Genome-Wide Analysis of Copy Number Variants in Attention Deficit Hyperactivity Disorder: The Role of Rare Variants and Duplications at 15q13.3
Abstract
Objective:
Method:
Results:
Conclusions:
Method
Participants
Statistical Analysis of Rare CNV Data
Validation of a Rare CNV on 15q13.3
Replication of Duplications at 15q13.3
Results
Burden of CNVs | Burden of Deletions Only | Burden of Duplications Only | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Measurea | ADHD Subjects | Comparison Subjects | Ratio | pb | ADHD Subjects | Comparison Subjects | Ratio | pb | ADHD Subjects | Comparison Subjects | Ratio | pb |
CNVs >100 kb | ||||||||||||
N | 460 | 1,102 | 161 | 406 | 299 | 696 | ||||||
Rate | 0.628 | 0.548 | 1.15 | 0.014 | 0.220 | 0.202 | 1.09 | 0.199 | 0.409 | 0.346 | 1.18 | 0.016 |
Proportion | 0.456 | 0.406 | 1.13 | 0.011 | 0.194 | 0.179 | 1.09 | 0.197 | 0.327 | 0.282 | 1.16 | 0.014 |
CNVs >500 kb | ||||||||||||
N | 89 | 191 | 22 | 47 | 67 | 144 | ||||||
Rate | 0.122 | 0.095 | 1.28 | 0.032 | 0.030 | 0.023 | 1.29 | 0.199 | 0.092 | 0.072 | 1.28 | 0.059 |
Proportion | 0.112 | 0.092 | 1.22 | 0.069 | 0.030 | 0.023 | 1.29 | 0.199 | 0.085 | 0.070 | 1.21 | 0.113 |
CNVs >100 kb, intersecting genes | ||||||||||||
N | 303 | 720 | 74 | 203 | 229 | 517 | ||||||
Rate | 0.414 | 0.358 | 1.16 | 0.025 | 0.101 | 0.101 | 1.00 | 0.524 | 0.313 | 0.257 | 1.22 | 0.013 |
Proportion | 0.329 | 0.290 | 1.14 | 0.031 | 0.097 | 0.092 | 1.06 | 0.359 | 0.262 | 0.219 | 1.20 | 0.010 |
ADHD Subjects | Comparison Subjects | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Sample | 15q13 Duplication (N) | No Duplication (N) | Duplication Frequency (%) | 15q13 Duplication (N) | No Duplication (N) | Duplication Frequency (%) | p | Odds Ratio | 95% CI | Breslow-Day Test |
Primary study | ||||||||||
IMAGE II | 8 | 724 | 1.10 | 6 | 2,004 | 0.30 | 0.016 | 3.68 | 1.27–10.63 | |
Replication studies | ||||||||||
Cardiff | 6 | 313 | 1.92 | 5 | 1,042 | 0.48 | 0.023 | 3.99 | 1.21–13.18 | |
Children's Hospital of Philadelphia | 15 | 998 | 1.50 | 32 | 4,073 | 0.79 | 0.039 | 1.91 | 1.03–3.55 | |
Toronto | 2 | 245 | 0.82 | 16 | 2,341 | 0.68 | 0.814 | 1.19 | 0.27–5.23 | |
PUWMa | 6 | 686 | 0.87 | 5 | 1,096 | 0.46 | 0.210 | 0.91 | 0.34–2.44 | |
All replication samples | 29 | 2,242 | 1.29 | 58 | 8,552 | 0.68 | 0.00275 | 2.02 | 1.26–3.21 | 0.62 |
All samples combined | 37 | 2,966 | 1.25 | 64 | 10,556 | 0.61 | 0.000178 | 2.22 | 1.46–3.38 | 0.28 |
All CNVs >100 kb | |||||
---|---|---|---|---|---|
Gene/Locus and Measure | Chromosome | Start (bp) | End (bp) | ADHD Subjects | Comparison Subjects |
Implicated in autism | |||||
NRXN1 | 2 | 50000991 | 51113178 | 0 | 0 |
SLC9A9 | 3 | 144466753 | 145049979 | 0 | 0 |
c3orf58 | 3 | 145173602 | 145193895 | 0 | 0 |
NIPBL | 5 | 36912617 | 37101678 | 0 | 0 |
NSD1 | 5 | 176492685 | 176659820 | 0 | 0 |
AHI1 | 6 | 135646816 | 135860576 | 0 | 0 |
CNTNAP2 | 7 | 145444385 | 147749019 | 0 | 0 |
CHD7 | 8 | 61753892 | 61942021 | 0 | 0 |
VPS13B | 8 | 100094669 | 100958984 | 0 | 0 |
TSC1 | 9 | 134756556 | 134809841 | 0 | 0 |
PTEN | 10 | 89613174 | 89718512 | 0 | 0 |
DHCR7 | 11 | 70823104 | 70837125 | 0 | 0 |
CACNA1C | 12 | 2032676 | 2677376 | 0 | 0 |
PTPN11 | 12 | 111340918 | 111432100 | 0 | 0 |
UBE3A | 15 | 23133488 | 23235221 | 0 | 0 |
TSC2 | 16 | 2037990 | 2078714 | 0 | 0 |
CREBBP | 16 | 3715056 | 3870122 | 0 | 0 |
RAI1 | 17 | 17525511 | 17655490 | 0 | 0 |
NF1 | 17 | 26446120 | 26728821 | 0 | 0 |
DMPK | 19 | 50964815 | 50977655 | 0 | 0 |
ADSL | 22 | 39072449 | 39092521 | 0 | 0 |
SHANK3 | 22 | 49459935 | 49518507 | 0 | 0 |
1p36 | 1 | 1 | 5308621 | 2 | 0 |
1q21.1 | 1 | 144979000 | 146204000 | 1 | 3 |
2q37 | 2 | 239619630 | 242951149 | 0 | 1 |
4p16 | 4 | 1 | 2043468 | 0 | 0 |
7q11.23 | 7 | 71970679 | 74254837 | 0 | 0 |
15q11.2–q13.1 | 15 | 21309483 | 26230781 | 2 | 1 |
15q13.3 | 15 | 28557287 | 30488774 | 9 | 7 |
15q24 | 15 | 72164227 | 73949332 | 0 | 0 |
16p11.2 | 16 | 29550000 | 30200000 | 1 | 4 |
22q11 | 22 | 17015754 | 20000000 | 3 | 4 |
CNVs overlapping | 18 | 20 | |||
CNVs not overlapping | 442 | 1,082 | |||
p | 0.009 | ||||
Frequency of CNV hits | 0.039 | 0.018 | |||
Ratio (case/control) | 2.156 | ||||
Implicated in schizoprenia | |||||
CNTNAP2 | 7 | 145444385 | 147749019 | 0 | 0 |
NRXN1 | 2 | 50000991 | 51113178 | 0 | 0 |
1q21.1 | 1 | 144940000 | 146290000 | 1 | 3 |
15q11.2 | 15 | 20310000 | 20780000 | 8 | 13 |
15q13.3 | 15 | 28720000 | 30300000 | 9 | 7 |
16p13.11 | 16 | 14890000 | 16390000 | 3 | 9 |
16p11.2 | 16 | 29554844 | 30085308 | 1 | 4 |
22q11 | 22 | 17500000 | 20000000 | 3 | 4 |
CNVs overlapping | 25 | 40 | |||
CNVs not overlapping | 435 | 1,062 | |||
p | 0.03 | ||||
Frequency of CNV hits | 0.054 | 0.036 | |||
Ratio (case/control) | 1.497 |
Discussion
Acknowledgments
Footnote
Supplementary Material
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