close

Вход

Забыли?

вход по аккаунту

?

An investigation of the neurotrophic factor genes GDNF NGF and NT3 in susceptibility to ADHD.

код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:375 –378 (2007)
Brief Research Communication
An Investigation of the Neurotrophic Factor Genes GDNF,
NGF, and NT3 in Susceptibility to ADHD
Zahoor Syed,1 Frank Dudbridge,2 and Lindsey Kent3*
1
Addenbrookes Hospital, Cambridge, United Kingdom
MRC Biostatistics Unit, Cambridge, United Kingdom
3
Developmental Psychiatry, University of Cambridge, Cambridge, United Kingdom
2
Attention deficit hyperactivity disorder (ADHD)
is a common, highly heritable, neurodevelopmental disorder with onset in early childhood. Genes
involved in neuronal development and growth
are, thus, important etiological candidates and
neurotrophic factors have been hypothesized to
play a role in the pathogenesis of ADHD. Glial
derived neurotrophic factor (GDNF), nerve
growth factor (NGF (beta subunit)), and neurotrophic factor 3 (NT3) are members of the neurotrophin family and are involved in the survival,
differentiation, and maintenance of neuronal
cells. We have examined 10 coding and intronic
single nucleotide polymorphisms (SNPs) across
GDNF, NGF, and NT3 in a family-based association sample of 120 DSM-IV ADHD probands and
their biological parents, as well as a case-control
analysis with 120 sex-matched controls. Borderline significant overtransmission of the C allele of
a non-synonymous C/T SNP (rs6330) in NGF which
codes an alanine/valine change was found in the
family-based sample (Chi-square ¼ 3.69, odds ratio
(OR) ¼ 1.65, P ¼ 0.05). Although this SNP is located
in the 50 pro-NGF sequence and not the mature
NGF protein, it may affect intracellular processing and secretion of NGF.
ß 2006 Wiley-Liss, Inc.
KEY WORDS:
attention deficit hyperactivity
disorder; association study; neurotrophic factor; polymorphism
Please cite this article as follows: Syed Z, Dudbridge F,
Kent L. 2007. An Investigation of the Neurotrophic
Factor Genes GDNF, NGF, and NT3 in Susceptibility to
ADHD. Am J Med Genet Part B 144B:375–378.
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 2–5% of school-aged
children with more boys diagnosed than girls [Swanson et al.,
1998]. It is characterized by marked and pervasive inattention,
overactivity, and impulsiveness and causes significant social,
educational, and psychological problems. Quantitative genetic
research over the last decade, from family, twin, and adoption
studies has firmly established that ADHD has a significant
Grant sponsor: The Wellcome Trust.
*Correspondence to: Lindsey Kent, Ph.D., Developmental
Psychiatry, University of Cambridge, Douglas House, 18b Trumpington Road, Cambridge CB2 2AH, UK.
E-mail: lk255@cam.ac.uk
Received 28 June 2006; Accepted 21 September 2006
DOI 10.1002/ajmg.b.30459
ß 2006 Wiley-Liss, Inc.
genetic contribution [Thapar et al., 1999]. Given that ADHD is
a neurodevelopmental disorder, genes involved in neuronal
development and growth represent an important set of
candidates for involvement in the pathogenesis. The neurotrophins are a family of polypeptide growth factors which are
essential for the proliferation, differentiation, survival, and
death of neuronal, and non-neuronal cells [see review Chao
et al., 2006]. A role has been suggested for brain-derived
neurotrophic factor (BDNF) in ADHD susceptibility [Lanktree
et al., 2004; Kent et al., 2005], raising the possibility that other
neurotrophic factors may also be involved in the pathogenesis
of this condition.
Of particular interest is glial derived neurotrophic factor
(GDNF), the gene for which is located at 5p13. Nominal
evidence for linkage to chromosome 5p13 has been demonstrated in all four published genome-wide linkage scans of
ADHD [Bakker et al., 2003; Ogdie et al., 2003, 2004; ArcosBurgos et al., 2004; Hebebrand et al., 2006]. GDNF plays a role
in the development, maintenance, and survival of dopaminergic midbrain neurons [Granholm et al., 2000] and has been
shown, in culture to enhance neuronal dopamine release
[Bourque and Trudeau, 2000]. Michelato et al. [2004] provided
some evidence of association with a GDNF repeat polymorphism and schizophrenia although others have not found this to
be the case [Lee et al., 2001a].
The gene for neurotrophin-3 (NT3) is located at 12p13, a
region implicated in a genome-wide scan of quantitative ADHD
traits [Fisher et al., 2002] and although there has been some
evidence to implicate genetic variation within neurotrophic
factor 3 (NT3) in the pathogenesis of schizophrenia [e.g.,
Hattori et al., 2002], most later studies have failed to replicate
this association [see review Lin and Tsai, 2004]. NT3 mRNA is
an abundant neurotrophin in the developing brain which is
highly expressed in the hippocampi of newborn and in
immature neocortical regions of the fetus [Maisonpierre
et al., 1991].
Finally, nerve growth factor (NGF) exerts within the CNS, a
trophic and functional role on basal forebrain cholinergic
neurones, which are involved in attentional systems [see
review by Sarter et al., 2006]. The NGF complex consists of
three types of subunits: alpha, beta, and gamma, but it is the
beta subunit which is solely responsible for nerve growth
stimulating activity of NGF. The gene for beta NGF (NGFB) is
located at 1p13.1.
For this study, 120 ADHD probands and their parents were
recruited from two child psychiatry clinics in the UK, following
approval from the appropriate research ethics committees. Of
these, 72 were full trios with DNA available from both parents.
After complete description of the study to the subjects, written
informed consent was obtained. Parents were interviewed by
trained psychiatrists or psychologists employing the Child and
Adolescent Psychiatric Assessment (CAPA) [Angold et al.,
1995]. In addition, Conners Teacher Rating Scale (CTRS)
[Conners, 1998] were completed on all children to confirm that
0.47
0.53
0.41
0.59
0.78
0.22
0.47
0.53
0.67
0.33
0.60
0.40
0.82
0.18
0.64
0.36
0.52
0.74
0.26
0.48
0.45
0.55
0.44
0.56
0.73
0.27
0.49
0.51
0.73
0.27
0.52
0.48
0.79
0.11
0.54
0.46
0.55
0.73
0.27
0.45
0.48
0.52
0.39
0.61
0.75
0.25
0.49
0.51
0.69
0.31
0.56
0.44
0.86
0.14
0.57
0.43
0.53
0.47
0.72
T
C
G
A
G
T
C
T
T
C
T
A
A
C
A
G
rs6330
rs11111
rs12514589
rs3749692
rs1862574
0.28
Probands
N ¼ 120
Parents
N ¼ 192
Controls
N ¼ 120
T
C
G
C
rs7132127
rs910330
rs6332
rs7958038
NTF3
NGFB
GDNF
symptoms met the criterion of pervasiveness. Established cutoff points for possible and likely ADHD caseness on the CTRS
were adhered to, that is, a T score above 55 was required.
All 120 probands were white and born in the UK (mean age ¼
11.1 years; range 5–16 years; SD ¼ 3.1 years). The sample was
predominantly male (91%). All probands fulfilled DSM-IV
diagnostic criteria for ADHD. Of these, 97 (81%) had ADHD
combined type, 11 (9%) had the inattentive subtype, and 12
(10%) had the hyperactive impulsive subtype. Children with an
IQ below 70, autistic spectrum disorder, or significant medical
conditions such as epilepsy were excluded. Twenty-nine
children (24%) had comorbid oppositional defiant disorder
and 15 children (13%) fulfilled criteria for comorbid conduct
disorder.
In addition to the family-based sample, a control group of
120 ethnically and sex-matched adolescents from schools and
colleges, local to the ADHD clinics were also employed for a
case-control analysis. Control subjects were psychiatrically
screened with the Strengths and Difficulties Questionnaire
[Goodman, 2001] and their mean age was 15.5 years (range
13–17 years). Recruitment of these controls was approved by
the same research ethics committees as before and they
consented specifically to be used as control samples for an
ADHD genetic study.
For this study, all cases, controls, and only parents which
contributed to full trios were genotyped, that is, where only one
parent for a proband was available they were not genotyped.
High molecular weight genomic DNA was extracted from
either whole blood or cheek swab according to routine
procedures. Single nucleotide polymorphisms (SNPs) for the
three genes were chosen from the ABI assay on demand or
assay by design service (https://www2.appliedbiosystems.com)
and all genotyping was performed by Geneservice (www.geneservice.co.uk), blind to affection status. Known coding SNPs
with a minor allele frequency greater than 0.1 were chosen
where possible, otherwise intronic SNPs were genotyped.
Additionally, 20 Geneservice control samples were typed in
duplicate with 100% concordance and 98.5% of all genotyping
was successful.
The transmission disequilibrium test (TDT) [Spielman et al.,
1993] was used to test for the presence of non-random
transmission of alleles to ADHD probands at each polymorphism, indicative of allelic association and case-control data were
analyzed using Pearson Chi-squared test.
Parental, proband, and control allele frequencies are shown
in Table I and were not significantly different from frequencies
reported in Caucasian/CEPH populations from several databases including Hapmap (www.hapmap.org) and summarized
on https://www2.appliedbiosystems.com.. Genotype frequencies demonstrated no significant departure from Hardy
Weinberg equilibrium.
There was no significant difference in allele or genotype
frequencies between cases and controls for each polymorphism. TDT analysis demonstrated borderline significant overtransmission of the C allele of rs6330, a non-synonymous SNP
in NGF (odds ratio ¼ 1.65, Chi-square ¼ 3.7, P ¼ 0.05)
(Table II).
This study provides some preliminary evidence that another
neurodevelopmentally relevant gene, in addition to BDNF,
may be involved in the pathogenesis of ADHD. This common,
non-synonymous C/T SNP in NGF produces an alanine-tovaline substitution at amino acid position 35 and although
located in the 50 pro-NGF sequence and not the mature NGF
protein, it may affect intracellular processing and secretion of
NGF as has been demonstrated for the Val66Met allele of
propeptide BDNF [Suter et al., 1991; Chen et al., 2004].
Additionally, proneurotrophins are more effective in inducing
p75 neurotrophin receptor-dependent apoptosis, than mature
NGF, whilst the mature forms of neurotrophins selectively
rs4930767
Syed et al.
TABLE I. Parent, Proband, and Control Allele Frequencies for GDNF, NGFB, and NTF3 SNPs
376
ADHD and Neurotrophic Factors
377
TABLE II. TDT Analyses on 72 Trios
Gene
SNP
GDNF
NGFB
NTF3
Overtransmitted
allele
T:U
Chi-square
P-value
C
A
A
T
C
T
G
T
C
T
15:10
31:27
24:18
31:25
38:23
29:20
34:30
31:26
33:29
36:27
1.0
0.28
0.86
0.64
3.69
1.65
0.25
0.44
0.26
1.29
n.s.
n.s.
n.s.
n.s.
0.05
n.s.
n.s.
n.s.
n.s.
n.s.
rs1862574
rs3749692
rs12514589
rs11111
rs6330
rs910330
rs6332
rs7958038
rs7132127
rs4930767
T, transmitted allele; U, untransmitted allele.
activate the Trk family of receptors to promote survival [Lee
et al., 2001b]. Cell death, mediated by proneurotrophins and
the p75 receptor may be important for correct targeting and
pruning of neuronal populations during development [see
review, Chao et al., 2006]. Genetic variation within the pro
domain of NGF may therefore be of biological relevance in
susceptibility to a developmental disorder such as ADHD.
However, these results should be viewed with caution. The
case-control sample of 120 probands has a power to detect an
association with the Ala35Val allele with an OR of 1.6, and
P < 0.05 of 80% yet did not confirm the family-based findings.
Additionally, the overtransmitted C allele actually had a
slightly higher frequency in the control sample compared to the
probands. These factors raise the possibility that our finding is
a Type 1 error, and further investigation of this polymorphism
in larger ADHD samples is warranted.
ACKNOWLEDGMENTS
We thank all the families for their participation and
Bhismadev Chakrabarti for assistance with bioinformatics.
REFERENCES
Angold A, Prendergast A, Cox R, Harrington E, Simonoff E, Rutter M. 1995.
The Child and Adolescent Psychiatric Assessment (CAPA). Psychol Med
25:739–753.
Arcos-Burgos M, Castellanos FX, Pineda D, Lopera F, Palacio JD,
Palacio LG, Rapoport JL, Berg K, Bailey-Wilson JE, Muenke M. 2004.
Attention-deficit/hyperactivity disorder in a population isolate: Linkage
to loci at 4q13.2, 5q33.3, 11q22, and 17p11. Am J Hum Genet 75:998–
1014.
Bakker SC, van der Meulen EM, Buitelaar JK, Sandkuijl LA, Pauls
DL, Monsuur AJ, van ’t Slot R, Minderaa RB, Gunning WB, Pearson
PL, Sinke RJ. 2003. A whole-genome scan in 164 Dutch sib pairs
with attention-deficit/hyperactivity disorder: Suggestive evidence
for linkage on chromosomes 7p and 15q. Am J Hum Genet 72:1251–
1260.
Bourque MJ, Trudeau LE. 2000. GDNF enhances the synaptic efficacy of
dopaminergic neurons in culture. Eur J Neurosci 12:3172–3180.
Conners CK. 1998. Rating scales in attention deficit hyperactivity disorder;
use in assessment, and treatment and monitoring. J Clin Psychiatry 59:
24–30.
Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, MacPhie IL,
Newbury DF, Crawford LR, Palmer CG, Woodward JA, Del’Homme M,
Cantwell DP, Nelson SF, Monaco AP, Smalley SL. 2002. A genomewide
scan for loci involved in attention-deficit/hyperactivity disorder. Am J
Hum Genet 70:1183–1196.
Goodman R. 2001. Psychometric properties of the strengths and
difficulties questionnaire. J Am Acad Child Adolesc Psychiatry 40:
1337–1345.
Granholm AC, Reyland M, Albeck D, Sanders L, Gerhardt G, Hoernig G,
Shen L, Westphal H, Hoffer B. 2000. Glial cell line-derived neurotrophic
factor is essential for postnatal survival of midbrain dopamine neurons.
J Neurosci 20:3182–3190.
Hattori M, Kunugi H, Akahane A, Tanaka H, Ishida S, Hirose T, Morita R,
Yamakawa K, Nanko S. 2002. Novel polymorphisms in the promoter
region of the neurotrophin-3 gene and their associations with schizophrenia. Am J Med Genet 114:304–309.
Hebebrand J, Dempfle A, Saar K, Thiele H, Herpertz-Dahlmann B, Linder
M, Kiefl H, Remschmidt H, Hemminger U, Warnke A, Knolker U, Heiser
P, Friedel S, Hinney A, Schafer H, Nurnberg P, Konrad K. 2006. A
genome-wide scan for attention-deficit/hyperactivity disorder in 155
German sib-pairs. Mol Psychiatry:196–205.
Kent L, Green E, Kirley A, Hawi Z, Lowe N, Fitzgerald M, O’Donovan M, Gill
M, Thapar A, Craddock N. 2005. Evidence that variation at brain derived
neurotrophic factor influences susceptibility to attention deficit hyperactivity disorder. Mol Psychiatry 10:939–943.
Lanktree M, Muglia P, Squassina A, Krinsky M, Jain U, Macciardi F, et al.
2004. A potential role for brain derived neurotrophic factor (BDNF) in
adult adhd. Abstract in: Am J Med Gen 130B:96–97.
Lee K, Kunugi H, Nanko S. 2001a. Glial cell line-derived neurotrophic factor
(GDNF) gene and schizophrenia: Polymorphism screening and association analysis. Psychiatry Res 104:11–17.
Lee R, Kermani P, Teng KK, Hempstead BL. 2001b. Regulation of cell
survival by secreted proneurotrophins. Science 294:1945–1948.
Lin P, Tsai G. 2004. Meta-analyses of the association between genetic
polymorphisms of neurotrophic factors and schizophrenia. Schizophr
Res 71:353–360.
Maisonpierre PC, Le Beau MM, Espinosa R 3rd, Ip NY, Belluscio L, de la
Monte SM, Squinto S, Furth ME, Yancopoulos GD. 1991. Human and rat
brain-derived neurotrophic factor and neurotrophin-3: Gene structures,
distributions, and chromosomal localizations. Genomics 10:558–568.
Chao MV, Rajagopal R, Lee FS. 2006. Neurotrophin signalling in health and
disease. Clin Sci 110:167–173.
Michelato A, Bonvicini C, Ventriglia M, Scassellati C, Randazzo R, Bignotti
S, Beneduce R, Riva MA, Gennarelli M. 2004. 30 UTR (AGG)n repeat of
glial cell line-derived neurotrophic factor (GDNF) gene polymorphism in
schizophrenia. Neurosci Lett 357:235–237.
Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, Lee FS.
2004. Variant brain derived neurotrophic factor (BDNF) (Met66) alters
the intracellular trafficking and activity-dependent secretion of wildtype BDNF in neurosecretory cells and cortical neurons. J Neurosci 24:
4401–4411.
Ogdie MN, Macphie IL, Minassian SL, Yang M, Fisher SE, Francks C,
Cantor RM, McCracken JT, McGough JJ, Nelson SF, Monaco AP,
Smalley SL. 2003. A genomewide scan for attention-deficit/hyperactivity
disorder in an extended sample: Suggestive linkage on 17p11. Am J Hum
Genet 72:1268–1279.
378
Syed et al.
Ogdie MN, Fisher SE, Yang M, Ishii J, Francks C, Loo SK, Cantor
RM, McCracken JT, McGough JJ, Smalley SL, Nelson SF. 2004. Attention
deficit hyperactivity disorder: Fine mapping supports linkage to 5p13,
6q12, 16p13, and 17p11. Am J Hum Genet 75:661–668.
Suter U, Heymach J, Shooter E. 1991. Two conserved domains in the
NGF polypeptide are necessary and sufficient for the biosynthesis of
correctly processed and biologically active NGF. EMBO J 10:2394–
2400.
Sarter M, Gehring WJ, Kozak R. 2006. More attention must be paid: The
neurobiology of attentional effort. Brain Res Brain Res Rev 51:145–160.
Swanson JM, Sergeant JA, Taylor E, Sonuga-Barke EJS, Jensen PS,
Cantwell DP. 1998. Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet 351:429–433.
Spielman KS, McGinnis RE, Ewens WJ. 1993. Transmission test for linkage
disequilibrium: The insulin gene region and insulin-dependent diabetes
mellitus (IDDM). Am J Hum Genet 52:506–516.
Thapar A, Holmes J, Poulton K, Harrington R. 1999. Genetic basis of
attention deficit and hyperactivity. Br J Psychiatry 174:105–111.
Документ
Категория
Без категории
Просмотров
1
Размер файла
57 Кб
Теги
investigation, factors, neurotrophic, genes, ngf, nt3, susceptibility, adhd, gdnf
1/--страниц
Пожаловаться на содержимое документа