A functional role for non-coding variation in schizophrenia genome-wide significant loci. P. Sklar1, A. Mitchell1, G. Voloudakis1, V. Pothula1, E. Stahl1, A. Georgakopoulos1, D. Ruderfer1, J. Fullard1, A. Charney1, Y. Okada2, K. Siminovitch3, J. Worthington4, L. Padyukov5, L. Klareskog5, P. Gregersen6, R. Plenge7, S. Raychaudhuri7, M. Fromer1, S. Purcell1, K. Brennand1, M. Fromer1, N. Robakis1, E. Schadt1, S. Akbarian1, P. Roussos1 1) Icahn School of Medicine at Mount Sinai, New York, NY; 2) Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; 3) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario; 4) Arthritis Research UK Centre for Genetics and Genomics, Musculoskeletal Research Centre, Institute for Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Manchester; 5) Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm; 6) The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York; 7) Division of Rheumatology, Immunology, and Allergy, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts.

   Our recent GWAS in schizophrenia (SCZ) identified 22 loci that reached genome-wide significance (Ripke et al. Nat Genet 2013). The majority of identified SNPs reside within non-coding regions. In order to to understand these associations mechanistically, it is important to develop strategies for honing in on regions and SNPs more likely to have functional effects. Functional annotations were developed in a variety of ways. Brain eQTLs were generated in 8 datasets. Brain cis-regulatory elements (CRE) (active promoter, active enhancer, poised promoter, repressed enhancer and open chromatin regions) were generated based on ChIP-seq of histone modifications. Next, GWAS SCZ SNPs were classified into categories: eQTL, CRE, eQTL in a cis regulatory element (creQTL) or functionally unannotated variants. Relative enrichment for the categories was calculated using an empirical cumulative distribution of the GWAS P values after controlling for genomic inflation. We mapped the physical interaction of enhancers in two genes (CACNA1C and NGEF) with the transcription start site of each gene in human prefrontal cortex (n=6) and hiPSC derived-neurons by chromosome conformation capture (3C) assay. The largest enrichment of GWAS SNPs occurs in eQTLs, active promoters and enhancers. Enrichment is greater when the combined creQTL functional category is analyzed for all types of CREs (CRE range: 1.58-7.08 fold; creQTL range: 4.06-29.51 fold). We detected overlapping eQTL and GWAS signals using the regulatory trait concordance score for 10 of 22 intervals, four times the number expected by chance (P=2x10-5). The SCZ-related eQTLs are associated with expression of 17 genes, 5 of which are associated with loci within enhancers. For CACNA1C and NGEF genes, we identified enhancer regions that demonstrate increased interaction with the promoter and affect transcriptional activity of each gene. Our findings point to a functional link between SCZ-associated non-coding SNPs and 3-dimensional genome architecture associated with chromosomal loopings and transcriptional regulation in the brain.

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