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MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNA target sites (poly-miRTS)- centric  multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)- and femoral neck (FN)-bone mineral density (BMD). In stage I, 41 102 poly-miRTSs were meta-analyzed in seven cohorts with a genome-wide significance (GWS) α = 0.05/41 102 = 1.22 × 10 −6 . By applying α = 5 × 10 −5  (suggestive significance), 11 poly-miRTSs were selected, with  FGFRL1  rs4647940 and  PRR5  rs3213550 as top signals for FN-BMD ( P  = 7.67 × 10 −6  and 1.58 × 10 −5 ) in gender-combined sample. In stage II  in silico  replication (two cohorts),  FGFRL1  rs4647940 was the only signal marginally replicated for FN-BMD ( P  = 5.08 × 10 −3 ) at α = 0.10/11 = 9.09 × 10 -3 .  PRR5  rs3213550 was also selected based on biological significance. In stage III  de novo  genotyping replication (two cohorts),  FGFRL1  rs4647940 was the only signal significantly replicated for FN-BMD ( P  = 7.55 × 10 −6 ) at α = 0.05/2 = 0.025 in gender-combined sample. Aggregating three stages,  FGFRL1  rs4647940 was the  single  stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD ( P  = 8.87 × 10 −12 ). Dual-luciferase reporter assays demonstrated that  FGFRL1  3′ untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel  FGFRL1  poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both  FGFRL1  and hsa-miR-140-5p are important for bone formation.

Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies