attention deficit hyperactivity disorder adhd. adhd childhood-onset, severe impairing inattention,...
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![Page 1: Attention Deficit Hyperactivity Disorder ADHD. ADHD Childhood-onset, severe impairing inattention, overactivity, impulsiveness Clinical variability Highly](https://reader036.vdocuments.us/reader036/viewer/2022062517/56649f295503460f94c4257a/html5/thumbnails/1.jpg)
Attention Deficit Hyperactivity Disorder ADHD
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ADHD
• Childhood-onset, severe impairing inattention, overactivity, impulsiveness
• Clinical variability
• Highly heritable especially when severe antisocial symptoms present
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Current work
• Identifying large, rare CNVs
• Identifying common variants-GWAS of 800
• Identifying biological pathways that underlie ADHD
• What are the links between biology, genes and clinical variability in ADHD?
• How do associated genes exert risk effects on the clinical outcome?
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In-house results
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Large rare copy number variants in ADHD
Burden of all CNVs
ADHD Controls ratio P
ADHD/Controls 14% vs 7% CNV(n) 57 78
n=366/1047 RATE 0.156 0.075 2.09 8.9x10-5
ADHD (IQ≥70)/Controls 11% CNV(n) 40 78
n=319/1047 RATE 0.125 0.075 1.68 0.0077
ADHD (IQ<70)/Controls 36% CNV(n) 14 78
n=33/1047 RATE 0.424 0.075 5.69 2.0x10-6
Williams et al, Lancet Sept 30th
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Large rare CNVs in ADHD
• Significant overlap of regions implicated in autism and schizophrenia
• 16p13.11 duplications
OR 13.9 p=0.0008 (95% CI 2.3-82.2)
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SNP Chr Position Closest gene Location relative to gene
Minor allele
Other allele
MAF P value OR (95% CI)
rs1744062 6 137350879 IL20RA Within non-coding gene
G A 0.43 4.16E-06 0.75 (0.67-0.85)
rs11079828 17 43964102 HOXB1 Upsteam T C 0.47 6.54E-06 1.32 (1.17-1.49)
rs42259 5 14439655 TRIO Intron T C 0.17 6.76E-06 1.41 (1.22-1.64)
rs3779312 7 77549692 MAGI2 Intron T C 0.21 8.38E-06 1.37 (1.19-1.57)
rs616668 12 110458663 ATXN2 Intron G T 0.20 8.62E-06 1.38 (1.20-1.59)
rs11175219 12 62648986 SRGAP1 Intron T C 0.12 1.06E-05 1.46 (1.23-1.73)
rs4238186 13 18588836 LOC100128765 Intergenic A G 0.18 1.11E-05 1.39 (1.20-1.61)
rs7746680 6 45885325 - Intergenic A G 0.24 1.14E-05 1.35 (1.18-1.54)
rs11686538 2 225526808 DOCK10 Intron G A 0.29 1.27E-05 0.74 (0.64-0.84)
rs1304358 2 198677828 PLCL1 Intron C T 0.49 1.27E-05 1.30 (1.16-1.47)
rs406742 10 8885947 - Intergenic G A 0.26 1.49E-05 1.33 (1.17-1.51)
rs790531 13 49623515 DLEU2 Within non-coding gene
G A 0.06 1.50E-05 1.62 (1.30-2.02)
rs6815704 4 93693589 GRID2 Intron A G 0.15 2.09E-05 1.40 (1.20-1.64)
rs9842394 3 181095930 PEX5L Intron T C 0.47 2.68E-05 0.77 (0.69-0.87)
rs2636788 10 98866931 SLIT1 Intron G A 0.17 2.74E-05 0.70 (0.59-0.83)
rs1490046 5 173888653 - Intergenic A G 0.08 2.87E-05 1.56 (1.27-1.92)
rs1050567 2 61559167 XPO1 3' UTR T C 0.11 2.89E-05 1.44 (1.22-1.72)
rs9384245 6 155201820 TIAM2 Intron T C 0.42 3.00E-05 0.77 (0.68-0.87)
rs1370072 13 54739939 - Intergenic T C 0.45 3.28E-05 1.29 (1.14-1.45)
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P-value (CNV)
P-val (corr)
P-value (GWAS) Description
2.06E-05 0.0024 0.0298abnormal cholesterol homeostasis
7.47E-05 0.0076 0.0230abnormal cholesterol level
1.33E-04 0.0108 0.0256abnormal circulating cholesterol level
2.76E-04 0.0208 0.0332chromosomal part
9.06E-04 0.0534 0.0256channel regulator activity
1.53E-03 0.0846 0.0330centrosome duplication
1.75E-03 0.0930 0.0138regulation of tumor necrosis factor production
3.45E-03 0.1562 0.0118abnormal somatosensory cortex morphology
3.45E-03 0.1562 0.0042abnormal parietal lobe morphology
3.56E-03 0.1620 0.0374peptidase activity
3.56E-03 0.1620 0.0380peptidase activity, acting on L-amino acid peptides
7.48E-03 0.2742 0.0016central nervous system development
8.78E-03 0.3064 0.0042transferase activity, transferring acyl groups
1.12E-02 0.3528 0.0418cation channel activity
1.25E-02 0.3806 0.0032acyltransferase activity
1.25E-02 0.3806 0.0038transferase activity, transferring acyl groups other than amino-acyl groups
2.84E-02 0.6206 0.0316positive regulation of RNA metabolic process
3.05E-02 0.6394 0.0138brain development
4.09E-02 0.7286 0.0096macromolecular complex assembly
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Questions?
• Does clinical variability in presentation index biological heterogeneity?
• Can we pick out biologically homogeneous subtypes?
• How do our GWAS and CNV findings relate to animal models of ADHD and imaging studies showing affected brain regions?
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COMT influencing antisocial behaviour in ADHD
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Conduct disorder symptoms among clinic children with ADHD, according to their COMT Val158Met genotype status
0.7
0.8
0.9
1
1.1
1.2
1.3
1.4
1.5Met/Met
Val/Met
Val/Val
Con
duct
dis
orde
r sy
mpt
oms
n = 59 130 52 Thapar et al, Archives of General Psychiatry, 2005
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Further replication in ALSPAC
Mean No. CD symptoms by COMT genotype
00.40.81.21.6
22.42.8
ADHD n=70 Not ADHDn=4239
Me
an
No
. CD
sy
mp
tom
s
Not val/val
Val/val
(OR=2.82, 95% CI: 2.02, 3.94, p<0.001 Greater than 4 CD symptoms)
Langley K, Heron J, O’Donovan M, Owen, Thapar A . Archives of General Psychiatry, 2010. .
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Mechanisms?
Antisocial behaviour in ADHD
COMTVal/val
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MechanismsResults from ALSPAC
COMT Impaired social understanding
Antisocialbehaviour
Langley et al, 2010. Archives of General Psychiatry,
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What next?
• Detailed cognitive and psychophysiological testing of ADHD children in experimental lab based on COMT Val158Met genotype
• What should we be looking at (gene/mutation-wise) that might be important in relation to COMT function and related pathways?
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….Final add on
• 3 wave study of psychiatric problems in adolescents who are at high genetic risk, developing a risk prediction tool
• Developing a risk prediction tool that is being incorporated into GP software (commercial software company)
• Computing/risk prediction expertise?