Background
Methods
Study population
Definition of HNSCC and subtypes
Genotype data quality control and imputation
UK Biobank
Penn Medicine Biobank
Polygenic risk score
Phenome-wide association study
Statistical analysis
Results
Participants
PRS association with HNSCC and validation in the UKBB and PMBB
PRS-PheWAS
Phenotype description | UK Biobanka | Penn Medicine Biobankb (replication cohort) | |||
---|---|---|---|---|---|
No. of cases (prevalence, %) | OR per SD increase (95% CI) | P-value | OR per SD increase (95% CI) | P-value | |
HNSCC PRS | |||||
Tobacco use disorder | 20,599 (6.7%) | 1.06 (1.05–1.08) | 3.50 × 10−15 | 1.04 (1.02–1.07) | 1.05 × 10−3 |
Alcoholism | 9636 (3.1%) | 1.06 (1.04–1.09) | 6.14 × 10−9 | 1.11 (1.01–1.22) | 2.29 × 10−2 |
Alcohol-related disorders | 6015 (1.9%) | 1.08 (1.05–1.11) | 1.09 × 10−8 | 1.11 (1.02–1.22) | 2.22 × 10−2 |
Emphysema | 2096 (0.7%) | 1.11 (1.06–1.16) | 5.48 × 10−6 | 1.10 (1.03–1.16) | 2.44 × 10−3 |
Chronic airway obstruction | 9151 (3.0%) | 1.05 (1.03–1.07) | 2.64 × 10−5 | 1.08 (1.04–1.11) | 2.16 × 10−5 |
Cancer of bronchus; lung | 2781 (0.9%) | 1.08 (1.04–1.13) | 4.68 × 10−5 | 1.12 (1.05–1.19) | 4.44 × 10−4 |
OPC PRS | |||||
Tobacco use disorder | 20,599 (6.7%) | 1.06 (1.04–1.07) | 2.85 × 10−13 | 1.04 (1.02–1.07) | 1.43 × 10−3 |
Cancer of bronchus; lung | 2781 (0.9%) | 1.09 (1.05–1.13) | 1.27 × 10−5 | 1.07 (1.01–1.14) | 2.05 × 10−2 |
Chronic airway obstruction | 9151 (3.0%) | 1.05 (1.02–1.07) | 4.32 × 10−5 | 1.04 (1.01–1.08) | 1.20 × 10−2 |
OC PRS | |||||
Tobacco use disorder | 20,599 (6.7%) | 1.04 (1.02–1.05) | 3.20 × 10−7 | 1.04 (1.02–1.07) | 1.48 × 10−3 |
PRS-PheWAS validation in the PMBB
Sensitivity analysis
Exclusion PheWAS
Phenotype description | Exclusion analysis1 | Exclusion analysis2 | Exclusion analysis3 | |||
---|---|---|---|---|---|---|
OR per SD increase (95% CI) | P-value | OR per SD increase (95% CI) | P-value | OR per SD increase (95% CI) | P-value | |
HNCSS PRS | ||||||
Tobacco use disorder | 1.06 (1.04–1.07) | 6.83 × 10−14 | 1.06 (1.05–1.08) | 3.41 × 10−15 | 1.06 (1.04–1.07) | 6.84 × 10−14 |
Alcoholism | 1.06 (1.04–1.08) | 5.38 × 10−8 | 1.06 (1.04–1.09) | 6.09 × 10−9 | 1.06 (1.04–1.08) | 5.28 × 10−8 |
Alcohol-related disorders | 1.08 (1.05–1.11) | 6.98 × 10−8 | 1.08 (1.05–1.11) | 1.04 × 10−8 | 1.08 (1.05–1.11) | 6.57 × 10−8 |
Emphysema | 1.11 (1.06–1.16) | 9.15 × 10−6 | 1.11 (1.06–1.16) | 4.92 × 10−6 | 1.11 (1.06–1.16) | 8.41 × 10−6 |
Chronic airway obstruction | 1.04 (1.02–1.07) | 1.20 × 10−4 | 1.05 (1.02–1.07) | 2.70 × 10−5 | 1.04 (1.02–1.07) | 1.12 × 10−4 |
Cancer of bronchus; lung | 1.08 (1.04–1.13) | 6.41 × 10−5 | 1.08 (1.04–1.13) | 5.01 × 10−5 | 1.08 (1.04–1.13) | 6.90 × 10−5 |
OPC PRS | ||||||
Tobacco use disorder | 1.05 (1.04–1.07) | 5.51 × 10−12 | 1.05 (1.04–1.07) | 2.72 × 10−12 | 1.05 (1.04–1.07) | 2.44 × 10−11 |
Cancer of bronchus; lung | 1.09 (1.05–1.13) | 2.30 × 10−5 | 1.09 (1.05–1.13) | 1.62 × 10−5 | 1.09 (1.05–1.13) | 2.49 × 10−5 |
Chronic airway obstruction | 1.04 (1.02–1.07) | 1.62 × 10−4 | 1.04 (1.02–1.07) | 1.06 × 10−4 | 1.04 (1.02–1.06) | 2.99 × 10−4 |
OC PRS | ||||||
Tobacco use disorder | 1.04 (1.02–1.05) | 1.36 × 10−6 | 1.04 (1.02–1.05) | 2.42 × 10−7 | 1.04 (1.02–1.05) | 9.64 × 10−7 |
MHC region exclusion analysis
Sex, age, and smoking status-stratified analyses
Phenotype description | Male (n = 140,232) | Female (n = 168,260) | Sex-interaction | |||
---|---|---|---|---|---|---|
No. of cases (%) | OR per SD increase (95% CI) | P-value | OR per SD increase (95% CI) | P-value | P-value for interaction | |
HNSCC PRS | ||||||
Tobacco use disorder | 20,599 (6.7%) | 1.06 (1.04–1.08) | 3.06 × 10−8 | 1.07 (1.04–1.09) | 1.26 × 10−8 | .207 |
Alcoholism | 9636 (3.1%) | 1.06 (1.03–1.09) | 1.44 × 10−5 | 1.07 (1.03–1.11) | 9.08 × 10−5 | .886 |
Alcohol-related disorders | 6015 (1.9%) | 1.08 (1.05–1.12) | 5.95 × 10−7 | 1.07 (1.02–1.13) | 4.35 × 10−3 | .830 |
Emphysema | 2096 (0.7%) | 1.10 (1.04–1.16) | 1.50 × 10−3 | 1.13 (1.05–1.21) | 9.79 × 10−4 | .470 |
Chronic airway obstruction | 9151 (3.0%) | 1.04 (1.02–1.08) | 2.95 × 10−3 | 1.05 (1.02–1.09) | 2.94 × 10−3 | .591 |
Cancer of bronchus; lung | 2781 (0.9%) | 1.10 (1.05–1.16) | 2.74 × 10−4 | 1.06 (1.00–1.12) | 4.04 × 10−2 | .365 |
Phenotype description | Younger (age ≤ 60 years) | Elderly (age > 60 years) | Never-smoker | Ever-smoker | ||||
---|---|---|---|---|---|---|---|---|
(n = 166,624) | (n = 141,868) | (n = 119,038) | (n = 190,562) | |||||
OR per SD increase (95% CI) | P-value | OR per SD increase (95% CI) | P-value | OR per SD increase (95% CI) | P-value | OR per SD increase (95% CI) | P-value | |
HNSCC PRS | ||||||||
Tobacco use disorder | 1.08 (1.06–1.10) | 1.54 × 10−13 | 1.04 (1.02–1.06) | 3.77 × 10−4 | 1.02 (0.94–1.10) | .631 | 1.06 (1.04–1.07) | 3.11 × 10−12 |
Alcoholism | 1.07 (1.04–1.10) | 1.16 × 10−5 | 1.06 (1.03–1.09) | 1.38 × 10−4 | 1.05 (1.00–1.09) | 3.09 × 10−2 | 1.07 (1.04–1.10) | 8.80 × 10−8 |
Alcohol-related disorders | 1.09 (1.05–1.13) | 6.24 × 10−7 | 1.07 (1.02–1.11) | 3.44 × 10−3 | 1.04 (0.98–1.11) | .149 | 1.08 (1.05–1.12) | 8.20 × 10−8 |
Emphysema | 1.13 (1.04–1.22) | 3.22 × 10−3 | 1.10 (1.04–1.16) | 4.34 × 10−4 | 1.26 (1.07–1.48) | 4.97 × 10−3 | 1.09 (1.04–1.14) | 3.70 × 10−4 |
Chronic airway obstruction | 1.06 (1.02–1.10) | 6.13 × 10−3 | 1.04 (1.02–1.07) | 1.25 × 10−3 | 0.99 (0.93–1.06) | .864 | 1.05 (1.02–1.07) | 6.61 × 10−5 |
Cancer of bronchus; lung | 1.06 (0.99–1.14) | 7.86 × 10−2 | 1.09 (1.04–1.14) | 1.90 × 10−4 | 1.05 (1.01–1.09) | .355 | 1.08 (1.04–1.13) | 1.25 × 10−4 |
Association between HNSCC PRS and smoking, alcohol consumption, and HPV seropositivity
Low genetic risk group (0th–24th) | Intermediate genetic risk group (25th–49th) | High genetic risk group (50th–74th) | Very high genetic risk group (75th–99th) | P-value | |
---|---|---|---|---|---|
(n = 76,502) | (n = 77,180) | (n = 77,142) | (n = 77,668) | ||
Status | |||||
Smoking status (UKBB field: 20116), No. (%) | < .001 | ||||
Never | 41,282 (54.2%) | 40,837 (53.1%) | 40,711 (53.0%) | 39,893 (51.6%) | |
Previous | 27,655 (36.3%) | 28,229 (36.7%) | 28,071 (36.5%) | 28,367 (36.7%) | |
Current | 7270 (9.5%) | 7834 (10.2%) | 8099 (10.5%) | 9101 (11.8%) | |
Current tobacco smoking (UKBB field: 1239), No. (%) | < .001 | ||||
No | 69,176 (90.5%) | 69,291 (89.8%) | 68,988 (89.5%) | 68,527 (88.3%) | |
Only occasionally | 2001 (2.6%) | 1997 (2.6%) | 2012 (2.6%) | 2096 (2.7%) | |
Yes | 5269 (6.9%) | 5837 (7.6%) | 6087 (7.9%) | 7005 (9.0%) | |
Amount | |||||
Number of cigarettes previously smoked daily (UKBB field: 2887), mean ± SD | 19.0 ± 10.5 | 19.5 ± 10.7 | 19.4 ± 10.6 | 19.7 ± 10.8 | < .001 |
Pack years of smoking (UKBB field: 20161), mean ± SD | 23.6 ± 18.9 | 24.1 ± 19.2 | 24.5 ± 19.5 | 25.3 ± 19.7 | < .001 |
History | |||||
Past tobacco smoking (UKBB field: 1249), No. (%) | < .001 | ||||
Smoked on most or all days | 18,951 (26.6%) | 19,780 (27.7%) | 19,716 (27.8%) | 20,420 (28.9%) | |
Smoked occasionally | 10,381 (14.6%) | 10,178 (14.3%) | 10,112 (14.2%) | 9833 (13.9%) | |
Just tried once or twice | 11,203 (15.7%) | 10,801 (15.1%) | 10,621 (15.0%) | 10,066 (14.3%) | |
I have never smoked | 30,603 (43.0%) | 30,542 (42.8%) | 30,584 (43.1%) | 30,284 (42.9%) | |
Maternal smoking around birth (UKBB field: 1787), No. (%) | < .001 | ||||
No | 46,341 (70.3%) | 45,699 (68.8%) | 44,992 (67.9%) | 43,882 (66.0%) | |
Yes | 19,532 (29.7%) | 20,716 (31.2%) | 21,318 (32.1%) | 22,587 (34.0%) | |
Age stopped smoking (UKBB field: 2897), mean ± SD | 40.3 ± 11.9 | 40.3 ± 11.9 | 40.5 ± 11.8 | 40.7 ± 11.9 | < .001 |
Number of unsuccessful stop-smoking attempts (UKBB field: 2926), mean ± SD | 2.9 ± 7.0 | 3.0 ± 6.8 | 3.0 ± 7.9 | 3.1 ± 7.5 | .006 |
Low genetic risk group (0th–24th) | Intermediate genetic risk group (25th–49th) | High genetic risk group (50th–74th) | Very high genetic risk group (75th–99th) | P-value | |
---|---|---|---|---|---|
(n = 76,502) | (n = 77,180) | (n = 77,142) | (n = 77,668) | ||
Status | |||||
Alcohol drinker status (UKBB field: 20117), No. (%) | .001 | ||||
Never | 2501 (3.3%) | 2455 (3.2%) | 2525 (3.3%) | 2468 (3.2%) | |
Previous | 2677 (3.5%) | 2770 (3.6%) | 2888 (3.7%) | 3023 (3.9%) | |
Current | 71,245 (93.2%) | 71,879 (93.2%) | 71,652 (93.0%) | 72,077 (92.9%) | |
Alcohol intake frequency (UKBB field: 1558), No. (%) | .045 | ||||
Daily or almost daily | 14,927 (19.5%) | 15,235 (19.7%) | 15,082 (19.6%) | 15,158 (19.5%) | |
Three or four times a week | 17,599 (23.0%) | 17,756 (23.0%) | 17,756 (23.0%) | 18,049 (23.2%) | |
Once or twice a week | 20,490 (26.8%) | 20,416 (26.5%) | 20,451 (26.5%) | 20,856 (26.9%) | |
One to three times a month | 8867 (11.6%) | 9087 (11.8%) | 8949 (11.6%) | 8775 (11.3%) | |
Special occasions only | 8989 (11.8%) | 8997 (11.7%) | 9007 (11.7%) | 8894 (11.5%) | |
Never | 5617 (7.3%) | 5677 (7.4%) | 5886 (7.6%) | 5927 (7.6%) | |
Amount | |||||
Amount of alcohol drunk on a typical drinking day (UKBB field: 20403), No. (%) | < .001 | ||||
1 or 2 | 12,035 (53.5%) | 11,304 (51.9%) | 11,374 (52.3%) | 10,423 (49.6%) | |
3 or 4 | 6031 (26.8%) | 5958 (27.4%) | 5797 (26.6%) | 5823 (27.7%) | |
5 or 6 | 2530 (11.2%) | 2544 (11.7%) | 2554 (11.7%) | 2596 (12.4%) | |
7, 8 or 9 | 1322 (5.9%) | 1319 (6.1%) | 1387 (6.4%) | 1542 (7.3%) | |
10 or more | 572 (2.5%) | 650 (3.0%) | 645 (3.0%) | 622 (3.0%) | |
Frequency of consuming six or more units of alcohol (UKBB field: 20416), No. (%) | < .001 | ||||
Never | 11,933 (52.9%) | 11,265 (51.6%) | 11,200 (51.3%) | 10,463 (49.7%) | |
Less than monthly | 5409 (24.0%) | 5155 (23.6%) | 5286 (24.2%) | 5014 (23.8%) | |
Monthly | 1854 (8.2%) | 1870 (8.6%) | 1770 (8.1%) | 1876 (8.9%) | |
Weekly | 2647 (11.7%) | 2779 (12.7%) | 2772 (12.7%) | 2895 (13.8%) | |
Daily or almost daily | 702 (3.1%) | 753 (3.5%) | 790 (3.6%) | 800 (3.8%) | |
Type | |||||
Alcohol usually taken with meals (UKBB field: 1618), No. (%) | < .001 | ||||
No | 12,880 (30.9%) | 13,435 (32.5%) | 13,721 (33.4%) | 14,685 (35.8%) | |
Yes | 28,817 (69.1%) | 27,866 (67.5%) | 27,384 (66.6%) | 26,379 (64.2%) | |
Other non-alcoholic drinks (UKBB field: 100510), No. (%) | .330 | ||||
No | 26,030 (78.1%) | 25,290 (78.3%) | 24,752 (78.0%) | 24,012 (78.6%) | |
Yes | 7284 (21.9%) | 7003 (21.7%) | 6973 (22.0%) | 6540 (21.4%) | |
History | |||||
Alcohol intake versus 10 years previously (UKBB field: 1628), No. (%) | < .001 | ||||
More nowadays | 10,268 (14.5%) | 10,477 (14.7%) | 10,474 (14.7%) | 11,148 (15.6%) | |
About the same | 26,488 (37.4%) | 26,201 (36.6%) | 25,685 (36.1%) | 24,997 (34.9%) | |
Less nowadays | 34,083 (48.1%) | 34,822 (48.7%) | 35,084 (49.2%) | 35,518 (49.6%) | |
More nowadays | 10,268 (14.5%) | 10,477 (14.7%) | 10,474 (14.7%) | 11,148 (15.6%) | |
Ever physically dependent on alcohol (UKBB field: 20404), No. (%) | .006 | ||||
No | 369 (74.7%) | 404 (73.1%) | 377 (69.4%) | 373 (65.8%) | |
Yes | 125 (25.3%) | 149 (26.9%) | 166 (30.6%) | 194 (34.2%) | |
Ever had known a person concerned about, or recommended reduction of, alcohol consumption (UKBB field: 20405), No. (%) | < .001 | ||||
No | 22,649 (91.9%) | 21,921 (91.3%) | 21,753 (91.2%) | 20,823 (90.6%) | |
Yes, but not in the last year | 1046 (4.2%) | 1088 (4.5%) | 1118 (4.7%) | 1184 (5.1%) | |
Yes, during the last year | 941 (3.8%) | 992 (4.1%) | 987 (4.1%) | 989 (4.3%) |
Low genetic risk group (0th–24th) | Intermediate genetic risk group (25th–49th) | High genetic risk group (50th–74th) | Very high genetic risk group (75th–99th) | P-value | |
---|---|---|---|---|---|
(n = 76,502) | (n = 77,180) | (n = 77,142) | (n = 77,668) | ||
Status | |||||
HPV type-16 (UKBB field: 23075), No. (%) | .768 | ||||
Positive | 69 (4.8%) | 76 (5.1%) | 66 (4.4%) | 65 (4.4%) | |
Negative | 1366 (95.2%) | 1424 (94.9%) | 1445 (95.6%) | 1421 (95.6%) |