Table 1.
Discovery and replication of chromosome Xq23 variants associated with lipid levels in TOPMed, UK Biobank, and HUNT.
| rsID | Minor allele | Trait | Discovery | Replication | Meta-analysis | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| TOPMed (N = 65,322) | UK Biobank Whites (N = 390,606) | UK Biobank non-Whites (N = 51,168) | HUNT (N = 66,287) | |||||||||||||||||
| MAF | Beta | SE | P | Beta | SE | P | Beta | SE | P | Beta | SE | P | Beta | SE | P | I2 | Pmeta | |||
| rs5942634 | T | TC | 34.4% | −1.95 | 0.24 | 2.0 × 10−16 | −1.17 | 0.077 | 1.17 × 10−52 | −1.043 | 0.23 | 6.47 × 10−6 | −1.24 | 0.20 | 3.4 × 10−10 | −1.23 | 0.066 | 3.78 × 10−77 | 71% | 0.016 |
| log(TG) | −0.017 | 0.0028 | 5.0 × 10−9 | −0.025 | 0.0018 | 1.18 × 10−44 | −0.027 | 0.0054 | 7.24 × 10−7 | −0.011 | 0.0024 | 3.8 × 10−6 | −0.020 | 0.0012 | 1.42 × 10−56 | 88% | 1.90 × 10−05 | |||
| HDL-C | 0.14 | 0.084 | 0.09 | 0.12 | 0.026 | 8.99 × 10−6 | 0.27 | 0.077 | 4.82 × 10−4 | 0.068 | 0.062 | 0.27 | 0.13 | 0.022 | 8.63 × 10−09 | 33% | 0.22 | |||
| LDL-C | −1.53 | 0.22 | 2.0 × 10−12 | −1.00 | 0.061 | 1.67 × 10−60 | −1.028 | 0.18 | 2.39 × 10−8 | −0.93 | 0.18 | 3.7 × 10−7 | −1.028 | 0.053 | 1.31 × 10−82 | 47% | 0.13 | |||
| rs5985504 | T | TC | 43.3% | −1.82 | 0.24 | 1.9 × 10−14 | −1.18 | 0.077 | 5.37 × 10−53 | −1.081 | 0.23 | 3.77 × 10−6 | −1.30 | 0.20 | 3.3 × 10−11 | −1.23 | 0.066 | 4.96 × 10−78 | 57% | 0.072 |
| log(TG) | −0.019 | 0.0029 | 4.2 × 10−11 | −0.024 | 0.0018 | 2.36 × 10−40 | −0.030 | 0.0055 | 3.39 × 10−8 | −0.012 | 0.0024 | 4.3 × 10−7 | −0.02 | 0.0013 | 1.29 × 10−57 | 85% | 0.00022 | |||
| HDL-C | 0.088 | 0.084 | 0.30 | 0.095 | 0.026 | 3.1 × 10−4 | 0.25 | 0.078 | 1.13 × 10−3 | 0.12 | 0.063 | 0.051 | 0.11 | 0.022 | 6.70 × 10−07 | 18% | 0.30 | |||
| LDL-C | −1.26 | 0.22 | 8.7 × 10−9 | −0.99 | 0.061 | 3.87 × 10−60 | −1.043 | 0.19 | 2.05 × 10−8 | −1.00 | 0.18 | 3.0 × 10−8 | −1.011 | 0.054 | 2.35 × 10−79 | 0% | 0.70 | |||
| rs5942648 | A | TC | 38.3% | −1.88 | 0.24 | 8.2 × 10−16 | −1.19 | 0.077 | 1.23 × 10−53 | −1.13 | 0.23 | 8.21 × 10−7 | −1.20 | 0.19 | 9.2 × 10−10 | −1.24 | 0.066 | 1.69 × 10−79 | 62% | 0.050 |
| log(TG) | −0.016 | 0.0028 | 7.6 × 10−9 | −0.025 | 0.0018 | 6.31 × 10−45 | −0.030 | 0.0054 | 3.59 × 10−8 | −0.012 | 0.0024 | 2.0 × 10−6 | −0.02 | 0.0012 | 7.28 × 10−58 | 88% | 2.17 × 10−05 | |||
| HDL-C | 0.14 | 0.083 | 0.094 | 0.11 | 0.026 | 2.77 × 10−05 | 0.24 | 0.076 | 2.0 × 10−3 | 0.090 | 0.063 | 0.15 | 0.12 | 0.022 | 4.71 × 10−08 | 0% | 0.40 | |||
| LDL-C | −1.53 | 0.22 | 1.2 × 10−12 | −1.00 | 0.061 | 5.79 × 10−61 | −1.076 | 0.18 | 3.47 × 10−9 | −0.89 | 0.18 | 7.4 × 10−7 | −1.028 | 0.053 | 1.02 × 10−82 | 51% | 0.101 | |||
Variants attaining P < 1 × 10−6 in TOPMed (discovery) and P < 0.002 in UK Biobank and HUNT (replication studies). Effect estimates for the minor alleles are presented from linear regression, adjusted for age, age2, sex, batch, and principal components of ancestry, as well as cohort-specific covariates where appropriate. Two-sided p-values are presented; accounting for multiple-hypothesis testing, p-values < 5.7 × 10−9 are considered significant. rs5942634 was the top association for total cholesterol, rs5985504 for triglycerides, and rs5942648 for LDL-C. Since the variants were in at least moderate linkage disequilibrium (minimum pairwise r2 = 0.61), there was evidence of association across all three of the aforementioned lipid traits for these three variants.
MAF minor allele frequency.