Table 2.
Gene-based association tests in the TRICL study, ranked by P-value from the combined multivariate and collapsing test.
| Genes | N. rare deleterious variants* | N. multi-marker genotypes | N. carriers LC /Control | KBAC test P-value | CMC test P-value | CMC test OR (95% CI) | Gene constraint LoF o/e (90% CI)& | Gene PhoRank to phenotype# |
|---|---|---|---|---|---|---|---|---|
| Risk genes | ||||||||
| CCDC105 | 20 | 11 | 28/5 | 0.012 | 0.013 | 5.63 (0.87–31.4) | 0.71 (0.46–1.12) | 0.12 _ PF |
| BMP8A | 3 | 4 | 11/2 | 0.014 | 0.014 | 4.22 (1.14–36.3) | 0.8 (0.49–1.35) | 0.32 _ PF |
| MME/CD10 | 5 | 6 | 7/0 | 0.014 | 0.015 | 1.85 (0.65–11.16) | 0.7 (0.54–0.92) | 0.83 _ LC |
| NPHP3 | 6 | 7 | 7/0 | 0.015 | 0.015 | 1.68 (0.76–15.4) | 0.5 (0.38–0.65) | 0.68 _ PF |
| MLNR | 5 | 6 | 11/2 | 0.005 | 0.022 | 4.19 (1.12–38.9) | 0.51 (0.5–1.16) | 0.09 _ PF |
| NKX6-1 | 9 | 11 | 47/31 | 0.064 | 0.048 | 1.30 (0.82–2.06) | 0.39 (0.18–1.0) | 0.28 _ LC |
| ENAM | 7 | 8 | 9/2 | 0.043 | 0.065 | 2.94 (0.79–9.07) | 0.6 (0.44–0.84)` | 0.32 _ PF |
| ATM | 15 | 15 | 16/11 | 0.591 | 0.098 | 1.58 (0.69–7.04) | 0.60 (0.51–0.71) | 0.95 _ LC |
| RHBDD3 | 9 | 10 | 11/4 | 0.101 | 0.102 | 1.64 (0.85–23.6) | 0.71 (0.41–1.27) | 0.16 _ PF |
| STAU2 | 27 | 31 | 107/76 | 0.141 | 0.213 | 1.21 (0.89–1.65) | 0.14 (0.07–0.32) | 0.23 _ LC |
| TALPID3 | 11 | 12 | 17/8 | 0.139 | 0.403 | 1.64 (0.93–2.24) | 0.54 (0.42–0.72) | 0.61 _ PF |
| MPZL2 | 6 | 7 | 7/3 | 0.153 | 0.403 | 1.34 (0.77–2.13) | 1.34 (0.9–1.86) | 0.12 _ LC |
| TP63 | 6 | 7 | 9/3 | 0.396 | 0.539 | 1.20 (0.59–12.3) | 0.13 (0.07–0.27) | 0.87 _ LC |
| POMC | 6 | 7 | 7/5 | 0.744 | 0.790 | 1.45 (0.57–3.71) | 0.74 (0.42–1.38) | 0.30 _ PF |
| F13B | 5 | 6 | 7/5 | 0.965 | 0.905 | 1.02 (0.81–1.27) | 0.59 (0.41–0.85) | 0.34 _ PF |
| Protective genes | ||||||||
| TXNDC15 | 11 | 12 | 10/27 | 0.746 | 0.001 | 0.31 (0.15–0.64) | 0.38 (0.21–0.76) | 0.60 _ PF |
| GJB6 | 2 | 3 | 0/6 | 0.877 | 0.008 | 0.12 (0.02–0.66) | 1.07 (0.66–1.74) | 0.31 _ LC |
| MOB3A | 3 | 4 | 3/12 | 0.587 | 0.008 | 0.21 (0.05–0.67) | 0.96 (0.54–1.7) | 0.10 _ LC |
| CASQ2 | 2 | 4 | 15/26 | 0.955 | 0.013 | 0.73 (0.44–1.23) | 0.94 (0.65–1.38) | 0.36 _ PF |
| OR51J1 | 2 | 3 | 1/6 | 0.351 | 0.037 | 0.14 (0.03–0.84) | 0.19 (0.07–0.88) | 0.10 _ PF |
| FAM111A | 5 | 6 | 11/21 | 0.406 | 0.076 | 0.42 (0.20–0.92) | 2.09 (0.66–1.95) | 0.29 _ LC |
| PHF13 | 9 | 10 | 16/12 | 0.097 | 0.742 | 1.23 (0.53–5.17) | 0.01 (0–0.25) | 0.28 _ LC + PF |
| MLKL | 17 | 19 | 30/28 | 0.055 | 0.689 | 0.95 (0.54–3.52) | 0.87 (0.63–1.24) | 0.20 _ PF |
| CHEK2 | 8 | 9 | 7/5 | 0.484 | 0.811 | 1.11 (0.64–2.02) | 1.15 (0.87–1.53) | 0.97 _ LC |
TRICL Transdisciplinary Research in Cancer of the Lung, CMC Combined Multivariate and Collapsing, KBAC Kernel-Based Adaptive Cluster, LoF loss of function, LC lung cancer, PF pulmonary function, OR odds ratio, CI confidence interval, o/e observed/expected.
*Number of rare deleterious variants within the genes. False discovery rate (FDR) adjusted P-value was reported.
&Gene constraint LoF o/e values developed with gnomAD: observed counts are based on sequencing data from gnomAD, expected counts are based on a mutational model that takes sequence context and coverage into account. Lower o/e, in particular, the upper bound of the CI < 0.35 are indicative of strong intolerance (disease-causing). The top three genes with the lowest o/e were bolded: PHF13, TP63, and STAU2.
#Genes Phevo PhoRank is based on gene functions relevant to the disease phenotype (LC, COPD/PF) from diverse biomedical ontologies. Disease-associated genes have a higher Phevor score. The top four genes with the highest scores were bolded: CHEK2, ATM, TP63, and MME/CD10.