The American Journal of Human Genetics, 04 December 2014, Vol.95(6), pp.744-753
Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in 〉100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans ( ) and ( ), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb / and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) 〈0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF 〈 0.5%, p = 0.003 for MAF 〈 0.1%). A rare enhancer SNP, 1:g.98515539A〉T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10 ). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A〉T reduced enhancer activity of its flanking sequence by 〉50% in human neuroblastoma cells, predicting lower expression of . Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A〉T influenced , but not the nearby . Our results suggest that rare noncoding risk variants are associated with SZ and BP at locus, with risk alleles decreasing expression.
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