Table 2.
GWAS-targeted analysis in a mega-dataset without exome extracts
| Burden test (variant MAF < 1%) | Burden test (variant MAF < 0.1%) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Locus sentinel GWAS SNP | Gene | Variant deleteriousness threshold | P | FDR | No. variants/no. carriers | Case/control OR (95% CI) | P | No. variants/no. carriers | Fraction of very rare variants, % | Case/control OR (95% CI) |
| aSORL1, TREM2, ABCA7 (Table 1 and Supplementary Table 8) | ||||||||||
|
SLC24A4/RIN3 rs7401792 rs12590654 |
RIN3 | LOF + REVEL ≥ 25 | 1.6 × 10−5 | 0.0003 | 44/622 | 1.4 (1.2–1.6) | 3.4 × 10−2 | 42/129 | 21 | 1.4 (1.0–2.1) |
| LOF + REVEL ≥ 50 | 1.0 × 10−5 | 0.0002 | 23/583 | 1.4 (1.2–1.7) | 1.5 × 10−2 | 21/89 | 15 | 1.8 (1.2–2.8) | ||
| aADAM10, ABCA1 (Table 1 and Supplementary Table 8) | ||||||||||
|
PTK2B/CLU rs73223431 rs11787077 |
CLU | LOF + REVEL ≥ 25 | 5.0 × 10−4 | 0.005 | 24/26 | 3.6 (1.6–8.3) | 5.0 × 10−4 | 24/26 | 100 | 3.6 (1.6–8.3) |
| LOF + REVEL ≥ 50 | 1.1 × 10−3 | 0.001 | 14/15 | 5.4 (1.6–28.6) | 1.1 × 10−3 | 14/15 | 100 | 5.3 (1.6–28.6) | ||
| LOF + REVEL ≥ 75 | 5.0 × 10−4 | 0.005 | 12/12 | 9.9 (1.6–44.0) | 5.0 × 10−4 | 12/12 | 100 | 9.8 (1.6–44.0) | ||
| LOF | 2.6 × 10−3 | 0.02 | 10/10 | 7.3 (1.9–27.2) | 2.6 × 10−3 | 10/10 | 100 | 7.3 (1.9–27.2) | ||
|
SPDYE3 rs7384878 |
ZCWPW1 | LOF + REVEL ≥ 25 | 6.1 × 10−3 | 0.042 | 22/77 | 1.8 (1.2–2.9) | 5.0 × 10−3 | 21/76 | 99 | 1.8 (1.2–2.9) |
| LOF + REVEL ≥ 50 | 3.1 × 10−3 | 0.022 | 16/70 | 1.9 (1.2–3.1) | 3.1 × 10−3 | 16/70 | 100 | 1.9 (1.2–3.1) | ||
| LOF + REVEL ≥ 75 | 1.1 × 10−3 | 0.001 | 11/15 | 5.0 (1.9–13.5) | 1.1 × 10−3 | 11/15 | 100 | 5.0 (1.9–13.5) | ||
| LOF | 7.8 × 10−4 | 0.008 | 11/15 | 5.0 (1.9–13.5) | 7.8 × 10−4 | 11/15 | 100 | 5.0 (1.9–13.5) | ||
|
ACE rs4277405 |
ACE | LOF + REVEL ≥ 75 | 9.0 × 10−4 | 0.008 | 38/99 | 2.0 (1.3–2.9) | 9.3 × 10−4 | 38/99 | 100 | 2.0 (1.3–2.9) |
Genes in all GWAS loci were prioritized as described in the Methods (Supplementary Table 7). Listed are genes for which burden tests were significant in the mega-analysis after multiple testing correction using a Benjamini–Hochberg FDR < 0.05. P values for burden tests were determined using ordinal logistic regression (two-sided tests); a case/control OR was computed for reference. aThese genes also included the SORL1, TREM2, ABCA7, ADAM10 and ABCA1 genes, which were also identified in the rare-variant burden analysis shown in Table 1 and therefore are not shown (see Supplementary Table 8 for the full analysis). Bold text: result of burden test MAF < 0.1% unchanged compared to the burden test MAF < 1%.