Integrated Genome-Wide Association Study Findings: Identification of a Neurodevelopmental Network for Attention Deficit Hyperactivity Disorder
Abstract
Objective:
Method:
Results:
Conclusions:
Method
Identification of ADHD Candidate Genes From GWASs
GWAS | SNP | p | Locus | Gene | Position Within Gene | Gene Size |
---|---|---|---|---|---|---|
Neale et al. (27)b | ||||||
rs9676447 | 1.00E-05 | 19q13.33 | NUCB1 | intronic | 23 kb | |
rs876477 | 2.70E-05 | 4p15.31 | KCNIP4 | intronic | 1,220 kb | |
rs7657608 | 3.00E-05 | 4q32.3 | SPOCK3 | intronic | 501 kb | |
rs3782309 | 5.50E-05 | 12p11.23 | ITPR2 | intronic | 498 kb | |
rs922781 | 5.50E-05 | 15q22.2 | RORA | intronic | 741 kb | |
rs12505502 | 5.60E-05 | 4q22.1 | FAM190A | intronic | 1,360 kb | |
rs1062793 | 7.00E-05 | 6q14.1 | SH3BGRL2 | 3′ untranslated region | 72 kb | |
rs703965 | 9.20E-05 | 10q22.3 | ZMIZ1 | intronic | 248 kb | |
rs4149601 | 9.30E-05 | 18q21.31 | NEDD4L | intronic | 357 kb | |
Lasky-Su et al. (28)c | ||||||
rs6565113 | d | 16q23.3 | CDH13 | intronic | 948 kb | |
rs552655 | d | 6p24.1 | GFOD1 | intronic | 130 kb | |
rs4128767 | 1.28E-06 | 15q25.1 | IL16 | intronic | 117 kb | |
rs11719664 | 2.48E-06 | 3p24.3 | ZNF385D | intronic | 955 kb | |
rs7577925 | 2.55E-06 | 2q21.2 | NAP5 | intronic | 897 kb | |
rs7495052 | 2.83E-06 | 15q26.1 | SLCO3A1 | intronic | 319 kb | |
rs17281813 | 3.46E-06 | 16q12.1 | ZNF423 | intronic | 336 kb | |
rs363512 | 3.89E-06 | 21q21.3 | GRIK1 | intronic | 403 kb | |
rs8041675 | 3.98E-06 | 15q14 | MEIS2 | intronic | 210 kb | |
rs17641078 | 4.73E-06 | 9p24.3 | DMRT2 | nonsynonymous, coding | 7 kb | |
rs930421 | 5.64E-06 | 2p21 | MTA3 | 3′ untranslated region | 262 kb | |
rs17651978 | 6.05E-06 | 3p13 | FOXP1 | intronic | 629 kb | |
rs478597 | 8.08E-06 | 12q24.22 | NOS1 | intronic | 163 kb | |
rs6791644 | 8.32E-06 | 3p14.2 | FHIT | intronic | 1,502 kb | |
rs260461 | 8.38E-06 | 19q13.43 | ZNF544 | intronic | 35 kb | |
rs2290416 | 8.51E-06 | 8q24.3 | NAPRT1 | synonymous, coding | 4 kb | |
rs1202199 | 8.52E-06 | 6p22.3 | MBOAT1 | intronic | 110 kb | |
Lesch et al. (29)e | ||||||
rs864643 | 1.30E-08 | 3p22.2 | MOBP | 3′ untranslated region | 59 kb | |
rs7995215 | 1.35E-08 | 13q31.3 | GPC6 | intronic | 1,180 kb | |
rs11243897 | 5.63E-08 | 9q34.13 | C9orf98 | intronic | 153 kb | |
rs7164335 | 1.30E-07 | 15q23 | ITGA11 | intronic | 130 kb | |
rs220470 | 1.34E-07 | 17p13.2 | ITGAE | intronic | 87 kb | |
rs10983238 | 1.37E-07 | 9q33.1 | ASTN2 | intronic | 990 kb | |
rs2587695 | 2.73E-07 | 2q14.2 | PCDP1 | intronic | 118 kb | |
rs2281597 | 5.41E-07 | 1p35.1 | CSMD2 | intronic | 652 kb | |
rs10514604 | 8.06E-07 | 16q24.1 | ATP2C2 | intronic | 96 kb | |
rs2677744 | 9.69E-07 | 15q26.1 | MAN2A2 | intronic | 18 kb | |
rs2502731 | 1.58E-06 | 9q34.11 | DNM1 | intronic | 52 kb | |
rs2199161 | 1.62E-06 | 5q13.2 | MAP1B | intronic | 100 kb | |
rs10786284 | 1.96E-06 | 10q24.1 | TLL2 | intronic | 149 kb | |
rs1555322 | 3.60E-06 | 20q11.22 | MMP24 | intronic | 50 kb | |
rs16928529 | 3.90E-06 | 10q22.1 | UNC5B | intronic | 90 kb | |
rs515910 | 4.36E-06 | 10q25.1 | C10orf79 | intronic | 102 kb | |
rs2237349 | 4.63E-06 | 7p15.1 | CREB5 | intronic | 527 kb | |
rs4964805 | 4.74E-06 | 12q23.3 | NT5DC3 | intronic | 71 kb | |
rs3799977 | 4.90E-06 | 6p21.1 | SUPT3H | intronic | 569 kb | |
rs11646411 | 7.40E-06 | 16q23.3 | CDH13 | intronic | 948 kb | |
rs469727 | 7.54E-06 | 5q22.2 | REEP5 | intronic | 46 kb | |
rs2241685 | 8.11E-06 | 2p25.3 | MYT1L | intronic | 542 kb | |
rs2242073 | 8.27E-06 | 2q33.3 | CRYGC | intronic | 2 kb | |
rs13395022 | 9.68E-06 | 2p12 | CTNNA2 | intronic | 1,460 kb | |
rs11594082 | 1.00E-05 | 10q22.1 | CDH23 | intronic | 419 kb | |
rs3893215 | 2.56E-05 | 11p15.1 | KCNC1 | intronic | 47 kb | |
Mick et al. (30)f | ||||||
rs2823819 | 6.70E-07 | 21q21.1 | C21orf34 | intronic | 539 kb | |
rs11074889 | 6.71E-07 | 16p13.13 | EMP2 | intronic | 52 kb | |
rs8074751 | 1.18E-06 | 17q24.1 | CCDC46 | intronic | 556 kb | |
rs1859156 | 2.05E-06 | 4q22.3 | BMPR1B | intronic | 400 kb | |
rs438259 | 3.71E-06 | 6p24.3 | AL024506.1 | intronic | 122 kb | |
rs2602381 | 3.85E-06 | 2q37.1 | UGT1A9 | intronic | 101 kb | |
rs10011926 | 8.07E-06 | 4q25 | ELOVL6 | intronic | 153 kb | |
rs11953346 | 1.59E-05 | 5q15 | MCTP1 | intronic | 578 kb | |
rs7702178 | 1.84E-05 | 5q35.1 | DUSP1 | intronic | 3 kb | |
rs17023218 | 1.88E-05 | 3p24.1 | RBMS3 | intronic | 1,166 kb | |
rs6561686 | 2.08E-05 | 13q14.3 | LECT1 | intronic | 37 kb | |
International Multicenter ADHD Genetics II consortium (31)g | ||||||
rs10823973 | 6.30E-07 | 10q21.1 | PRKG1 | intronic | 1,307 kb | |
rs2291567 | 2.00E-06 | 7q32.1 | FLNC | intronic | 29 kb | |
rs13238831 | 5.60E-06 | 7q32.1 | KCP | intronic | 48 kb | |
rs11593241 | 5.70E-06 | 10q26.3 | TCERG1L | intronic | 219 kb | |
rs12317552 | 9.10E-06 | 12q14.1 | PPM1H | 3′ untranslated region | 291 kb | |
rs17151821 | 1.10E-05 | 7p21.3 | NXPH1 | intronic | 319 kb | |
rs17095690 | 1.60E-05 | 1p31.1 | C1orf173 | intronic | 106 kb | |
rs8045006 | 2.30E-05 | 16q23.3 | CDH13 | intronic | 948 kb | |
rs1023556 | 2.60E-05 | 7p14.3 | AC005493.1 | intronic | 14 kb | |
rs2394538 | 2.80E-05 | 10q22.1 | HK1 | intronic | 132 kb | |
rs1278776 | 2.90E-05 | 13q34 | ATP11A | intronic | 197 kb | |
rs17495366 | 3.10E-05 | 2p16.3 | NRXN1 | intronic | 1,114 kb | |
rs906219 | 3.70E-05 | 10q22.1 | HKDC1 | nonsynonymous, coding | 47 kb | |
rs1472147 | 4.10E-05 | 7q32.1 | ATP6V1F | intronic | 3 kb | |
rs589943 | 4.90E-05 | 11q22.3 | DYNC2H1 | intronic | 370 kb | |
rs2962393 | 5.60E-05 | 5q34 | GABRB2 | intronic | 260 kb | |
rs846971 | 5.60E-05 | 6q21 | SOBP | intronic | 170 kb | |
rs10445861 | 6.50E-05 | 2q14.3 | CNTNAP5 | intronic | 890 kb | |
rs4261672 | 7.20E-05 | 2q22.2 | LRP1B | intronic | 1,900 kb | |
rs6986578 | 7.30E-05 | 8q13.2 | PREX2 | intronic | 280 kb | |
rs12090000 | 7.40E-05 | 1q25.2 | FAM5B | intronic | 111 kb | |
rs1565630 | 8.00E-05 | 7q32.1 | CCDC136 | intronic | 31 kb | |
rs4533267 | 8.30E-05 | 15q26.3 | ADAMTS17 | intronic | 370 kb | |
rs2979307 | 9.00E-05 | 3q21.2 | OSBPL11 | intronic | 66 kb |
Ingenuity and BiNGO Pathway Analyses
Literature Analysis
Results
Category | Genes | Significance | Adjusted Significance |
---|---|---|---|
Ingenuity Pathway Toolb | |||
Neurological disease (44/85 genes) | ADAMTS17, ASTN2, ATP2C2, BMPR1B, C10ORF79, C21ORF34, C9ORF98, CCDC46, CDH13, CDH23 , CNTNAP5, CREB5, CSMD2, CTNNA2, DYNC2H1, FAM190A, FHIT, FOXP1, GABRB2, GFOD1, GRIK1, ITGA11, ITPR2, KCNIP4, LRP1B, MAP1B , MCTP1, MEIS2, MOBP, MYT1L , NAPRT1, NOS1, NRXN1, NXPH1, PPM1H , PRKG1, RBMS3, RORA, SLCO3A1, SPOCK3, TLL2, UNC5B, ZNF385D, ZNF423 | 4.67E-10 | 4.11E-08 |
Biological Network Gene Ontology toolc | |||
Gene ontology termd | |||
Ion binding | ADAMTS17 , ATP11A, ATP2C2 , BMPR1B , CDH13, CDH23 , CREB5, DMRT2 , DUSP1, FHIT , FOXP1, GABRB2, HK1 , ITGA11, ITGAE, ITPR2, KCNC1, KCNIP4 , LRP1B, MAN2A2 , MCTP1, MMP24 , MTA3, MYT1L , NOS1, NRXN1, NT5DC3 , NUCB1 , RORA, SOBP, SPOCK3, TLL2, ZMIZ1 , ZNF385D, ZNF423, ZNF544 | 4.10E-06 | 2.94E-03 |
Metal ion binding | ADAMTS17 , ATP11A, ATP2C2 , BMPR1B , CDH13, CDH23 , CREB5, DMRT2 , DUSP1, FHIT , FOXP1, HK1 , ITGA11, ITGAE, ITPR2, KCNC1, KCNIP4, LRP1B, MAN2A2 , MCTP1, MMP24 , MTA3, MYT1L , NOS1, NRXN1, NT5DC3 , NUCB1, RORA , SOBP, SPOCK3, TLL2, ZMIZ1 , ZNF385D, ZNF423, ZNF544 | 7.45E-06 | 2.94E-03 |
Cation binding | ADAMTS17 , ATP2C2 , BMPR1B , CDH13, CDH23 , CREB5, DMRT2 , DUSP1, FHIT , FOXP1, HK1 , ITGA11, ITGAE, ITPR2, KCNC1, KCNIP4 , LRP1B, MAN2A2 , MCTP1, MMP24 , MTA3, MYT1L , NOS1, NRXN1, NUCB1, RORA, SOBP, SPOCK3, TLL2, ZMIZ1 , ZNF385D, ZNF423, ZNF544 | 1.19E-05 | 3.14E-03 |
Calcium ion binding | ATP2C2 , CDH13, CDH23 , ITGA11, ITGAE, ITPR2, KCNIP4 , LRP1B, MCTP1, MMP24 , NRXN1, NUCB1, SPOCK3, TLL2 | 2.76E-05 | 5.43E-03 |
Hexokinase activity | HK1, HKDC1 | 1.71E-04 | 2.69E-02 |
Locus | Gene | Copy Number Variant | Phenotype | Additional Comments | Study |
---|---|---|---|---|---|
2p12 | CTNNA2a | deleted | ADHD | Genome-wide copy number variant analysis | Elia et al. (20) |
2p16.3 | NRXN1a | deleted | ADHD | Genome-wide copy number variant analysis | Bradley et al. (35) |
2q21.2 | NAP5a | deleted | Attention deficit disorder | Baker et al. (36) | |
3q26.1 | SERPINI1 | duplicated | ADHD | Genome-wide copy number variant analysis | Elia et al. (20) |
3q26.1 | SERPINI1 | deleted | ADHD | Genome-wide copy number variant analysis | Lesch et al. (21) |
12q24.22 | NOS1a | duplicated | ADHD | Cappellacci et al. (37) | |
16p11.2 | ERK1 | duplicated | ADHD | Six/eight unrelated people with ADHD | Shinawi et al. (38) |
16p11.2 | ERK1 | duplicated | ADHD | Genome-wide copy number variant analysis | Williams et al. (22) |
16p11.2 | ERK1 | deleted | ADHD | Four/15 unrelated people with ADHD | Shinawi et al. (38) |
16p11.2 | ERK1 | deleted | ADHD | Genome-wide copy number variant analysis | Williams et al. (22) |
16q12.1 | ZNF423a | duplicated | ADHD | van den Berg et al. (39) | |
18q21.31 | NEDD4La | duplicated | Attention deficit disorder | Two siblings with attention deficit disorder | Ceccarini et al. (40) |
20p12.3 | BMP2 | deleted | Attention deficit disorder | Lalani et al. (41) |
Category | Genes | Significanceb | Adjusted Significancec |
---|---|---|---|
ADHD | |||
Neurological disease (13/20 genes) | ASTN2, ATP2C2, C21ORF34, C9ORF98, CCDC46, CDH13, CSMD2, GFOD1, ITGA11, MAP1B, MOBP, PRKG1, TLL2 | 1.53E-04 | 7.55E-03 |
Biogenesis of lamellipodiad | CDH13 | 5.49E-03 | 2.10E-02 |
Diabetes type I | |||
Neurological disease (1/20 genes) | TH | 1.42E-02 | 3.02E-02 |
Long-term depression | INS | 1.30E-03 | 8.11E-03 |
Crohn's disease | |||
Neurological disease (0/20 genes) |
Category | Genes | Significanceb | Adjusted Significancec |
---|---|---|---|
ADHDd | |||
Gene ontology term | |||
Regulation of chemotaxis | CDH13, IL16 | 3.58E-05 | 4.40E-03 |
Regulation of behavior | CDH13, IL16 | 5.25E-05 | 4.40E-03 |
Regulation of response to external stimulus | CDH13, IL16 | 2.77E-04 | 1.32E-02 |
Integrin complex | ITGA11, ITGAE | 2.98E-04 | 1.32E-02 |
Cell migration | CDH13, IL16, ITGA11 | 6.38E-04 | 2.34E-02 |
Diabetes type Ie | |||
Gene ontology term | |||
Growth factor binding | ERBB3, IL7R, INS | 4.46E-05 | 2.27E-02 |
Regulation of secretion | ERBB3, INS | 3.35E-04 | 3.54E-02 |
Anion transport | C1QTNF6, CFTR, COL1A2 | 4.75E-04 | 3.54E-02 |
Regulation of insulin receptor signaling | INS | 9.76E-04 | 3.54E-02 |
Tyrosine 3-monooxygenase activity | TH | 9.76E-04 | 3.54E-02 |
Crohn's diseasef | |||
Gene ontology term | |||
Protein kinase cascade | GCKR, LRRK2, MST1, STAT3, TNFSF15 | 5.10E-06 | 2.28E-03 |
Intracellular signaling cascade | GCKR, LRRK2, MST1, NOD2, STAT3, TNFSF15 | 6.10E-04 | 2.42E-02 |
Cell communication | ATG16L1, BSN, GCKR, ITLN1, LRRK2, MST1, NOD2, PTPN22, STAT3, TNFSF15 | 7.95E-04 | 2.42E-02 |
Protein amino acid autophosphorylation | LRRK2, MST1 | 9.08E-04 | 2.42E-02 |
Macrophage activation during immune response | SBNO2 | 9.76E-04 | 2.42E-02 |
Discussion
Acknowledgments
Footnote
Supplementary Material
- Download
- 94.27 KB
References
Information & Authors
Information
Published In
History
Authors
Funding Information
Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
There are no citations for this item
View Options
View options
PDF/ePub
View PDF/ePubGet Access
Login options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).