Table 1.
Genes identified by POLMM-GENE that reached the exome-wide significant threshold with p values < 2.5e−6
| Genes |
LoF: p value (number of variants) |
LoF+Missense: p value (number of variants) |
Cauchy p value | ||
|---|---|---|---|---|---|
| Ultra-rare variants (MAC) | Rare variants (MAF < 1%) | Ultra-rare variants (MAC) | Rare variants (MAF < 1%) | ||
| Alcohol intake frequency | |||||
| ADH1C (MIM: 103730) | 4.64e−01 (n = 18, MAC = 40) | 4.98e−16 (n = 22) | 8.49e−01 (n = 155, MAC = 405) | 2.61e−16 (n = 178) | 1.11e−15 |
| GIGYF1 (MIM: 612064) | 3.02e−07 (n = 98, MAC = 164) | 5.74e−06 (n = 113) | 2.05e−02 (n = 626, MAC = 1,604) | 2.55e−02 (n = 767) | 1.06e−06 |
| Morning/evening person (chronotype) | |||||
| PER3 (MIM: 603427) | 2.26e−02 (n = 92, MAC = 229) | 2.45e−05 (n = 105) | 4.30e−02 (n = 611, MAC = 1,513) | 5.05e−19 (n = 759) | 3.03e−18 |
| MTNR1B (MIM: 600804) | 1.39e−01 (n = 24, MAC = 52) | 1.84e−01 (n = 26) | 1.05e−02 (n = 180, MAC = 511) | 6.50e−13 (n = 218) | 3.90e−12 |
| PER2 (MIM: 603426) | 4.10e−10 (n = 80, MAC = 148) | 2.15e−10 (n = 85) | 1.66e−01 (n = 568, MAC = 1,373) | 5.88e−05 (n = 675) | 4.30e−10 |
| Cognitive symptoms severity (ultra-rare variants are defined as MAC) | |||||
| MRGPRX1 (MIM: 607227) | 4.77e−02 (n = 7, MAC = 10) | 6.31e−08 (n = 9) | 8.43e−01 (n = 86, MAC = 182) | 7.15e−01 (n = 122) | 1.89e−07 |
| Comparative body size at age 10 | |||||
| MC4R (MIM: 155541) | 3.35e−07 (n = 11, MAC = 27) | 1.11e−23 (n = 17) | 2.04e−05 (n = 122, MAC = 280) | 1.03e−22 (n = 168) | 1.98e−33 |
| EPHB2 (MIM: 600997) | 2.50e−01 (n = 24, MAC = 55) | 3.10e−01 (n = 28) | 5.28e−02 (n = 416, MAC = 1,160) | 2.58e−07 (n = 504) | 1.55e−06 |
| CALCR (MIM: 114131) | 3.02e−06 (n = 44, MAC = 138) | 1.03e−05 (n = 56) | 6.45e−04 (n = 234, MAC = 616) | 1.59e−04 (n = 289) | 1.59e−06 |
| Comparative height size at age 10 | |||||
| ZFAT (MIM: 610391) | 4.56e−10 (n = 46, MAC = 89) | 2.58e−10 (n = 48) | 9.83e−10 (n = 505, MAC = 1,339) | 7.77e−30 (n = 628) | 4.66e−29 |
| ACAN (MIM: 155760) | 1.96e−06 (n = 43, MAC = 75) | 1.37e−06 (n = 47) | 5.23e−03 (n = 934, MAC = 2,519) | 1.04e−27 (n = 1,208) | 6.26e−27 |
| SCMH1 (MIM: 616396) | 9.98e−06 (n = 34, MAC = 69) | 1.04e−05 (n = 35) | 6.94e−02 (n = 274, MAC = 650) | 2.18e−26 (n = 328) | 1.31e−25 |
| ADAMTS17 (MIM: 607511) | 3.36e−04 (n = 75, MAC = 186) | 1.00e−09 (n = 86) | 3.48e−06 (n = 649, MAC = 1,798) | 1.41e−13 (n = 832) | 5.41e−22 |
| NPR3 (MIM: 108962) | 6.55e−02 (n = 30, MAC = 71) | 7.82e−03 (n = 34) | 5.76e−02 (n = 273, MAC = 674) | 7.00e−22 (n = 312) | 4.20e−21 |
| NPR2 (MIM: 607072) | 1.70e−11 (n = 30, MAC = 80) | 9.74e−11 (n = 30) | 1.43e−13 (n = 358, MAC = 894) | 3.34e−18 (n = 437) | 8.28e−18 |
| GH1 (MIM: 139250) | 2.60e−01 (n = 11, MAC = 13) | 2.60e−01 (n = 11) | 1.64e−02 (n = 118, MAC = 311) | 3.84e−06 (n = 157) | 1.06e−17 |
| STC2 (MIM: 603665) | 4.23e−01 (n = 5, MAC = 12) | 4.23e−01 (n = 5) | 3.40e−02 (n = 119, MAC = 357) | 9.65e−17 (n = 144) | 2.89e−16 |
| FBN2 (MIM: 612570) | 5.49e−02 (n = 73, MAC = 119) | 8.57e−02 (n = 77) | 5.97e−02 (n = 1195, MAC = 2,893) | 1.83e−14 (n = 1406) | 1.10e−13 |
| ADAMTS10 (MIM: 608990) | 5.47e−05 (n = 32, MAC = 48) | 1.25e−04 (n = 33) | 1.45e−10 (n = 460, MAC = 1,106) | 2.17e−04 (n = 565) | 4.80e−13 |
| PDE3B (MIM: 602047) | 2.83e−03 (n = 63, MAC = 139) | 9.02e−12 (n = 78) | 4.92e−02 (n = 472, MAC = 1,147) | 5.82e−10 (n = 584) | 5.33e−11 |
| PIEZO1 (MIM: 611184) | 2.03e−06 (n = 229, MAC = 509) | 1.52e−04 (n = 266) | 9.62e−06 (n = 2047, MAC = 5,529) | 9.09e−08 (n = 2,646) | 1.64e−10 |
| MC3R (MIM: 155540) | 5.68e−02 (n = 12, MAC = 24) | 1.62e−02 (n = 14) | 3.68e−01 (n = 156, MAC = 441) | 2.93e−11 (n = 183) | 1.76e−10 |
| DDR2 (MIM: 191311) | 5.31e−02 (n = 22, MAC = 46) | 5.31e−02 (n = 22) | 3.74e−04 (n = 284, MAC = 693) | 2.44e−10 (n = 339) | 3.65e−10 |
| GHSR (MIM: 601898) | 6.07e−04 (n = 21, MAC = 56) | 7.30e−07 (n = 25) | 6.52e−04 (n = 189, MAC = 468) | 2.69e−10 (n = 234) | 8.08e−10 |
| SMIM29 (MIM: 611419) | 6.43e−02 (n = 7, MAC = 15) | 5.65e−01 (n = 12) | 4.02e−01 (n = 69, MAC = 186) | 1.86e−10 (n = 93) | 1.12e−09 |
| GRAMD2A (MIM: 620181) | 6.75e−01 (n = 24, MAC = 61) | 3.14e−06 (n = 28) | 1.47e−01 (n = 125, MAC = 326) | 2.16e−10 (n = 159) | 1.29e−09 |
| HSD11B2 (MIM: 614232) | 8.21e−01 (n = 23, MAC = 39) | 6.11e−01 (n = 28) | 1.47e−02 (n = 189, MAC = 480) | 2.19e−10 (n = 233) | 1.31e−09 |
| FGFR3 (MIM: 134934) | 9.59e−01 (n = 27, MAC = 61) | 1.15e−01 (n = 31) | 1.08e−03 (n = 421, MAC = 1,135) | 2.36e−10 (n = 533) | 1.41e−09 |
| PDE11A (MIM: 604961) | 1.49e−01 (n = 68, MAC = 182) | 4.31e−06 (n = 87) | 4.86e−02 (n = 452, MAC = 1,201) | 5.65e−10 (n = 562) | 3.39e−09 |
| IHH (MIM: 600726) | 4.93e−05 (n = 10, MAC = 14) | 4.93e−05 (n = 10) | 2.68e−05 (n = 186, MAC = 443) | 2.53e−09 (n = 225) | 3.75e−09 |
| MICA (MIM: 600169) | 9.89e−01 (n = 11, MAC = 37) | 4.02e−04 (n = 18) | 6.96e−01 (n = 144, MAC = 352) | 9.78e−10 (n = 193) | 5.87e−09 |
| NPAS4 (MIM: 608554) | 1.84e−02 (n = 9, MAC = 11) | 1.21e−01 (n = 12) | 9.99e−01 (n = 297, MAC = 670) | 1.62e−09 (n = 354) | 9.72e−09 |
| SCUBE3 (MIM: 614708) | 3.66e−06 (n = 47, MAC = 82) | 3.66e−06 (n = 47) | 1.52e−05 (n = 396, MAC = 966) | 4.42e−03 (n = 476) | 9.79e−09 |
For the phenotype of “comparative height size at age 10,” the significance level is 1e−8. LoF ultra-rare variants (URVs) and LoF+Missense URVs are the marker of the collapsed ultra-rare variants in the annotation of LoF and LoF+Missense, respectively. Genome position is based on the GRCh38 reference. LoF rare variants and LoF+Missense rare variants are SKAT-O test p values with MAF cutoffs 1%. Cauchy p values are calculated to combine six SKAT-O p values with three MAF cutoffs, including 0.01%, 0.1%, and 1%, and two annotation groups, including LoF and LoF+Missense.