A rare regulatory noncoding variant in GWAS-implicated MIR137/MIR2682 locus potentially confers risk to both schizophrenia and bipolar disorder. J. Duan1.2, J. Shi3, A. Fiorentino4, C. Leites1, J. Chen6, W. Moy1, B. Alexandrov7,8, D. He1, J. Freda1, A. Bishop7,8, N. L. OBrien4, . MGS9, . GPC10, X. Chen6, A. Usheva7, A. McQuillin4, A. R. Sanders1,2, H. M. D. Gurling4, M. T. Pato5, K. S. Kendler6, C. N. Pato5, P. V. Gejman1,2 1) Dept Psychiatry, Northshore Univ Healthsystem/Univ of Chicago, Evanston, IL; 2) Department of Psychiatry and Behavioral Sciences, The University of Chicago, Chicago, IL; 3) Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Insititute, Bethesda, MD; 4) Molecular Psychiatry Laboratory, Division of Psychiatry, University College of London, UK; 5) Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine at USC, Los Angeles, CA; 6) Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA; 7) Department of Medicine, Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; 8) Los Alamos National Laboratory, Los Alamos, NM; 9) Molecular Genetics of Schizophrenia collaboration; 10) Genomic Psychiatric Cohort collaboration.

   Genome-wide association studies (GWAS) have identified common genetic risk variants in >100 susceptibility loci for the risk developing schizophrenia (SZ); however, the contribution of rare variants at these loci remains to be explored. We sequenced one of the most strongly associated loci spanning two microRNAs, MIR137 and MIR2682, in 2,610 SZ cases & 2,611 controls of European ancestry from the Molecular Genetics of Schizophrenia (MGS) study, covering ~6.9 kb of both microRNAs and the upstream ENCODE-annotated enhancers, promoters, and insulators. The burden test aggregating all the rare variants (MAF<0.5%) did not yield significant association with SZ; however, those within ENCODE-annotated promoters/enhancers were associated with SZ (P=0.021), and the association was improved (P=0.0007) when restricting the rare variants to those with MAF<0.1%;. We found an enhancer SNP, chr1_98515539, in 11 cases that was absent in controls (P=0.00048; Fishers exact test). We further genotyped this SNP (or extracted genotypes for it from whole genome sequencing datasets) in 3 additional SZ samples (N=2,434 cases), 3 bipolar disorder (BP) samples (N=4,713 cases), SZ/BP study controls (N=3,572), and population controls (UK10K-TwinsUK, N=1,603; 1000Genome, N=85). In these additional datasets, we identified the rare allele in 2 SZ cases, 11 BP cases, and 3 controls (combined P for SZ, BP, and SZ/BP was 0.0004, 0.004, and 0.00029, respectively). Our reporter gene assay showed that the risk allele of chr1_98515539 reduced enhancer activity of its flanking sequence by >50%; in neuronal cells. Both an electrophoresis mobility shift assay and a local DNA breathing dynamics analysis confirmed the weakened transcription factor Ying-Yang 1 (YY1) binding by the risk allele of chr1_98515539. A chromatin conformation capture (3C) assay further indicated that the functional SNP influences MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest the existence of rare SZ risk variants at the GWAS-implicated MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression. Furthermore, for the first time, we have shown that SZ and BP may share rare risk variants at the same locus.

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