I:ten.1371/journal.pgen.1003247.gPLOS Genetics www.plosgenetics.orgGenetic Determinants of Bone MicrostructureFigure 2. Regional association plots for the five independent P2Y6 Receptor Formulation signals in the discovery genome-wide meta-analysis of cortical vBMD. (A) rs1021188, (B) rs271170, (C) rs7839059, (D) rs6909279, (E) rs17638544. Circles show the GWA meta-analysis p-values, with unique colors indicating varying linkage disequilibrium with the indicated SNP (diamond). SNPs inside the exact same region identified within a current large-scale GWA metaanalysis of aBMD are indicated by a red outer circle . LocusZoom: http://csg.sph.umich.edu/locuszoom/. doi:10.1371/journal.pgen.1003247.gwas conditioned around the identified aBMD hit rs2062377; ESR1 region, rs6909279 was conditioned on known aBMD hits rs7751941 and rs4869742; ). The two cortical vBMD RANKL signals (rs1021188 and rs17638544) have been distinct in the previously reported aBMD signal (rs9533090; ) within this area, supported by the fact that (i) rs9533090 was not considerably connected with cortical vBMD (Figure 2A), (ii) adjustment for rs9533090 did not influence the associations for rs1021188 or rs17638544 with cortical vBMD as well as the two cortical vBMD signals displayed a low r2 (,0.04) with rs9533090 (Table S2). It is hard to identify if the identified cortical vBMD signal inside the OPG area is separate in the previous reported aBMD signal in this area (rs2062377; ) as this previous aBMD signal also was considerably connected with cortical vBMD (Figure 2C), the r2 among the two SNPs was 0.39, and adjustment for rs2062377 slightly but not fully attenuated the association for rs7839059 with cortical vBMD (Table S2).PLOS Genetics www.plosgenetics.orgThe identified cortical vBMD SNP inside the ESR1 region (rs6909279) is independent from one of many prior reported aBMD signals (rs7751941) even though the other reported independent aBMD SNP in this area (rs4869742 ) displayed a fairly higher r2 with rs6909279 (r2 = 0.60) (Figure 2D). Nevertheless, adjustment for rs4869742 only slightly attenuated the association for rs6909279 with cortical vBMD (Table S2). GWA meta-analysis of trabecular volumetric BMD. Within the trabecular vBMD GWA meta-analysis there was tiny systematic inflation of test statistics (All round l = 1.005 (1.020 for Very good; 1.018 for YFS)), but a substantial deviation from the null distribution amongst the lowest observed p-values (Figure 3A). We identified one novel bone-related genetic variant reaching genome-wide significance (Figure 3B). The greatest evidence for association in between genetic variation and trabecular vBMD was observed for rs9287237 (0.22 SD raise per T allele; p = three.361028) on chromosome 1, within the formin 2 gene (FMN2 gene; Table two,Genetic Determinants of Bone MicrostructureTable 2. Top cortical and trabecular vBMD signals from pQCT GWA meta-analyses followed by replication.Discovery Meta-analysis SNP Cortical vBMD rs1021188 rs271170 rs7839059 rs6909279 rs17638544 Trabecular vBMD rs9287237 FMN2 1 T 0.15 2500 0.22 0.04 3.3E-08 TLR9 Purity & Documentation TNFSF11 LOC285735 TNFRSF11B C6orf97/ESR1 TNFSF11 13 6 eight 6 13 C T A G T 0.17 0.33 0.34 0.40 0.07 5878 5878 5878 5878 5873 20.15 0.02 20.11 0.02 20.ten 0.02 20.09 0.02 0.13 0.03 1.4E-12 2.9E-11 4.1E-09 1.0E-08 4.2E-05 Closest gene Chr Effect allele EAF n Beta SE PReplication MrOS n EAF Beta SE pCombined All cohorts n Effect SE p1052 1025 1025 10270.15 0.29 0.33 0.38 0.20.15 0.06 20.10 0.05 20.11 0.04 20.09 0.04 0.18 0.7.0E-03 3.0E-02 9.0E-03 three.8E-02 3.8.