Attention Deficit Hyperactivity Disorder ADHD

ADHD

• Childhood-onset, severe impairing inattention, overactivity, impulsiveness

• Clinical variability

• Highly heritable especially when severe antisocial symptoms present

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?

In-house results

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

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)

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)

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

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?

COMT influencing antisocial behaviour in ADHD

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

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. .

Mechanisms?

Antisocial behaviour in ADHD

COMTVal/val

MechanismsResults from ALSPAC

COMT Impaired social understanding

Antisocialbehaviour

Langley et al, 2010. Archives of General Psychiatry,

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?

….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?