Table 2.
Significant association results of single-variant and gene-based tests.
| Single-variant test | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Chr | Position (hg19) | Alt | Ref | Gene | Type/Category | AA change | Stage | AA/AG/GG (MAF) in cases | AA/AG/GG (MAF) in controls | OR | (95% CI) | P* |
| 1 | 55505604 | A | G | PCSK9 | Missense/Non-synonymous | E32K | Discovery | 1/86/2685 (0.016) | 0/47/2916 (0.0079) | 2.0 | (1.4, 2.9) | 8.6 × 10−5 |
| Replication | 4/201/6976 (0.015) | 3/97/5307 (0.0095) | 1.5 | (1.2, 1.9) | 3.5 × 10−4 | |||||||
| Combined | 5/287/9661 (0.015) | 3/144/8223 (0.0090) | 1.7 | (1.4, 2.0) | 3.5 × 10−7 | |||||||
| Gene-based test | ||||||||||||
| Gene | Grouping (test method) | Stage | Carriers/non-carriers (%Freq) in cases | Carriers/non-carriers (%Freq) in controls | OR | (95% CI) | P | |||||
| LDLR | Damaging (CAST) | Discovery | 28/2747 (1.0) | 5/2960 (0.17) | 6.0 | (2.3, 20) | 2.6 × 10−5 | |||||
| Replication | 61/7120 (0.85) | 12/5396 (0.22) | 3.9 | (2.1, 7.9) | 2.1 × 10−6 | |||||||
| Combined | 89/9867 (0.89) | 17/8356 (0.20) | 4.4 | (2.6, 7.4) | 7.2 × 10−10 | |||||||
| PCSK9 | All non-synonymous (SKAT) | Discovery | — | — | — | — | 3.7 × 10−5 | |||||
| Replication | — | — | — | — | 7.5 × 10−4 | |||||||
| Combined | — | — | — | — | 2.3 × 10−7 | |||||||
| Gain-of-function (CAST) | Discovery | 159/2616 (5.7) | 110/2855 (3.7) | 1.5 | (1.2, 2.0) | 3.5 × 10−4 | ||||||
| Replication | 394/6787 (5.4) | 262/5146 (4.8) | 1.2 | (1.0, 1.4) | 2.4 × 10−2 | |||||||
| Combined | 553/9403 (5.6) | 372/8001 (4.5) | 1.3 | (1.1, 1.5) | 1.0 × 10−4 | |||||||
| Loss-of-function (CAST) | Discovery | 33/2742 (1.2) | 72/2893 (2.4) | 0.49 | (0.32, 0.76) | 7.8 × 10−4 | ||||||
| Replication | 123/6933 (1.7) | 125/5283 (2.3) | 0.74 | (0.58, 0.97) | 2.7 × 10−2 | |||||||
| Combined | 156/9675 (1.6) | 197/8176 (2.4) | 0.66 | (0.53, 0.81) | 1.1 × 10−4 | |||||||
Single-variant test:
A result exceeding the pre-defined study-wide significance (P < 3.1 × 10−5). P values were calculated using Fisher’s exact test. Combined P values were calculated using the Cochran-Mantel-Haenszel method. Abbreviations: AA, amino acid; MAF, minor allele frequency; OR, odds ratio; 95% CI, 95% confidence interval; Ref, the reference allele based on hg19; Alt, the alternative allele.
Gene-based test:
Significant results exceeding the gene-wide significance (P < 4.6 × 10−4). Abbreviations: Freq, percentage of cases or controls carrying at least one categorized variant; OR, odds ratio.