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Attention Deficit Hyperactivity Disorder ADHD. ADHD Childhood-onset, severe impairing inattention, overactivity, impulsiveness Clinical variability Highly.

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Presentation on theme: "Attention Deficit Hyperactivity Disorder ADHD. ADHD Childhood-onset, severe impairing inattention, overactivity, impulsiveness Clinical variability Highly."— Presentation transcript:

1 Attention Deficit Hyperactivity Disorder ADHD

2 ADHD Childhood-onset, severe impairing inattention, overactivity, impulsiveness Clinical variability Highly heritable especially when severe antisocial symptoms present

3 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?

4 In-house results

5 Large rare copy number variants in ADHD Burden of all CNVs ADHDControlsratioP ADHD/Controls 14% vs 7%CNV(n)5778 n=366/1047RATE0.1560.0752.098.9x10 -5 ADHD (IQ≥70)/Controls 11%CNV(n)4078 n=319/1047RATE0.1250.0751.680.0077 ADHD (IQ<70)/Controls 36%CNV(n)1478 n=33/1047RATE0.4240.0755.692.0x10 -6 Williams et al, Lancet Sept 30th

6 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)

7 SNPChrPositionClosest gene Location relative to gene Minor allele Other allele MAFP valueOR (95% CI) rs17440626137350879IL20RA Within non-coding gene GA0.434.16E-060.75 (0.67-0.85) rs110798281743964102HOXB1UpsteamTC0.476.54E-061.32 (1.17-1.49) rs42259514439655TRIOIntronTC0.176.76E-061.41 (1.22-1.64) rs3779312777549692MAGI2IntronTC0.218.38E-061.37 (1.19-1.57) rs61666812110458663ATXN2IntronGT0.208.62E-061.38 (1.20-1.59) rs111752191262648986SRGAP1IntronTC0.121.06E-051.46 (1.23-1.73) rs42381861318588836LOC100128765IntergenicAG0.181.11E-051.39 (1.20-1.61) rs7746680645885325-IntergenicAG0.241.14E-051.35 (1.18-1.54) rs116865382225526808DOCK10IntronGA0.291.27E-050.74 (0.64-0.84) rs13043582198677828PLCL1IntronCT0.491.27E-051.30 (1.16-1.47) rs406742108885947-IntergenicGA0.261.49E-051.33 (1.17-1.51) rs7905311349623515DLEU2 Within non-coding gene GA0.061.50E-051.62 (1.30-2.02) rs6815704493693589GRID2IntronAG0.152.09E-051.40 (1.20-1.64) rs98423943181095930PEX5LIntronTC0.472.68E-050.77 (0.69-0.87) rs26367881098866931SLIT1IntronGA0.172.74E-050.70 (0.59-0.83) rs14900465173888653-IntergenicAG0.082.87E-051.56 (1.27-1.92) rs1050567261559167XPO13' UTRTC0.112.89E-051.44 (1.22-1.72) rs93842456155201820TIAM2IntronTC0.423.00E-050.77 (0.68-0.87) rs13700721354739939-IntergenicTC0.453.28E-051.29 (1.14-1.45)

8 P-value (CNV) P-val (corr) P-value (GWAS)Description 2.06E-050.00240.0298abnormal cholesterol homeostasis 7.47E-050.00760.0230abnormal cholesterol level 1.33E-040.01080.0256abnormal circulating cholesterol level 2.76E-040.02080.0332chromosomal part 9.06E-040.05340.0256channel regulator activity 1.53E-030.08460.0330centrosome duplication 1.75E-030.09300.0138regulation of tumor necrosis factor production 3.45E-030.15620.0118abnormal somatosensory cortex morphology 3.45E-030.15620.0042abnormal parietal lobe morphology 3.56E-030.16200.0374peptidase activity 3.56E-030.16200.0380peptidase activity, acting on L-amino acid peptides 7.48E-030.27420.0016central nervous system development 8.78E-030.30640.0042transferase activity, transferring acyl groups 1.12E-020.35280.0418cation channel activity 1.25E-020.38060.0032acyltransferase activity 1.25E-020.38060.0038transferase activity, transferring acyl groups other than amino-acyl groups 2.84E-020.62060.0316positive regulation of RNA metabolic process 3.05E-020.63940.0138brain development 4.09E-020.72860.0096macromolecular complex assembly

9 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?

10 COMT influencing antisocial behaviour in ADHD

11 Conduct disorder symptoms among clinic children with ADHD, according to their COMT Val 158 Met genotype status Met/Met Val/Met Val/Val Conduct disorder symptomsn = 59 130 52 Thapar et al, Archives of General Psychiatry, 2005

12 Further replication in ALSPAC (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..

13 Mechanisms? Antisocial behaviour in ADHD COMT Val/val

14 Mechanisms Results from ALSPAC COMT Impaired social understanding Antisocial behaviour Langley et al, 2010. Archives of General Psychiatry,

15 What next? Detailed cognitive and psychophysiological testing of ADHD children in experimental lab based on COMT Val 158 Met genotype What should we be looking at (gene/mutation-wise) that might be important in relation to COMT function and related pathways?

16 ….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?

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