaluate whether SNPs associated with these disorders are also associated with control of gene expression of genes in the same region. The advantage of this method is that it utilises GWAS and expression QTL (eQTL) data from different samples. eQTL data were taken from whole blood and brain samples. We have results from application to multiple data sets (published and submitted) and multiple eQTL data sets. For example, application of SMR using 5967 eQTL discovered in whole blood (5311 samples) and applied to the schizophrenia GWAS results we identified 34 genes that were significant after correcting for multiple testing, and of these an additional test provides confidence that 16 reflect a single causal association. Of these only two genes were the nearest gene to the SNP association from the GWAS study. Additional follow-up SMR analyses were conducted for six genes using eQTL from brain. Two novel genes were identified as associated with risk of schizophrenia, SNX19 and NMRAL1. We have applied SMR to multiple psychiatric data GWAS data sets and identify novel risk genes. Our analyses suggest that only about one-third of GWAS results showed evidence of control of gene expression at the nearest gene. Importantly, in cases where there are several of genes within the region of association, SMR helps to identify the most plausible, functional candidate for future follow-up studies.