Table 2 Significant variant-level associations. We applied SAIGE’s GLMM test with Bonferroni adjustment to identify significant variant associations for each rare disease and Bonferroni adjustment is applied. Genomic positions are provided in hg38 build and HGVS nomenclature. The ACMG/AMP classification for each association was determined through the use of Varsome and InterVar. Associations are specified as being reported if they have previously been indicated as pathogenic or likely pathogenic in ClinVar for that disease. Abbreviations are as follows: MAC, minor allele count; MAF, minor allele frequency. Although additional significant variant-level associations were identified for systemic lupus erythematosus and von Willebrand disease, these diseases were indicated as not being rare in the USA by NIH’s GARD. Furthermore, significant variant-level associations with interatrial communication, benign epithelial tumor salivary glands, and endophthalmitis were excluded because these diseases were not listed on NIH’s GARD, so it is difficult to confirm their rareness in the USA
From: Enhanced rare disease mapping for phenome-wide genetic association in the UK Biobank
Disease | ORPHA | Marker | ACMG/AMP classification | Reported? | p-value | Case MAC | Percent affected | Control MAF |
|---|---|---|---|---|---|---|---|---|
Polycythemia vera | 729 | 9:5073770_G/T (JAK2: missense) NC_000009.12:g.5073770G>T | Pathogenic (PS3/PS4) | Yes | 1.32 × 10−114 | 51/370 | 47% | 1.71 × 10−04 |
Chronic myeloproliferative disease | 86830 | 9:5073770_G/T (JAK2: missense) NC_000009.12:g.5073770G>T | Pathogenic (PS3/PS4) | Yes | 2.40 × 10−67 | 30/154 | 28% | 2.33 × 10−04 |
Essential thrombocythemia | 3318 | 9:5073770_G/T (JAK2: missense) NC_000009.12:g.5073770G>T | Pathogenic (PS3/PS4) | Yes | 2.91 × 10−42 | 21/218 | 19% | 2.60 × 10−04 |
Primary myelofibrosis | 824 | 9:5073770_G/T (JAK2: missense) NC_000009.12:g.5073770G>T | Pathogenic (PS3/PS4) | Yes | 5.30 × 10−40 | 16/52 | 15% | 2.75 × 10−04 |
Immune thrombocytopenic purpura | 3002 | 9:5073770_G/T (JAK2: missense) NC_000009.12:g.5073770G>T | Pathogenic (PS3/PS4) | No | 2.63 × 10−18 | 11/368 | 10% | 2.90 × 10−04 |
Chronic myelomonocytic leukemia | 98823 | 17:76736877_G/A (SRSF2: missense) NC_000017.11:g.76736877G>A | Likely pathogenic (PS4/PM1) | No | 1.19 × 10−13 | 4/32 | 27% | 3.29 × 10−05 |
Essential thrombocythemia | 3318 | 19:12943813_A/ATTGTC (CALR: frameshift variant) NC_000019.10:g.12943813_12943814insTTGTC | Pathogenic (PVS1/PS4) | No | 2.82 × 10−13 | 5/218 | 50% | 1.50 × 10−05 |
Beta-thalassemia | 848 | 11:5226774_G/A (HBB: stop gained) NC_000011.10:g.5226774G>A | Pathogenic (PVS1/PS4) | Yes | 3.46 × 10−12 | 3/12 | 33% | 1.79 × 10−05 |
Congenital factor XI deficiency | 329 | 4:186288589_T/G (F11: missense) NC_000004.12:g.186288589T>G | Pathogenic (PS4/PM1/PM2/PP2/PP3) | No | 3.41 × 10−11 | 3/18 | 12% | 6.58 × 10−05 |
B-cell chronic lymphocytic leukemia | 67038 | 3:38141150_T/C (MYD88: stop lost) NC_000003.12:g.38141150T>C | Pathogenic (PS4/PM2/PM4/PP3/PP5) | Yes | 2.42 × 10−10 | 4/490 | 57% | 8.98 × 10−06 |
Acute panmyelosis with myelofibrosis | 86843 | 9:5073770_G/T (JAK2: missense) NC_000009.12:g.5073770G>T | Pathogenic (PS3/PS4) | No | 7.81 × 10−10 | 3/8 | 3% | 3.14 × 10−04 |
Immune thrombocytopenic purpura | 3002 | 16:83907050_G/A (MLYCD: missense) NC_000016.10:g.83907050G>A | Likely pathogenic (PS4/PM2) | No | 7.60 × 10−08 | 4/368 | 8% | 1.35 × 10−04 |
Osteochondritis dissecans | 2764 | 17:10505866_C/T (MYH1: missense) NC_000017.11:g.10505866C>T | Likely pathogenic (PS4/PM1) | No | 1.01 × 10−07 | 3/56 | 3% | 2.84 × 10−04 |
AA amyloidosis | 85445 | 2:151727817_T/TGCTGGCTGTGCCAGA (NEB: disruptive inframe insertion) NC_000002.12:g.151727823_151727837dup | Likely pathogenic (PS4/PM4) | No | 1.97 × 10−07 | 3/24 | 1% | 7.56 × 10−04 |