close

Вход

Забыли?

вход по аккаунту

?

Association study of the brain-derived neurotropic factor (BDNF) gene in attention deficit hyperactivity disorder.

код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:976 –981 (2007)
Association Study of the Brain-Derived Neurotropic Factor
(BDNF) Gene in Attention Deficit Hyperactivity Disorder
Jonghun Lee,1,2 Nancy Laurin,1 Jennifer Crosbie,3 Abel Ickowicz,3 Tejaswee Pathare,3 Molly Malone,3
Rosemary Tannock,3 James L. Kennedy,4 Russell Schachar,3 and Cathy L. Barr1,3*
1
Cell and Molecular Biology Division, Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
Department of Psychiatry, Catholic University of Daegu, Daegu, South Korea
3
Brain and Behaviour Programme, The Hospital for Sick Children, Toronto, Ontario, Canada
4
Department of Psychiatry, Neurogenetics Section, University of Toronto, Toronto, Ontario, Canada
2
Attention deficit hyperactivity disorder (ADHD)
is a prevalent neurodevelopmental childhood
psychiatric disorder. Brain-derived neurotropic
factor (BDNF) has been suggested to play a role in
the pathogenesis of ADHD and two family-based
association studies demonstrated an association
of BDNF polymorphisms with ADHD. The aim of
the current study was to investigate the BDNF
gene for association with ADHD in a large sample
of families from Toronto. The transmission of
three polymorphisms of the BDNF gene (rs6265,
rs11030104, and rs2049046) was examined in 266
nuclear families ascertained through a proband
with ADHD (315 affected children) using the
transmission/disequilibrium test (TDT). In addition, we conducted quantitative analysis to assess
the relationship between these marker alleles
and the symptom dimensions of ADHD (inattention and hyperactivity/impulsivity) and cognitive
measures of working memory. None of the individual marker alleles showed significant evidence
of association with ADHD, dimensional symptom
scores, or working memory ability in our sample
of ADHD families. There was no significant evidence for biased transmission of individual haplotypes with frequency >10% (global x2 for these
three haplotypes: x2 ¼ 6.349, df ¼ 3, P ¼ 0.096). One
uncommon haplotype (A-G-G; frequency 2.2%)
showed a significant association with ADHD in
the categorical (x2 ¼ 5.293, df ¼ 1, P ¼ 0.021) and
quantitative analyses (parents’ rated inattention:
Z ¼ 2.504, P ¼ 0.012; and hyperactivity/impulsivity: Z ¼ 2.651, P ¼ 0.008). These results should
be interpreted cautiously, however, because of the
low haplotype frequency. In light of the evidence
for an involvement of BDNF in ADHD, further
analysis of the BDNF gene in ADHD is warranted.
ß 2007 Wiley-Liss, Inc.
Grant sponsor: Hospital for Sick Children Psychiatric Endowment Fund; Grant sponsor: Canadian Institutes of Health
Research; Grant numbers: MT14336, MOP14336.
*Correspondence to: Cathy L. Barr, The Toronto Western
Hospital, 399 Bathurst St., Room MP14-302, Toronto, ON,
Canada. M5T 2S8. E-mail: CBarr@uhnres.utoronto.ca
Received 11 May 2006; Accepted 16 August 2006
DOI 10.1002/ajmg.b.30437
ß 2007 Wiley-Liss, Inc.
KEY WORDS:
attention deficit hyperactivity
disorder (ADHD); genetics; brainderived neurotropic factor; BDNF;
transmission/disequilibrium test
Please cite this article as follows: Lee J, Laurin N,
Crosbie J, Ickowicz A, Pathare T, Malone M, Tannock R,
Kennedy JL, Schachar R, Barr CL. 2007. Association
Study of the Brain-Derived Neurotropic Factor (BDNF)
Gene in Attention Deficit Hyperactivity Disorder. Am J
Med Genet Part B 144B:976–981.
INTRODUCTION
Attention deficit hyperactivity disorder (ADHD) is a common
childhood-onset psychiatric condition characterized by marked and pervasive inattention, hyperactivity and impulsiveness. Family, twin, and adoption studies provided compelling
evidence that genetic influences play an important role in
mediating susceptibility to ADHD [Faraone et al., 2005].
ADHD is a neurodevelopmental disorder. Neuroanatomical
studies have suggested that the regions subserving complex
motor and cognitive process are implicated in the pathophysiology of ADHD [Casey et al., 1997; Faraone and Biederman,
1998; Lou et al., 1998; Rubia et al., 2000]; therefore genes
related to neuronal development and differentiation may
represent an important set of candidates for involvement in
the pathogenesis of ADHD.
Brain-derived neurotropic factor (BDNF) is recognized as a
critical regulator in the survival and differentiation of central
neurons during childhood development and in adulthood, and
is also implicated in the synaptic plasticity of brain functions
[Ernfors et al., 1994; Linnarsson et al., 2000; Schinder and Poo,
2000; Huang and Reichardt, 2001]. BDNF was suggested to
play an important role in the pathophysiology of several
psychiatric diseases, including mood disorders [Duman, 2002;
Neves-Pereira et al., 2002; Sklar et al., 2002; Geller et al., 2004;
Hashimoto et al., 2004; Strauss et al., 2005], symptoms of
which are often observed in individuals with ADHD.
Deficits in executive functions are a main feature of the
cognitive difficulties in children with ADHD. Executive
functions are defined as neurocognitive processes that maintain an appropriate problem-solving set to attain a later goal
and include processes such as response inhibition, vigilance,
working memory, and planning [Willcutt et al., 2005].
Several lines of evidence suggest that the gene coding for
BDNF plays a role in the pathogenesis of ADHD [Tsai, 2003].
Mice in which the BDNF gene were inactivated postnatally
demonstrated significantly more locomotor activity when
stressed, for example, after transfer to a new cage than normal
mice and, in contrast to normal mice, BDNF mutant mice
are still agitated after a period of habituation [Rios et al.,
2001]. Animal studies indicate that BDNF is critical for
0.655
0.200
0.655
0.200
0.819
0.053
37
39
42
38
38
42
0.777
0.080
0.490
0.484
39
37
38
42
42
38
0.413
0.671
33
40
28
23
24
26
0.627
0.237
0.536
0.464
40
33
23
28
26
24
0.534
rs6265
rs11030104
w2 (1 df)
T
P-value
w2 (1 df)
NT
T
P-value
w2 (1 df)
0.388
100
109
80
71
73
79
109
100
71
80
79
73
0.464
0.536
0.235
0.765
0.217
0.783
T
A
G
A
A
G
Diagnostic Assessment and Subjects
Subject assessment and diagnostic criteria for inclusion in
this study are described in detail elsewhere [Barr et al., 1999;
Quist et al., 2000; Laurin et al., 2005]. Briefly, probands and
affected siblings between 7 and 16 years old were referred to
the Child Development and Neuropsychiatry Clinics at the
Hospital for Sick Children, Toronto. Diagnosis was based on
information from semi-structured interviews of parents and
teachers: Parent Interview for Child Symptoms (PICS-IV)
[Ickowicz et al., 2006] and Teacher Telephone Interview (TTI-IV)
[Tannock et al., 2002]. Children who met DSM-IV criteria for
ADHD were included in the study. All children were free of
medication for 24 hr before assessment. This protocol was
approved by the Hospital for Sick Children’s Research Ethics
Board and informed written consent or assent was obtained for
rs2049046
MATERIALS AND METHODS
NT
working memory [Kiprianova et al., 1999; Mizuno et al., 2000].
Several drugs acting on the catecholamine-mediated regulation of executive control functions, including amphetamine,
tricyclic antidepressants, and serotonin reuptake inhibitors,
lead to elevation of central BDNF mRNA levels in animal
studies [Nibuya et al., 1995; Meredith et al., 2002].
Three recent studies have assessed the role of the BDNF
gene in ADHD. Kent et al. [2005] found evidence of preferential
transmission of the valine allele of the Val66Met polymorphism (rs6265) in 341 ADHD families from the UK and Ireland
while Xu et al. [2005] reported evidence of association with the
C270T polymorphism, but not with the Val66Met variant, in
ADHD samples from the UK and Taiwan. In contrast, Friedel
et al. [2005] did not find an association between ADHD and the
same BDNF polymorphisms (Val66Met, C270T) in a small
sample of 88 ADHD cases.
The gene encoding BDNF is located at chromosome 11p14.1
[Hanson et al., 1992] and codes for a precursor peptide
(proBDNF), which is proteolytically cleaved to form the mature
protein [Mowla et al., 2001]. The gene displays an important
structural complexity with seven alternatively used noncoding exons and one coding exon. The multiple promoters, in
addition to alternative splicing and several polyadenylation
sites, result in various transcripts with different levels of
expression in different tissues and different brain regions [Liu
et al., 2005]. Antisense transcripts are also produced at the
BDNF locus and could potentially be part of the BDNF gene
regulation mechanism [Liu et al., 2005].
The aim of the current research was to test for an association
between BDNF markers and ADHD in an independent sample
of families having a child proband with ADHD. We examined
three single nucleotide polymorphisms (SNPs), including the
Val66Met (rs6265) polymorphism previously studied [Friedel
et al., 2005; Kent et al., 2005; Xu et al., 2005]. We performed a
transmission/disequilibrium test (TDT) analysis to test for
evidence of biased transmission of alleles and haplotypes in 266
nuclear families selected through a proband with ADHD. We
also conducted quantitative analysis to assess the relationship
between these marker alleles or haplotypes and the symptom
dimensions of ADHD (inattention and hyperactivity/impulsivity) and a measure of working memory.
T
0.273
0.241
0.863
Frequency
1.000
0.988
0.987
Allele
rs11030104
rs6265
rs6265
Polymorphism
D2
Paternal transmissions
D0
All transmissions
rs2049046
rs2049046
rs11030104
Marker 2
TABLE II. Allele Frequencies and TDT Analysis of BDNF SNPs
Marker 1
Maternal transmissions
TABLE I. Linkage Disequilibrium Estimates (D and D )
Between BDNF Markers
NT
2
P-value
BDNF and ADHD
0
977
978
Lee et al.
TABLE III. BDNF Haplotype Frequencies and TRANSMIT Analysis*
Transmission
Haplotypea
TAG
AAG
AGA
AGG
TAA
AAA
Frequency
Observedb
Expectedc
Var(O-E)
0.469
0.294
0.213
0.022
0.001
0.001
272.00
159.00
112.00
6.00
—
—
261.39
163.64
111.94
11.48
—
—
64.85
59.70
46.97
5.68
—
—
w2 (1 df)
1.735
0.360
7.54E-5
5.293
—
—
P-value
0.188
0.548
0.993
0.021
—
2
*Global w on 3 df for haplotypes with frequencies >10% ¼ 6.349, P ¼ 0.096.
a
Test statistic representing the observed number of transmissions.
b
Expected value of the test statistic under the null hypothesis of no association.
c
Haplotypes are composed, in order, of rs2049046, rs11030104, and rs6265.
all participants. The study sample comprised 266 nuclear
families recruited in the Toronto area, including 49 affected
siblings of the probands, for a total of 315 affected children
(80.8% boys).
For the quantitative analysis, we used the symptom scores
obtained for both ADHD dimensions (inattention and hyperactivity/impulsivity) from the PICS-IV and TTI-IV semistructured interviews. Verbal short-term and working
TABLE IV. FBAT Analysis of BDNF Allele Transmission in Relation to ADHD Symptom Scores and Short-Term and Working Memory
Measures
Polymorphism
Allele
Informative
families
Parent rated inattention
rs2049046
T
A
rs11030104
G
A
rs6265
A
G
Parent rated hyperactivity/impulsivity
rs2049046
T
A
rs11030104
G
A
rs6265
A
G
Teacher rated inattention
rs2049046
T
A
rs11030104
G
A
rs6265
A
G
Teacher rated hyperactivity/impulsivity
rs2049046
T
A
rs11030104
G
A
rs6265
A
G
Digit span forward
rs2049046
T
A
rs11030104
G
A
rs6265
A
G
Digit span backward
rs2049046
T
A
rs11030104
G
A
rs6265
A
G
a
b
132
101
101
130
101
101
128
98
98
128
98
98
100
76
72
100
76
72
Sa
E(S)b
Var(S)
Z
P-value
642.300
759.100
318.600
787.600
325.900
735.200
636.358
765.042
355.592
750.608
334.767
726.333
1250.314
0.168
0.168
1.258
1.258
0.307
0.307
0.867
631.800
732.200
335.800
765.800
346.200
719.600
613.850
750.150
341.650
759.950
322.800
743.000
1302.868
0.497
0.497
0.196
0.196
0.802
0.802
0.619
583.800
692.400
299.200
699.200
323.600
659.000
582.017
694.183
306.383
692.017
306.433
676.167
1128.936
0.053
0.053
0.261
0.261
0.619
0.619
0.958
471.500
579.000
263.000
558.000
274.500
518.000
480.375
570.125
257.375
563.625
251.250
541.250
1007.797
0.280
0.280
0.215
0.215
0.893
0.893
0.780
113.600
191.200
58.200
139.800
64.300
128.700
122.767
182.033
65.583
132.417
63.683
129.317
341.597
133.600
207.200
54.200
149.800
53.300
147.700
151.433
189.367
57.917
146.083
57.517
143.483
Test statistic.
Expected value of the test statistic under the null hypothesis of no association.
864.053
833.628
894.522
852.225
755.206
770.209
682.984
677.375
226.255
209.845
440.264
256.571
241.711
0.496
0.496
0.491
0.491
0.043
0.043
0.850
0.850
0.232
0.232
0.271
0.271
0.208
0.759
0.845
0.423
0.794
0.536
0.830
0.372
0.620
0.624
0.966
0.395
0.817
0.786
BDNF and ADHD
979
TABLE V. FBAT Analysis of BDNF Haplotype Transmission in Relation to ADHD Symptom Scores and Short-Term and Working
Memory Measures
Haplotypesa
Sb
E(S)c
Var(S)
Z
P-value
783.000
576.300
332.900
12.650
771.596
545.300
351.504
35.675
1247.449
1038.162
733.625
84.534
0.323
0.962
0.687
2.504
0.747
0.336
0.492
0.012
815.000
531.400
353.200
9.700
790.225
540.400
336.575
38.150
1351.116
1147.848
728.022
115.137
0.674
0.266
0.616
2.651
0.500
0.791
0.538
0.008
730.500
529.900
328.600
17.700
718.392
534.400
323.208
29.750
987.161
1059.743
634.222
70.133
0.385
0.138
0.214
1.439
0.700
0.890
0.830
0.150
569.750
400.250
277.500
10.750
570.187
398.750
260.812
26.375
957.788
843.396
587.084
69.078
0.014
0.052
0.689
1.880
0.989
0.959
0.491
0.060
145.800
129.600
55.600
—
151.867
114.600
59.033
—
340.832
282.217
167.472
—
0.329
0.893
0.265
—
0.742
0.372
0.791
—
161.800
188.600
63.600
—
175.533
171.100
64.367
—
440.382
397.267
193.339
—
0.654
0.878
0.055
—
0.513
0.380
0.956
—
Informative families
Parent rated inattention
TAG
116
AAG
119
AGA
84
AGG
12
Parent rated hyperactivity/impulsivity
TAG
114
AAG
117
AGA
84
AGG
12
Teacher rated inattention
TAG
112
AAG
117
AGA
81
AGG
11
Teacher rated hyperactivity/impulsivity
TAG
112
AAG
117
AGA
81
AGG
11
Digits span forward
TAG
90
AAG
87
AGA
65
AGG
9
Digits span backward
TAG
90
AAG
87
AGA
65
AGG
9
a
Haplotypes are composed, in order, of rs2049046, rs11030104, and rs6265.
Test statistic.
c
Expected value of the test statistic under the null hypothesis of no association.
b
memory were assessed using the digit span subtest of the
WISC-III [Wechsler, 1991; Kaplan et al., 1999]. This test
provides two subscale scores (digits span forward and digits
span backward) which index the ability to store and manipulate auditory-verbal information, respectively, as well as an
overall memory score.
Isolation of DNA and Genotyping of Markers
DNA was extracted from blood lymphocytes using a
standard high salt extraction method [Miller et al., 1988]. A
total of three SNPs (rs6265, chr. 11:27, 636, 492; rs11030104,
chr. 11:27, 641, 093; and rs2049046, chr. 11:27, 680, 351) were
genotyped using the ABI 7900-HT Sequence Detection Systems1 (Applied Biosystems, Foster City, CA) and TaqMan 50
nuclease assays for allelic discrimination [Livak et al., 1995].
The Val66Met (rs6265) polymorphism is located in the coding
exon and the two other SNPs (rs11030104 and rs2049046) are
located in intronic sequences. Primer and probe sequences are
available on request. The PCR reactions (5 ml) contained 30 ng
of genomic DNA, 10 mM of TaqMan Universal PCR Master
Mix1 (Applied Biosystems) and 0.1 ml of allelic discrimination
mix (Applied Biosystems). The thermal cycling conditions were
958C for 10 min and 40–50 cycles of 958C for 15 sec and the
annealing temperature (58–598C) for 1 min.
Statistical Analysis
We examined the allelic transmission of the three individual
markers using the TDT statistic calculated with the extended
TDT (ETDT) program [Sham and Curtis, 1995]. Given previous
findings of preferential paternal transmission bias with the
Val66Met variant in ADHD [Kent et al., 2005], we assessed
paternal and maternal transmission separately for all markers.
Evidence for linkage disequilibrium (LD) between the three
makers was examined by calculating the D0 and D2 coefficients
using the Haploview program [Barrett et al., 2005]. For the
analysis of the haplotypes, we employed the TRANSMIT
program version 2.5, using the robust estimator of variance
option [Clayton, 1999]. Quantitative trait TDT analyses,
examining the transmission of individual alleles or haplotypes
in relation to symptom scores of inattention and hyperactivity/
impulsivity and to short-term memory and working memory
measures, were carried out using the FBAT program version
1.5.5, with the additive model of inheritance [Laird et al., 2000;
Horvath et al., 2001]. We used population-based mean scores for
the tests as an offset value to mean center the trait. The P values
reported in this study were not corrected for multiple tests. We
did not observe any significant departure from Hardy–Weinberg
equilibrium for the genotype frequencies.
RESULTS
According to the HapMap data (build 21) and genetic studies
on this gene, BDNF is enclosed in a unique haplotype block
[Barrett et al., 2005; Liu et al., 2005; Strauss et al., 2005]. We
thus selected three SNPs, as they tag the major haplotypes of
this block, to perform an association study. Pairwise LD
coefficients D0 and D2 to assess the strength of LD support the
high correlation between the three markers in our sample of
families (Table I).
980
Lee et al.
As shown in Table II, when considering ADHD as a
categorical trait, we did not observe significant evidence of
biased transmission of these three individual markers,
including the Val66Met allele implicated previously in ADHD.
Moreover, we did not observe preferential transmission of the
paternal Val66Met allele after separate analysis of paternal
and maternal transmissions, as was suggested in the study by
Kent et al.
The transmission of the haplotypes consisting of the three
polymorphisms was tested using the TRANSMIT program
(Table III). No significant evidence for biased transmission of
any of the three haplotypes with frequency >10% was found
(global w2 for haplotypes with frequencies >10%: w2 ¼ 6.349,
df ¼ 3, P ¼ 0.096).
We then analyzed the markers using a quantitative
approach for ADHD inattentive and hyperactive-impulsive
symptom dimensions as well as for short-term and working
memory measures. We found no significant evidence for a
relationship between individual alleles or common haplotypes
(with frequency >10%) and the two ADHD symptom dimensions or short-term and working memory scores (Tables III
and V).
Of note, one uncommon haplotype, A-G-G (frequency 2.2%),
demonstrated a significant association with ADHD in categorical (undertransmission w2 ¼ 5.293, df ¼ 1, P ¼ 0.021) and
quantitative analyses (parents’ rated inattention: Z ¼
2.504, P ¼ 0.012; and hyperactivity/impulsivity: Z ¼ 2.651,
P ¼ 0.008) (Tables III and V). However, the number of
transmission for this haplotype was considered too low to
provide a definitive result (i.e., quantitative analysis was based
on 12 informative families).
DISCUSSION
Genetic variations in the BDNF gene have recently been
found to be associated with ADHD [Kent et al., 2005; Xu et al.,
2005]. To further evaluate the association of variation in BDNF
with ADHD, we performed a genetic study using three SNPs in
a relatively large family-based sample from Toronto. Using
TDT and quantitative analysis, we found no evidence for
association between ADHD and the individual alleles or the
haplotypes with frequency >10%. Significant undertransmission of the haplotype A-G-G was found in our sample, however,
this haplotype was present at a low frequency (2.2%).
Our results regarding BDNF markers differ from previous
family-based association studies. Those studies found evidence
for preferential transmission of the valine (G) allele of the
Val66Met polymorphism (rs6265) with a strong paternal effect
in a sample from the UK and Ireland [Kent et al., 2005] or with
the C270T polymorphism in a combined sample from the UK
and Taiwan [Xu et al., 2005]. Although we did not directly
assess the C270T polymorphism, this variant is embedded in
the haplotype block tagged by the markers genotyped for this
study. Another study did not find an association between the
Val66Met (rs6265) or C270T polymorphisms and ADHD in
88 patients with ADHD [Friedel et al., 2005].
The reasons for the discrepancies between studies are
unclear. The present study was carried out using approximately the same number of affected children as the Kent et al.’s
[2005] study (315 children vs. 341 children, respectively). The
Xu et al. [2005] study was composed of two samples of ADHD
probands from the UK (180 children) and Taiwan (212 children).
Therefore, our study would have been adequately powered to
detect an association assuming that there are no betweensample differences in effect size or LD structure in the gene.
The ethnic composition, however, was different among the
study samples. In our sample, the majority of the families were
of European Caucasian descent, while 10% of families were of
‘‘other’’ or ‘‘mixed’’ background, including Chinese, African,
Indian, and Native-Americans. The sample of Kent et al. [2005]
was described as consisting of Caucasians with all individuals
born in the UK or Ireland and Xu et al.’s [2005] was a
combination of European-Caucasian and Taiwanese. These
ethnic differences could have had an effect on the results since
variable allelic frequencies and genotypes of the BDNF gene
polymorphism (Val66Met) have been reported in different
ethnic groups [Shimizu et al., 2004]. The allele frequency of
this polymorphism between our sample and the Kent et al.
[2005] sample was not strikingly different (80% Val, 20% Met
vs. 87% Val, 13% Met, respectively), however, an important
difference is present with regards to the same allele frequencies of the Taiwanese sample in the Xu et al.’s [2005] report
(47% Val, 53% Met).
Another aspect potentially explaining discrepancies in the
different association studies is a variable distribution of the
assessed phenotype in each sample. A higher proportion of
Kent et al. [2005] sample (81%) and Xu et al. [2005] (UK 100%,
Taiwan 78%) were diagnosed with DSM-IV ADHD combined
subtype compared to our sample (62%). Conversely, more
children were diagnosed with predominantly inattentive
subtype in our sample (24%) than in Kent et al. [2005] sample
(9%). It is possible that the clinical heterogeneity between
samples may have masked a real association, but it is currently
unclear how clinical heterogeneity may relate to genetic risk
for this gene.
BDNF has been implicated in learning and memory functions in animal studies [Kiprianova et al., 1999; Mizuno et al.,
2000]. Children with ADHD often perform poorly on tasks of
working memory, with deficits reported both in spatial and
verbal components [Hervey et al., 2004; Martinussen et al.,
2005]. Based on these findings, we also tested the association
between BDNF and verbal working memory in this sample of
families with an ADHD proband. These analyses did not yield
significant results suggesting that BDNF is not playing a major
role in the verbal WM performance of those children, as
measured by the digit span subtest.
It is difficult to make firm conclusions about the relationship
between BDNF and ADHD given the contrasting results
between studies. In the present study, we found little evidence
that BDNF is a major genetic susceptibility factor contributing
to ADHD. However, in light of the evidence for an involvement
of BDNF in ADHD in other samples, and the evidence for
biased transmission of an uncommon haplotype in our sample,
further study of the BDNF gene in ADHD is warranted.
ACKNOWLEDGMENTS
This work was supported by Postdoctoral Fellowships from
the Hospital for Sick Children Research Training Centre (N.L.)
and the Canadian Institutes of Health Research (N.L.) and by
grants from The Hospital for Sick Children Psychiatric
Endowment Fund (C.L.B), and the Canadian Institutes of
Health Research MT14336 and MOP14336 (C.L.B).
REFERENCES
Barr CL, Wigg K, Malone M, Schachar R, Tannock R, Roberts W, Kennedy
JL. 1999. Linkage study of Catechol-O-Methyltransferase and attention-deficit hyperactivity disorder. Am J Med Genet 88(6):710–713.
Barrett JC, Fry B, Maller J, Daly MJ. 2005. Haploview: Analysis and
visualization of LD and haplotype maps. Bioinformatics 21(2):263–265.
Epub 2004 Aug 5.
Casey BJ, Castellanos FX, Giedd JN, Marsh WL, Hamburger SD, Schubert
AB, Vauss YC, Vaituzis AC, Dickstein DP, Sarfatti SE, et al. 1997.
Implication of right frontostriatal circuitry in response inhibition and
attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc
Psychiatry 36(3):374–383.
Clayton D. 1999. A generalization of the transmission/disequilibrium test
for uncertain-haplotype transmission. Am J Hum Genet 65(4):1170–
1177.
BDNF and ADHD
Duman RS. 2002. Pathophysiology of depression: The concept of synaptic
plasticity. Eur Psychiatry 17(Suppl 3):306–310.
Ernfors P, Lee KF, Jaenisch R. 1994. Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368(6467):147–150.
Faraone SV, Biederman J. 1998. Neurobiology of attention-deficit hyperactivity disorder. Biol Psychiatry 44(10):951–958.
Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA,
Sklar P. 2005. Molecular genetics of attention-deficit/hyperactivity
disorder. Biol Psychiatry 57(11):1313–1323.
Friedel S, Horro FF, Wermter AK, Geller F, Dempfle A, Reichwald K, Smidt
J, Bronner G, Konrad K, Herpertz-Dahlmann B, et al. 2005. Mutation
screen of the brain derived neurotrophic factor gene (BDNF): Identification of several genetic variants and association studies in patients with
obesity, eating disorders, and attention-deficit/hyperactivity disorder.
Am J Med Genet B Neuropsychiatr Genet 132(1):96–99.
Geller B, Badner JA, Tillman R, Christian SL, Bolhofner K, Cook EH Jr.
2004. Linkage disequilibrium of the brain-derived neurotrophic factor
Val66Met polymorphism in children with a prepubertal and early
adolescent bipolar disorder phenotype. Am J Psychiatry 161(9):1698–
1700.
Hanson IM, Seawright A, van Heyningen V. 1992. The human BDNF gene
maps between FSHB and HVBS1 at the boundary of 11p13–p14.
Genomics 13(4):1331–1333.
Hashimoto K, Shimizu E, Iyo M. 2004. Critical role of brain-derived
neurotrophic factor in mood disorders. Brain Res Rev 45(2):104–114.
Hervey AS, Epstein JN, Curry JF. 2004. Neuropsychology of adults with
attention-deficit/hyperactivity disorder: A meta-analytic review. Neuropsychology 18(3):485–503.
Horvath S, Xu X, Laird NM. 2001. The family based association test method:
Strategies for studying general genotype–phenotype associations. Eur J
Hum Genet 9(4):301–306.
981
Martinussen R, Hayden J, Hogg-Johnson S, Tannock R. 2005. A metaanalysis of working memory impairments in children with attentiondeficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry
44(4):377–384.
Meredith GE, Callen S, Scheuer DA. 2002. Brain-derived neurotrophic
factor expression is increased in the rat amygdala, piriform cortex and
hypothalamus following repeated amphetamine administration. Brain
Res 949(1–2):218–227.
Miller SA, Dykes DD, Polesky HF. 1988. A simple salting out procedure for
extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):
1215.
Mizuno M, Yamada K, Olariu A, Nawa H, Nabeshima T. 2000. Involvement
of brain-derived neurotrophic factor in spatial memory formation and
maintenance in a radial arm maze test in rats. J Neurosci 20(18):7116–
7121.
Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG,
Murphy RA. 2001. Biosynthesis and post-translational processing of the
precursor to brain-derived neurotrophic factor. J Biol Chem 276(16):
12660–12666.
Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL.
2002. The brain-derived neurotrophic factor gene confers susceptibility
to bipolar disorder: Evidence from a family-based association study. Am
J Hum Genet 71(3):651–655.
Nibuya M, Morinobu S, Duman RS. 1995. Regulation of BDNF and trkB
mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15(11):7539–7547.
Quist JF, Barr CL, Schachar R, Roberts W, Malone M, Tannock R, Basile VS,
Beitchman J, Kennedy JL. 2000. Evidence for the serotonin HTR2A
receptor gene as a susceptibility factor in attention deficit hyperactivity
disorder (ADHD). Mol Psychiatry 5(5):537–541.
Huang EJ, Reichardt LF. 2001. Neurotrophins: Roles in neuronal development and function. Annu Rev Neurosci 24:677–736.
Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R, Lechan RM, Jaenisch R.
2001. Conditional deletion of brain-derived neurotrophic factor in the
postnatal brain leads to obesity and hyperactivity. Mol Endocrinol
15(10):1748–1757.
Ickowicz A, Schachar R, Sugarman R, Chen S, Millette C, Cook L. 2006. The
parent interview for child symptoms (PICS): A situation-specific clinicalresearch interview for attention deficit hyperactivity and related
disorders. Can J Psychiatry 50:325–328.
Rubia K, Overmeyer S, Taylor E, Brammer M, Williams SC, Simmons
A, Andrew C, Bullmore ET. 2000. Functional frontalisation with
age: Mapping neurodevelopmental trajectories with fMRI. Neurosci
Biobehav Rev 24(1):13–19.
Kaplan E, Fein D, Kramer J, Delis D, Morris R. 1999. WISC-III PI Manual.
San Antonio, Texas: The Psychological Corporation.
Schinder AF, Poo M. 2000. The neurotrophin hypothesis for synaptic
plasticity. Trends Neurosci 23(12):639–645.
Kent L, Green E, Hawi Z, Kirley A, Dudbridge F, Lowe N, Raybould R,
Langley K, Bray N, Fitzgerald M, et al. 2005. Association of the
paternally transmitted copy of common Valine allele of the Val66Met
polymorphism of the brain-derived neurotrophic factor (BDNF) gene
with susceptibility to ADHD. Mol Psychiatry 10(10):939–943.
Sham PC, Curtis D. 1995. An extended transmission/disequilibrium test
(TDT) for multi-allele marker loci. Ann Hum Genet 59(Pt 3):323–336.
Kiprianova I, Sandkuhler J, Schwab S, Hoyer S, Spranger M. 1999. Brainderived neurotrophic factor improves long-term potentiation and
cognitive functions after transient forebrain ischemia in the rat. Exp
Neurol 159(2):511–519.
Laird NM, Horvath S, Xu X. 2000. Implementing a unified approach to
family-based tests of association. Genet Epidemiol 19(Suppl 1):S36–42.
Laurin N, Misener VL, Crosbie J, Ickowicz A, Pathare T, Roberts W, Malone
M, Tannock R, Schachar R, Kennedy JL, et al. 2005. Association of the
calcyon gene (DRD1IP) with attention deficit/hyperactive disorder. Mol
Psychiatr 10(12):1117–1125.
Linnarsson S, Willson CA, Ernfors P. 2000. Cell death in regenerating
populations of neurons in BDNF mutant mice. Mol Brain Res 75(1):
61–69.
Shimizu E, Hashimoto K, Iyo M. 2004. Ethnic difference of the BDNF 196G/
A (val66met) polymorphism frequencies: The possibility to explain
ethnic mental traits. Am J Med Genet B Neuropsychiatr Genet 126(1):
122–123.
Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, Schaffner S,
Kirov G, Jones I, Owen M, et al. 2002. Family-based association study of
76 candidate genes in bipolar disorder: BDNF is a potential risk locus.
Brain-derived neutrophic factor. Mol Psychiatry 7(6):579–593.
Strauss J, Barr CL, George CJ, Devlin B, Vetro A, Kiss E, Baji I, King N,
Shaikh S, Lanktree M, et al. 2005. Brain-derived neurotrophic factor
variants are associated with childhood-onset mood disorder: Confirmation in a Hungarian sample. Mol Psychiatry 10(9):861–867.
Tannock R, Hum M, Masellis M, Humphries T, Schachar R. 2002. Teacher
telephone interview for children’s academic performance, attention,
behavior and learning: DSM-IV Version (TTI-IV). Toronto, Canada: The
Hospital for Sick Children, Unpublished Document.
Liu QR, Walther D, Drgon T, Polesskaya O, Lesnick TG, Strain KJ, de
Andrade M, Bower JH, Maraganore DM, Uhl GR. 2005. Human brain
derived neurotrophic factor (BDNF) genes, splicing patterns, and
assessments of associations with substance abuse and Parkinson’s
Disease. Am J Med Genet B Neuropsychiatr Genet 134(1):93–103.
Tsai SJ. 2003. Attention-deficit hyperactivity disorder and brain-derived
neurotrophic factor: A speculative hypothesis. Med Hypotheses 60(6):
849–851.
Livak KJ, Flood SJ, Marmaro J, Giusti W, Deetz K. 1995. Oligonucleotides
with fluorescent dyes at opposite ends provide a quenched probe system
useful for detecting PCR product and nucleic acid hybridization. PCR
Methods Appl 4(6):357–362.
Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF. 2005. Validity
of the executive function theory of attention-deficit/hyperactivity
disorder: A meta-analytic review. Biol Psychiatry 57(11):1336–1346.
Lou HC, Andresen J, Steinberg B, McLaughlin T, Friberg L. 1998. The
striatum in a putative cerebral network activated by verbal awareness in
normals and in ADHD children. Eur J Neurol 5(1):67–74.
Wechsler D. 1991. Wechsler intelligence scale for children. 3rd Edition. San
Antonio, Texas: Harcourt Brace & Co.
Xu X, Mill J, Zhou K, Brookes K, Chen CK, Asherson P. 2005. Family-based
association study between brain-derieved neurotrophic factor gene
polymorphisms and attention deficit hyperactivity disorder. Am J Med
Genet B Neuropsychiatr Genet 138B(1):53.
Документ
Категория
Без категории
Просмотров
2
Размер файла
82 Кб
Теги
factors, neurotropic, associations, stud, disorder, hyperactivity, bdnf, genes, brain, attention, deficit, derived
1/--страниц
Пожаловаться на содержимое документа