Background
Methods
Subjects
Family-based study | Case-control study | |||
---|---|---|---|---|
ADHD (trios) | ADHD (indep.) | Controls | P values | |
N
| 1397 | 569 | 957 | |
Mean Age
(SD)
| 9.9 (2.5) | 10.5 (2.6) | 15.4 (8.5) | < 0.001 |
N Male
(%)
| 1171 (83.9) | 465 (81.7) | 617 (64.5) | < 0.001 |
N subtypes
(%)
| ||||
Inattentive | 706 (50.5) | 295 (51.8) | ||
Hyperactive-impulsive | 71 (5.1) | 22 (3.9) | ||
Combined | 620 (44.4) | 252 (44.3) |
DNA isolation
SNP selection and genotyping
No. | SNP marker | Sourcea | Includedb | Location | Allele |
---|---|---|---|---|---|
SNP 1 | rs4969239 | Tag SNP | Y | Intron 1 | A/G |
SNP 2 | rs4969358 | Tag SNP | Y | Intron 1 | A/C |
SNP 3 | rs6565531 | Tag SNP | Y | Intron 1 | A/G |
SNP 4 | rs8079626 | Tag SNP | Y | Intron 1 | A/G |
SNP 5 | rs3934492 | Tag SNP | Y | Intron 3 | C/G |
SNP 6 | rs9901648 | Tag SNP | Y | Intron 3 | A/G |
SNP 7 | rs4076037 | Tag SNP | Y | Intron 3 | A/G |
SNP 8 | rs8066330 | Tag SNP | Y | Intron 3 | C/T |
SNP 9 | rs4969385 | reported | Y | Intron 6 | C/T |
rs8067235 | Tag SNP | N, located on the same block with rs6565531(D’ = 1, r
2
= 0.642) | |||
rs6565532 | Tag SNP | N, located on the same block with rs6565531 (D’ = 1, r
2
= 0.798) | |||
rs8070741 | Tag SNP | N, with moderate LD with rs9901648 (D’ = 0.896, r
2
= 0.803) | |||
rs11657997 | Tag SNP | N, with moderate LD with rs9901648 (D’ = 1, r
2
= 0.783) | |||
rs4969355 | Tag SNP | N, located on the same block with rs4969239 (D’ = 1, r
2
= 0.764) and rs4969359 (D’ = 1,r
2
= 0.783) |
Statistical analyses
Results
Family-based association tests
Single-marker analyses
SNP no. | SNP | All (n = 1397) | ADHD-I (n = 706) | ADHD-HI (n = 71) | ADHD-C (n = 620) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Allele | T:NT | χ
2
|
P
| Allele | T:NT | χ
2
|
P
| Allele | T:NT | χ
2
|
P
| Allele | T:NT | χ
2
|
P
| ||
SNP 1 | rs4969239 | A | 598:577 | 0.38 | 0.540 | G | 297:286 | 0.21 | 0.649 | A | 32:28 | 0.27 | 0.606 | A | 280:252 | 1.47 | 0.225 |
SNP 2 | rs4969358 | A | 640:637 | 0.01 | 0.933 | A | 332:317 | 0.34 | 0.556 | C | 35:32 | 0.13 | 0.714 | C | 285:276 | 0.14 | 0.704 |
SNP 3 | rs6565531 | G | 606:602 | 0.01 | 0.908 | G | 335:296 | 2.41 | 0.121 | A | 39:33 | 0.50 | 0.480 | A | 267:238 | 1.67 | 0.197 |
SNP 4 | rs8079626 | G | 617:598 | 0.30 | 0.586 | G | 337:293 | 3.07 | 0.080 | A | 35:34 | 0.01 | 0.904 | A | 270:246 | 1.12 | 0.291 |
SNP 5 | rs3934492 | C | 679:615 | 3.17 | 0.075 |
C
|
361:
305
|
4.71
|
0.030
| C | 37:31 | 0.53 | 0.467 | C | 281:279 | 0.01 | 0.933 |
SNP 6 | rs9901648 | G | 550:542 | 0.06 | 0.809 | A | 285:267 | 0.59 | 0.444 | G | 30:24 | 0.67 | 0.414 | G | 253:233 | 0.82 | 0.364 |
SNP 7 | rs4076037 | G | 659:630 | 0.65 | 0.419 | G | 351:315 | 1.95 | 0.163 | A | 37:26 | 1.92 | 0.166 | G | 282:278 | 0.03 | 0.866 |
SNP 8 | rs8066330 | T | 669:652 | 0.22 | 0.640 | C | 347:327 | 0.59 | 0.441 | T | 37:28 | 1.25 | 0.264 | T | 305:277 | 1.34 | 0.246 |
SNP 9 | rs4969385 | C | 371:357 | 0.27 | 0.604 | T | 193:178 | 0.61 | 0.436 | C | 22:17 | 0.64 | 0.423 | C | 171:147 | 1.81 | 0.178 |
Multi-marker haplotype-based association tests
Haplotypea | Freq.b | T:NT | χ
2
| Nominal P | Empirical Pc |
---|---|---|---|---|---|
GA | 0.440 | 303.9:359.5 | 4.66 |
0.031
| 0.207 |
CG | 0.329 | 272.2:289.4 | 0.53 | 0.466 | 1.000 |
CA | 0.229 | 281.3:207.4 | 11.18 |
8.0e-
4
|
0.005
|
Case-control studies
Single-marker analyses
SNP | Allele | Alleles | Genotypes | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 2 | 2 vs. 1 | Cases N (%) | Controls N (%) | Genotype 11 vs. 12+22 | Genotype 11+12 vs. 22 | |||||||||
OR (95% CI) |
P
| 11 | 12 | 22 | 11 | 12 | 22 |
P
| OR (95% CI) |
P
| OR (95% CI) |
P
| |||
ADHD in general | |||||||||||||||
rs4969239 | A | G | 1.10 (0.93-1.29) | 0.261 | 226 (42.6) | 233 (44.0) | 71 (13.4) | 423 (44.6) | 421 (44.4) | 104 (11.0) | 0.366 | ||||
rs4969358 | A | C | 1.12 (0.97-1.31) | 0.135 | 97 (17.3) | 280 (49.8) | 185 (32.9) | 148 (15.6) | 452 (47.6) | 350 (36.8) | 0.284 | ||||
rs6565531 | A | G | 1.05 (0.90-1.23) | 0.503 | 82 (14.6) | 252 (44.9) | 227 (40.5) | 146 (15.3) | 441 (46.3) | 366 (38.4) | 0.726 | ||||
rs8079626 | A | G | 1.06 (0.91-1.23) | 0.482 | 84 (15.5) | 249 (45.9) | 209 (38.6) | 155 (16.3) | 444 (46.7) | 352 (37.0) | 0.819 | ||||
rs3934492 | C | G | 1.16 (0.99-1.35) | 0.055 | 184 (33.4) | 273 (49.5) | 94 (17.1) | 297 (31.7) | 428 (45.6) | 213 (22.7) |
0.033
| 1.09 (0.86-1.35) | 0.490 | 1.43 (1.09-1.85) |
0.009
|
rs9901648 | A | G | 1.02 (0.87-1.20) | 0.811 | 249 (46.6) | 232 (43.4) | 53 (9.9) | 465 (49.1) | 374 (39.5) | 109 (11.5) | 0.283 | ||||
rs4076037 | A | G | 1.11 (0.96-1.29) | 0.165 | 132 (24.5) | 272 (50.5) | 135 (25.0) | 267 (28.1) | 460 (48.5) | 222 (23.4) | 0.305 | ||||
rs8066330 | C | T | 1.08 (0.93-1.26) | 0.289 | 146 (26.0) | 279 (49.6) | 137 (24.4) | 220 (23.2) | 496 (52.2) | 234 (24.6) | 0.444 | ||||
rs4969385 | C | T | 1.27 (1.04-1.55) |
0.018
| 368 (67.6) | 153 (28.1) | 23 (4.2) | 681 (71.4) | 259 (27.1) | 14 (1.5) |
0.003
| 1.19 (0.95-1.50) | 0.129 | 2.96 (1.51-5.81) |
0.001
b
|
Inattentive subtype | |||||||||||||||
rs4969239 | A | G | 1.29 (1.06-1.58) |
0.010
| 103 (37.5) | 126 (45.8) | 46 (16.7) | 423 (44.6) | 421 (44.4) | 104 (11.0) |
0.015
| 1.35 (1.02-1.77) |
0.035
| 1.63 (1.12-2.38) |
0.010
|
rs4969358 | A | C | 1.21 (0.99-1.46) | 0.052 | 55 (18.9) | 146 (50.2) | 90 (30.9) | 148 (15.6) | 452 (47.6) | 350 (36.8) | 0.135 | ||||
rs6565531 | A | G | 1.07 (0.89-1.30) | 0.474 | 37 (12.7) | 139 (47.6) | 116 (39.7) | 146 (15.3) | 441 (46.3) | 366 (38.4) | 0.535 | ||||
rs8079626 | A | G | 1.05 (0.87-1.27) | 0.612 | 40 (14.0) | 140 (49.0) | 106 (37.1) | 155 (16.3) | 444 (46.7) | 352 (37.0) | 0.611 | ||||
rs3934492 | C | G | 1.22 (1.01-1.48) |
0.039
| 104 (36.0) | 1396 (47.1) | 49 (17.0) | 297 (31.7) | 428 (45.6) | 213 (22.7) | 0.091 | 0.82 (0.63-1.09) | 0.171 | 0.70 (0.49-0.98) |
0.037
|
rs9901648 | A | G | 1.00 (0.82-1.23) | 0.985 | 130 (46.6) | 124 (44.4) | 25 (9.0) | 465 (49.1) | 374 (39.5) | 109 (11.5) | 0.239 | ||||
rs4076037 | A | G | 1.18 (0.98-1.43) | 0.084 | 59 (21.0) | 153 (54.4) | 69 (24.6) | 267 (28.1) | 460 (48.5) | 222 (23.4) | 0.054 | ||||
rs8066330 | C | T | 1.08 (0.89-1.30) | 0.412 | 77 (26.4) | 145 (49.7) | 70 (24.0) | 220 (23.2) | 496 (52.2) | 234 (24.6) | 0.526 | ||||
rs4969385 | C | T | 1.27 (0.99-1.62) | 0.061 | 194 (68.3) | 76 (26.8) | 14 (4.9) | 681 (71.4) | 259 (27.1) | 14 (1.5) |
0.003
| 1.16 (0.87-1.54) | 0.318 | 3.48 (1.64-7.39) |
0.001
b
|
Combined subtype | |||||||||||||||
rs4969239 | A | G | 1.13 (0.91-1.41) | 0.281 | 114 (48.7) | 98 (41.9) | 22 (9.4) | 423 (44.6) | 421 (44.4) | 104 (11.0) | 0.497 | ||||
rs4969358 | A | C | 1.06 (0.87-1.30) | 0.569 | 39 (15.7) | 125 (50.2) | 85 (34.1) | 148 (15.6) | 452 (47.6) | 350 (36.8) | 0.711 | ||||
rs6565531 | A | G | 1.04 (0.84-1.28) | 0.732 | 41 (16.6) | 104 (42.1) | 102 (41.3) | 146 (15.3) | 441 (46.3) | 366 (38.4) | 0.502 | ||||
rs8079626 | A | G | 1.08 (0.87-1.32) | 0.499 | 40 (17.2) | 98 (42.1) | 95 (40.8) | 155 (16.3) | 444 (46.7) | 352 (37.0) | 0.436 | ||||
rs3934492 | C | G | 1.10 (0.90-1.35) | 0.341 | 74 (30.8) | 125 (52.1) | 41 (17.1) | 297 (31.7) | 428 (45.6) | 213 (22.7) | 0.103 | ||||
rs9901648 | A | G | 1.03 (0.82-1.28) | 0.823 | 110 (47.2) | 98 (42.1) | 25 (10.7) | 465 (49.1) | 374 (39.5) | 109 (11.5) | 0.761 | ||||
rs4076037 | A | G | 1.06 (0.87-1.30) | 0.553 | 66 (28.0) | 108 (45.8) | 62 (26.3) | 267 (28.1) | 460 (48.5) | 222 (23.4) | 0.624 | ||||
rs8066330 | C | T | 1.07 (0.88-1.31) | 0.486 | 63 (25.4) | 122 (49.2) | 63 (25.4) | 220 (23.2) | 496 (52.2) | 234 (24.6) | 0.666 | ||||
rs4969385 | C | T | 1.31 (1.01-1.71) |
0.042
| 158 (66.4) | 71 (29.8) | 9 (3.8) | 681 (71.4) | 259 (27.1) | 14 (1.5) | 0.060 | 1.26 (0.93-1.71) | 0.131 | 2.64 (1.13-6.17) |
0.040
|
B | S.E. | Wald |
P
| OR (95% CI) | |
---|---|---|---|---|---|
ADHD vs. Control
(569 vs. 957)
| |||||
Age | −0.014 | 0.001 | 149.647 | < 0.001 | 0.99 (0.98-0.99) |
Gender | −1.410 | 0.141 | 100.549 | < 0.001 | 0.24 (0.19-0.32) |
rs3934492 (11 + 12 vs. 22) | 0.354 | 0.153 | 5.365 |
0.021
| 1.43 (1.06-1.92) |
Age | −0.014 | 0.001 | 151.851 | < 0.001 | 0.99 (0.98-0.99) |
Gender | −1.429 | 0.142 | 100.615 | < 0.001 | 0.24 (0.18-0.32) |
rs4969385 (11 + 12 vs. 22) | 0.850 | 0.377 | 5.092 |
0.024
| 2.33 (1.02-5.00) |
ADHD-
I vs. Control
(295 vs. 957)
| |||||
Age | −0.011 | 0.001 | 76.853 | < 0.001 | 0.99 (0.99-0.99) |
Gender | −1.265 | 0.176 | 51.643 | < 0.001 | 0.28 (0.20-0.40) |
rs4969239 (11 vs. 12 + 22) | 0.327 | 0.150 | 4.743 |
0.029
| 1.39 (1.03-1.86) |
Age | −0.011 | 0.001 | 76.411 | < 0.001 | 0.99 (0.99-0.99) |
Gender | −1.259 | 0.176 | 51.106 | < 0.001 | 0.28 (0.20-0.40) |
rs4969239 (11 + 12 vs. 22) | 0.513 | 0.208 | 6.090 |
0.014
| 1.67 (1.11-2.51) |
Age | −0.011 | 0.001 | 76.882 | < 0.001 | 0.99 (0.99-0.99) |
Gender | −1.285 | 0.172 | 55.511 | < 0.001 | 0.28 (0.20-0.39) |
rs3934492 (11 + 12 vs. 22) | 0.368 | 0.186 | 3.915 |
0.048
| 1.45 (1.00-2.08) |
Age | −0.011 | 0.001 | 77.292 | < 0.001 | 0.99 (0.99-0.99) |
Gender | −1.297 | 0.173 | 54.534 | < 0.001 | 0.27 (0.19-0.39) |
rs4969385 (11 + 12 vs. 22) | 1.023 | 0.412 | 6.174 |
0.013
| 2.78 (1.24-6.24) |
ADHD-
C vs. Control
(252 vs. 957)
| |||||
Age | −0.015 | 0.002 | 84.927 | < 0.001 | 0.99 (0.98-0.99) |
Gender | −1.500 | 0.196 | 58.497 | < 0.001 | 0.22 (0.15-0.33) |
rs4969385 (11 + 12 vs. 22) | 0.820 | 0.478 | 2.938 | 0.086 | 2.27 (0.89-5.80) |
Multi-marker haplotype-based association tests
Haplotype | ADHD (n = 569) | ADHD-I (n = 295) | ADHD-C (n = 252) | |||||||
---|---|---|---|---|---|---|---|---|---|---|
χ2 | Nominal P | Empirical Pc | χ2 | Nominal P | Empirical Pc | χ2 | Nominal P | Empirical Pc | ||
Block2
a
| GA↓ | 3.31 | 0.069 | 0.307 | 3.98 |
0.046
| 0.217 | 0.76 | 0.384 | 0.890 |
CG
| 0.15 | 0.696 | 0.993 | 0.01 | 0.909 | 1.000 | 0.11 | 0.736 | 0.996 | |
CA↑ | 3.26 | 0.071 | 0.312 | 5.20 |
0.023
| 0.110 | 0.56 | 0.456 | 0.936 | |
Block3
b
|
TC
| 1.11 | 0.291 | 0.781 | 0.66 | 0.419 | 0.902 | 0.49 | 0.484 | 0.948 |
CC
| 0.49 | 0.482 | 0.937 | 0.33 | 0.561 | 0.967 | 0.63 | 0.427 | 0.916 | |
CT↑ | 5.44 |
0.019
| 0.097 | 3.47 | 0.062 | 0.274 | 3.96 |
0.047
| 0.215 |