Figure 3. G6PC2.

(a) Regional association results (−log₁₀p) for fasting glucose of the G6PC2 locus on chromosome 2. Minor allele frequencies (MAF) of common and rare G6PC2 SNVs from single-variant analyses are shown. P values for rs560887, rs563694 and rs552976 were artificially trimmed for the figure. Linkage disequilibrium (r²) indicated by colour scale legend. y-Axis scaled to show associations for variant rs560887 (purple dot, MAF=43%, P=4.2 × 10⁻⁸⁷). Triangle symbols indicate variants with MAF>5%, square symbols indicate variants with MAF1–5% and circle symbols indicate variants with MAF <1%. (b) Regional association results (−log₁₀p) for fasting glucose conditioned on rs560887 of G6PC2. After adjustment for rs560887, both rare SNVs rs2232326 (S324P) and rs146779637 (R283X), and common SNV rs492594 remain significantly associated with FG indicating the presence of multiple independent associations with FG at the G6PC2 locus. (c) Inset of G6PC2 gene with depiction of exon locations, amino-acid substitutions and MAFs of the 15 SNVs included in gene-based analysis (MAF<1% and nonsynonymous, splice-site and gain/loss-of-function variation types as annotated by dbNSFPv2.0). (d) The contribution of each variant on significance and effect of the SKAT test when one variant is removed from the test. Gene-based SKAT P values (blue line) and test statistic (red line) of G6PC2 after removing one SNV at a time and re-calculating the association. (e) Haplotypes and haplotype association statistics and P values generated from the 15 rare SNVs from gene-based analysis of G6PC2 from 18 cohorts and listed in panel (c). Global haplotype association, P=1.1 × 10⁻¹⁷. Haplotypes ordered by decreasing frequency with haplotype 1 as the reference. Orange highlighting indicates the minor allele of the SNV on the haplotype.