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Association study of brain-derived neurotrophic factor (BDNF) and LIN-7 homolog (LIN-7) genes with adult attention-deficithyperactivity disorder.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:945 –951 (2008)
Association Study of Brain-Derived Neurotrophic Factor
(BDNF) and LIN-7 Homolog (LIN-7) Genes With Adult
Attention-Deficit/Hyperactivity Disorder
Matthew Lanktree,1 Alessio Squassina,1 Marilee Krinsky,1 John Strauss,1 Umesh Jain,1 Fabio Macciardi,1,2
James L. Kennedy,1 and Pierandrea Muglia1*
1
Neurogenetics Section, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada
Department of Medical Genetics, University of Milan, Milan, Italy
2
Attention-deficit/hyperactivity disorder (ADHD)
is a common psychiatric disorder with a large
genetic component that has been shown to persist
into adulthood in 30–60% of childhood ADHD
cases. Adult ADHD confers an increased risk
of ADHD in relatives when compared to childhood
ADHD, possibly due to a greater genetic liability
than the childhood form. Brain-derived neurotrophic factor (BDNF) is a neurotrophin expressed in the brain throughout life and is involved in
survival, differentiation, and synaptic plasticity
of several neuronal systems including dopaminergic pathways. Mammalian LIN-7 homolog is
selectively expressed in specific neuronal populations and is involved in the postsynaptic density
of neuronal synapses. LIN-7 is also a positional
candidate, as it lies immediately downstream of
BDNF. We tested for association between five
BDNF polymorphisms, two LIN-7 polymorphisms
and adult ADHD. The sample consisted of 80 trios
comprised of an adult ADHD proband and their
biological parents and an independent sample
of 121 adult ADHD cases and a corresponding
number of sex, age, and ethnically matched controls (total 201 probands). Allelic and haplotype
association was found between both BDNF and
adult ADHD, and LIN-7 and adult ADHD. HapMap
indicates BDNF and LIN-7 occur in different
haplotype blocks, though some linkage disequilibrium exists between the SNPs in these adjacent
genes. Further investigations into the pathologic
mechanisms of BDNF and LIN-7 in adult ADHD
are required.
ß 2008 Wiley-Liss, Inc.
KEY WORDS:
brain-derived neurotrophic factor
(BDNF); LIN-7 homolog (LIN-7);
attention-deficit/hyperactivity
disorder (ADHD); association
study; psychiatry; neuroscience
*Correspondence to: Pierandrea Muglia, M.D., R-30, Neurogenetics Section, Centre for Addiction and Mental Health,
250 College St., Toronto, ON, Canada M5T 1R8.
E-mail: pierandrea.muglia@utoronto.ca
Received 2 June 2007; Accepted 28 December 2007
DOI 10.1002/ajmg.b.30723
ß 2008 Wiley-Liss, Inc.
Please cite this article as follows: Lanktree M, Squassina
A, Krinsky M, Strauss J, Jain U, Macciardi F, Kennedy
JL, Muglia P. 2008. Association Study of Brain-Derived
Neurotrophic Factor (BDNF) and LIN-7 Homolog (LIN-7)
Genes With Adult Attention-Deficit/Hyperactivity Disorder. Am J Med Genet Part B 147B:945–951.
INTRODUCTION
Attention-deficit/hyperactivity disorder (ADHD) is a common childhood psychiatric disorder affecting approximately
3–5% of school age children characterized by inattention,
excessive motor activity, impulsivity, and distractibility.
ADHD persists into adulthood in a portion of subjects leading
to lower educational attainment, lower income, and underemployment [Mannuzza et al., 1993]. The percentage of
children who retain the diagnosis into adulthood varies across
studies from 30% to 60% according to the criteria used to assess
ADHD symptoms in the adult population [Barkley et al., 1990;
Mannuzza et al., 1991; Weiss et al., 2000]. Compelling evidence
from genetic epidemiological studies [Thapar et al., 1999]
and twin studies [Levy et al., 1997] suggest a large genetic
influence in the etiology of ADHD. Patients whose ADHD
symptoms persist into adulthood have higher rates of ADHD in
their relatives compared to patients whose ADHD symptoms
diminish with age [Faraone et al., 2000]. Since the form of
ADHD that persists into adulthood is less common and appears
to have a greater genetic liability, the decline of ADHD with
increasing age may be advantageous to genetic investigations,
reducing heterogeneity from the sample [Faraone and Tsuang,
2001].
The efficacy of psychostimulants (i.e., methylphenidate and
dextro-amphetamine) in ameliorating ADHD symptoms
together with evidence from neuroimaging studies supports a
dopamine (DA) system dysfunction in the etiology of ADHD
[Cheon et al., 2003]. A number of association studies have
suggested that polymorphisms of the dopamine system genes,
including the dopamine transporter (DAT1) [Waldman et al.,
1998], dopamine D4 (DRD4) [Muglia et al., 2000], D5 (DRD5)
[Lowe et al., 2004], and D1 receptor genes (DRD1) [Misener
et al., 2004], may increase the risk for ADHD. Brain-derived
neurotrophic factor (BDNF) is a neurotrophic factor involved
in a variety of trophic and neuromodulatory effects that
include an important role in the development and survival of
dopaminergic neurons [Hyman et al., 1991; Vicario-Abejon
et al., 2002]. Animal studies have also shown strong links
between BDNF and the DA system. Heterozygous BDNF
knock-out mice exhibit an altered dopaminergic transmission
[Dluzen et al., 2001], attenuated cocaine locomotor stimulating
946
Lanktree et al.
response and reduced rewarding effects from cocaine [Hall
et al., 2003b]. The key role of BDNF in the development of the
dopamine system and the implication of the dopamine system
in the pathology of ADHD, leads to the hypothesis that an
altered BDNF expression or modified protein structure could
alter the dopamine pathways increasing the risk for ADHD
[Tsai, 2003].
The BDNF gene is located on chromosome 11p14.1 and spans
67 kb (www.ncbi.nlm.nih.gov). The only common non-conservative polymorphism within BDNF occurs in the pro-domain
and produces an amino acid substitution (valine to methionine)
at codon 66 (Val66Met, rs6265) [Cargill et al., 1999]. Evidence
exists that the val66met polymorphism affects intracellular
trafficking and packaging of pro-BDNF molecules and the
methionine variant shows a lower depolarization-induced secretion of the protein in cultured hippocampal neurons
[Egan et al., 2003]. To date, polymorphisms within BDNF have
been associated with many psychiatric disorders, including
obsessive compulsive disorder [Hall et al., 2003a], bipolar
disorder [Neves-Pereira et al., 2002], schizophrenia [Muglia
et al., 2003; Neves-Pereira et al., 2005], and childhood-onset
mood disorders [Strauss et al., 2004, 2005]. However, recent
meta-analyses of association between BDNF and schizophrenia and bipolar disorder have shown weak or no association
[Kanazawa et al., 2007; Xu et al., 2007b; Zintzaras, 2007]. In
childhood ADHD, one study reported positive association with
the valine allele, especially when paternally transmitted [Kent
et al., 2005], one study reported no association with the
val66met polymorphism, but significant over-transmission
of the C allele of the C270T polymorphism and undertransmission of the T-Val haplotype [Xu et al., 2007a], while
three other studies reported no association [Friedel et al., 2005;
Kim et al., 2007; Schimmelmann et al., 2007].
The first gene downstream of BDNF is the mammalian
homolog of LIN-7, which codes for a small protein first
discovered in Caenorhabditis elegans. LIN-7 is found on the
same strand and 149 kb downstream of BDNF (www.
ncbi.nlm.nih.gov). Rapid and reliable transmission of neuronal
messages via neurotransmitters requires the assembly of
multiple proteins in the postsynaptic density (PSD) of neuronal
synapses [Kornau et al., 1995]. The exact mechanism of
organizing excitatory signal transduction cascades is unclear,
however the production of the PSD is essential and is in part
mediated by protein interactions with PSD-95/discs large/zona
occludens-1 (PDZ) motifs [Kornau et al., 1995; Craven and
Bredt, 1998]. LIN-7 contains little more than a single
PDZ domain [Jo et al., 1999]. Mammalian LIN-7 (MALS) is
selectively expressed in specific neuronal populations in the
brain, are enriched in PSD fractions, and cluster with PSD-95
and NMDA type glutamate receptors in cultured hippocampal
neurons [Jo et al., 1999]. As of yet, no other studies
have examined LIN-7 for association with any psychiatric
conditions.
In this investigation we test for association between five
SNPs throughout the 30 end of the BDNF gene, including
the val66met polymorphism which is known to alter BDNF
protein secretion, and Adult ADHD. As well, we examined two
SNPs within the adjacent LIN-7 gene which lies immediately
downstream to BDNF.
MATERIALS AND METHODS
Subjects and Laboratory Methods
The sample used for this study has been extensively
described in three previous studies of Adult ADHD [Muglia
et al., 2000, 2002, 2003]. This study was approved by the Centre
for Addiction and Mental Health (CAMH) ethical review
committee. Patients were invited to participate in the study
after a clinician-referral to the Adult and Adolescent ADHD
Research Program of CAMH, an affiliate teaching hospital of
the University of Toronto. The diagnosis of ADHD was based
upon fulfilling the criteria for ADHD in the DSM-IV both at
the time of interview and during childhood, as recalled by the
patient and at least one first-degree relative. In order to rule
out additional psychiatric conditions, patients were assessed
using the Structural Clinical Interview for DSM-IV (axis I) by a
psychiatrist (U.J.). Approximately 30% of referrals to the
clinic were excluded due to co-morbid psychiatric conditions.
All probands within the sample were patients diagnosed
with adult ADHD (with age 34.7 12.7). The family sample
contains 268 individuals in 64 complete trios (one proband plus
two parents), 14 families with one affected and one unaffected
child, 4 families with two affected children, and 1 family
with one affected and two unaffected children. A case-control
sample comprised of 121 cases with a corresponding number
of controls matched for age, ethnicity and sex were included.
A total of 201 (80 þ 121) probands were included in this
study. The majority of participants were of mixed European
Caucasian ancestry (94%). The remaining 6% was composed of
ten probands of African descent and two of Chinese descent.
The genotypes inconsistent with family structure were
found to be 2% and such families were excluded from the
analysis. Blood samples for DNA extraction were collected
from all the subjects that gave a written informed consent to
participate to the study. DNA was extracted following standard high salt procedures. The BDNF val66met polymorphism
was selected because of its functional consequences, and C270T
(rs27656701) was selected because of the frequency of its study.
Hall et al. [2003a] described the linkage disequilibrium (LD)
structure of the area surrounding BDNF, and suggested LD
existed between SNPs within the 30 end of BDNF and SNPs
extending as far as LIN-7. Since LIN-7 seemed like a plausible
candidate, we selected LIN-7_1 (rs10835188) within LIN-7 and
LIN-7_2 (rs3763965) just upstream (on the reverse strand) of
LIN-7. As well, markers with ideal heterozygosity were
selected through the 30 of BDNF. The val66met polymorphism
was amplified using the PCR method provided by the NCBI
SNP database (SNP ID#: rs6265). The PCR products were
digested by Eco721 (Fermentas, Burlington, Ontario, Canada)
and the fragments were separated on 4% agarose gel.
Determination of genotypes was performed independently by
two lab technicians and in the case of unclear genotypes, the
Sequence Detection System ABI 7000 (Applied Biosystem,
Foster City, CA) was used. Lab technicians that worked in the
genotype procedures were blind to the diagnosis and to the
family structure of all samples. The remainder of the SNPs in
this study was completely genotyped with the ABI 7000
Sequence Detection System and is labeled in the direction of
the þ-strand, not in the direction of the gene. The polymorphisms are listed here with rs numbers, alleles and chromosomal positions as listed by the NCBI reference sequence build
36.2 (www.ncbi.nlh.nih.gov): LIN-7_1 (rs10835188 A/C
27479762), LIN-7_2 (rs3763965 A/T 27485563), BDNF1
(rs4923463 G/A 27629076), BDNF2 (rs11030104 G/A
27641093), BDNF3 (rs2049045 G/C 27650817), and BDNF4
(rs7103411 T/C 27656701). The SNPs were amplified and
genotyped using ABI TaqMan 50 -exonuclease Assays-onDemandTM according to the manufacturer’s protocols.
Statistical Methods
Pedigrees were analyzed for genotype inconsistencies using
PedManager (v0.9). Chi-square analysis was used to compare
allele counts in the case-control sample and transmission
disequilibrium test (TDT) in the family sample. To combine the
samples, inferred controls were constructed using PedSplit
[Lanktree et al. 2004] via haplotype relative risk (HRR) [Falk
BDNF, LIN-7, and Adult ADHD
and Rubinstein, 1987]. Hence, if the parents have genotype
A1/A2 and A3/A4, and the affected offspring has genotype
A1/A3, the inferred control is created with a genotype of A2/A4.
The produced inferred control is robust to population
admixture [Lander and Schork, 1994]. Chi-squares were then
calculated to compare cases and controls/inferred controls in
the combined sample. Even background levels of LD make
a straight Bonferroni correction for multiple testing overconservative, markedly decreasing power. Therefore, all
P values are displayed without correction for multiple
testing, but SNPSpD [Nyholt, 2004] was used to determine
the appropriate significant threshold required to keep the Type
I error rate at 5% (a ¼ 0.05). Combining the case-control
and family samples resulted in a power of 80% to detect a
difference of 0.11 between the allele frequencies of cases and
matched controls/inferred controls with a ¼ 0.05 (two-tailed)
(Sample Power, SPSS, Inc., Chicago, IL). To examine the LD
between polymorphisms the Lewontin D0 was calculated, and
haplotype frequencies were predicted using the expectationmaximization (EM) algorithm as implemented in Haploview
[Barrett et al., 2005]. The EM algorithm approximates
haplotype frequencies within populations of individuals where
phase is unknown. In the case-control sample, haplotype
association is obtained by summing the fractional likelihoods of
each haplotype in each case and comparing it to the sum of the
fractional likelihoods in the controls [Barrett et al., 2005]. In
the family sample, transmission and non-transmission of a
haplotype is weighted by the likelihood of the haplotype.
Finally, in the combined sample, haplotype frequencies were
deduced by examining the cases, the controls and the inferred
controls via the EM algorithm.
RESULTS
The genotype distributions for cases, controls, and HRR
inferred controls did not deviate from the Hardy–Weinberg
equilibrium at the two LIN-7 polymorphisms and five BDNF
polymorphisms. Very strong LD was found between the two
LIN-7 polymorphisms and across the markers within BDNF
(Fig. 1). The haplotype block structure as indicated by the
International HapMap Project was similar and is also shown in
Figure 1 [IHMC, 2005]. SNPSpD found that a significance level
of 0.014 should be used to retain a low false positive rate
(a ¼ 0.05) in the single SNP association tests.
947
Allelic Association
The family-based sample was initially analyzed using TDT
and the Val66Met, BDNF_2, and BDNF_4 polymorphisms
showed marginal significance (P < 0.05), but are above the
multiple testing threshold set by SNPSpD (Table I, top panel).
The LIN-7_1 C allele was significantly over-transmitted to
Adult ADHD probands (P ¼ 0.01). In the case-control sample,
no significant differences were observed between cases and
controls (Table I, middle panel). HRR allows us to create
inferred controls from the alleles not transmitted from parents
to affected probands, enabling us combine family and casecontrol samples. With the increase in power from the now
larger sample, a difference between cases and controls could be
seen at all polymorphisms with the exception of LIN-7_2
(Table I, bottom panel). The LIN-7_1, Val66Met, and BDNF_2
showed association able to withstand correction for multiple
testing (P < 0.01).
Haplotype Analysis
LD in our sample and HapMap CEPH families showed that
the polymorphisms exist in two haplotype blocks (Fig. 1). In the
family sample, the A-G-A-G-T BDNF and C-T LIN-7 haplotypes were more frequently transmitted to cases (P ¼ 0.0086;
P ¼ 0.025) (Table II, top panel). In the case-control sample, the
opposite BDNF haplotype, G-A-G-C-C, was significantly more
common in controls (P ¼ 0.0054). On the other hand, the C-T
LIN-7 haplotype had a trend to be more common in controls
(P ¼ 0.093) (Table II, middle panel). When the samples were
combined via HRR, the A-G-A-G-T BDNF haplotype was
found to be significantly more common in affected individuals
[OR ¼ 1.47 (1.05–2.05), P ¼ 0.025], while the G-A-G-C-C
haplotype was more common in controls [OR ¼ 0.50 (0.33–
0.77), P ¼ 0.0013]. In the LIN-7 block the C-T haplotype
was significantly more common in affected individuals
[OR ¼ 1.58 (1.14–2.20), P ¼ 0.0063] while the A-T haplotype
was more common in controls [OR ¼ 0.67 (0.48–0.93),
P ¼ 0.020] (see Table II, bottom panel).
DISCUSSION
In this study we looked for an association between seven
polymorphisms within two genes, BDNF and LIN-7, and
Adult ADHD. Five polymorphisms were selected within and
Fig. 1. Confidence bounds of linkage disequilibrium in BDNF and LIN-7. Linkage disequilibrium (D0 value) within the region as (A) calculated from our
data, and (B) calculated from the CEPH families in the International HapMap Project (www.hapmap.org) (BDNF_1 is not in HapMap). Dark gray boxes
indicate areas with evidence of linkage, white areas have evidence for recombination and light gray areas were uninformative.
LIN-7_2
rs6265
27636492
G(V)
33:18
4.41
0.036
A(M):G(V)
31:203 (0.13)
43:191 (0.18)
1.47 (0.89–2.44)
2.31
0.13
A(M):G(V)
52:346 (0.13)
78:314 (0.20)
1.65 (1.13–2.42)
6.71
0.0096
A
32:19
3.31
0.069
G:A
33:163 (0.17)
44:152 (0.22)
1.43 (0.87–2.36)
1.96
0.16
G:A
55:295 (0.16)
79:271 (0.23)
1.56 (1.07–2.29)
5.32
0.021
Val66Met
rs4923463
27629076
BDNF_1
G:A
54:310 (0.15)
80:276 (0.22)
1.66 (1.14–2.44)
6.93
0.0085
G:A
34:180 (0.16)
46:164 (0.22)
1.48 (0.91–2.43)
2.51
0.11
A
31:16
4.79
0.029
rs11030104
27641093
BDNF_2
T:C
328:70 (0.18)
298:98 (0.25)
1.54 (1.09–2.17)
5.54
0.019
T:C
190:46 (0.19)
178:58 (0.25)
1.04 (0.66–1.65)
1.78
0.18
T
36:20
4.57
0.033
rs7103411
27656701
BDNF_3
G:C
342:50 (0.13)
313:73 (0.19)
1.60 (1.08–2.36)
6.10
0.014
G:C
198:32 (0.14)
185:45 (0.20)
1.51 (0.92–2.47)
2.64
0.11
G
27:17
2.27
0.13
rs2049045
27650817
BDNF_4
Position is taken from build 36.2 of NCBI reference sequence (www.ncbi.nlh.nih.gov). The allele indicated was counted for transmission (T) and non-transmission (NT) via transmission disequilibrium test
(TDT). Allele counts are given for cases and controls (i.e., Allele 1 count: Allele 2 count) with minor allele frequency (MAF). Odds ratio (OR) and 95% confidence interval (95% CI) are given. w2 represents Pearson
Chi-square statistic. P represents two-tailed nominal P values. Haplotype relative risk (HRR) was used to calculate the allele counts of the familial cases and inferred controls. SNPSpD found that P 0.014 is
the appropriate significance required for multiple testing corrections.
Rs #
rs10835188
rs3763965
Position
27479762
27485563
Family
Allele
C
T
T:NT
31:14
40:33
6.42
0.67
w2
P
0.011
0.41
Case-control
Allele
A:C
A:T
Case (MAF)
170:56 (0.25)
118:100 (0.46)
Control (MAF)
182:44 (0.19)
116:102 (0.47)
OR (95% CI)
1.36 (0.87–2.13)
1.04 (0.71–1.51)
2
1.85
0.04
w
P
0.17
0.85
Combined (cases, controls, and inferred controls)
Allele
A:C
A:T
Case (MAF)
271:107 (0.28)
200:182 (0.48)
Control (MAF)
284:70 (0.20)
203:173 (0.46)
OR (95% CI)
1.61 (1.14–2.27)
1.07 (0.80–1.42)
7.26
0.20
w2
P
0.0071
0.65
LIN-7_1
TABLE I. Allelic Association in Family, Case-Control and Combined Samples
BDNF, LIN-7, and Adult ADHD
949
TABLE II. Haplotype in Family, Case-Control and Combined Samples
Block1 (LIN-7)
A-A
C-T
Family
T:NT
32.9:38.2
33.7:17.6
0.39
5.00
w2
P
0.54
0.025
Case-control
Case
0.537
0.213
Control
0.521
0.281
OR (95% CI)
1.06 (0.73–1.53)
0.70 (0.46–1.06)
0.11
2.82
w2
P
0.74
0.093
Combined (cases, controls, and inferred controls)
Case
0.519
0.282
Control
0.529
0.198
OR (95% CI)
0.96 (0.73–1.27)
1.58 (1.14–2.20)
2
0.09
7.47
w
P
0.77
0.0063
Block2 (BDNF)
A-T
A-G-A-G-T
G-A-G-C-C
23.7:33.5
1.65
0.20
39.1:19.0
6.90
0.0086
15.1:25.0
2.46
0.12
0.248
0.193
1.38 (0.89–2.15)
2.10
0.15
0.776
0.747
1.17 (0.88–1.37)
0.54
0.46
0.093
0.181
0.46 (0.27–0.80)
7.75
0.0054
0.196
0.266
0.67 (0.48–0.94)
5.46
0.020
0.804
0.736
1.47 (1.05–2.05)
5.04
0.025
0.098
0.177
0.50 (0.33–0.77)
10.37
0.0013
Haplotype blocks are as indicated in Figure 1 (Block1: LIN-7_1, LIN-7_2; Block2: BDNF_1, Val(G)66Met(A), BDNF_2, BDNF_3, BDNF_4). Letters denote
allele at the given polymorphism. Transmitted (T) and non-transmitted (NT) haplotypes are reported for the family sample, while frequencies are reported
for the case-control and combined samples. Only haplotypes with frequency >.05 are shown. w2 represents Pearson Chi-square statistic. P represents twotailed nominal P values.
surrounding the 30 end of BDNF, including the functional
val66met polymorphism. First, we looked for biased transmission of alleles within the family sample using TDT. Three of
the BDNF alleles showed marginal significance, including
over-transmission of the valine allele to the probands. We then
genotyped an independent sample of cases and age-, sex-, and
ethnicity-matched controls. Both case-control and familybased ascertainment methods have their own inherent biases
and the fact that we used both strategies reduces the chances
that one bias could have an over-riding effect to create a false
positive. In the case-control sample, no polymorphisms showed
association. In order to increase the power of our study, we
than used HRR to jointly analyze the two samples for
association. In the combined sample all six SNPs were found
to be in association with adult ADHD (P < 0.05), two of which
were significant after correction for multiple testing (P < 0.01).
The valine allele of the functional val66met and the nearby A
allele of BDNF_2 showed the highest odds ratios [OR ¼ 1.65
(1.13–2.42), P ¼ 0.0096; OR ¼ 1.66 (1.14–2.44), P ¼ 0.0085].
Due to the strong LD within the BDNF haplotype block, only
two haplotypes had a frequency of greater than 5%. Of these
haplotypes, the one containing the valine allele was found to
be more common in cases [OR ¼ 1.47 (1.05–2.05) P ¼ 0.025],
while the one containing the methionine allele was more
common in controls [OR ¼ 0.51 (0.34–0.78) P ¼ 0.0013].
While many genetic investigations have connected BDNF
with psychiatric illness, LIN-7, which also plays an important
role in neuronal function and lies directly adjacent to BDNF
making it an ideal functional and positional candidate, has not
yet been investigated. In order to ensure that the association
observed between BDNF and adult ADHD was not due to LD
with the nearby LIN-7, two polymorphisms were genotyped
within LIN-7. The International HapMap Consortium
indicates that LIN-7 and BDNF are in different haplotype
blocks. We genotyped the family and case-control samples and
found the same haplotype block structure as HapMap, however
LIN-7 polymorphisms did appear to be in some amount of LD
with the BDNF polymorphisms. Similar to BDNF, we found
marginally significant over-transmission of the C allele of
rs10835188 in the family sample, and no significance in the
case-control sample, but with the increase in power from
combining the samples, the C allele of rs10835188 was
significantly more common in cases [OR ¼ 1.61 (1.14–2.27),
P ¼ 0.0071]. When examining the LIN-7 haplotypes, the C-T
haplotype was strongly associated with adult ADHD [OR ¼
1.58 (1.14–2.20), P ¼ 0.0063].
The use of HRR and inferred controls has not been a popular
choice for association studies, likely due to the difficulty of
obtaining family samples, especially in adult diseases, and
the additional cost of genotyping family members. Nevertheless, it remains validated method that is robust to
population admixture [Lander and Schork, 1994]. A limitation
of our approach is that instead of determining the phased
haplotypes in cases and inferred controls by examining the
complete trios (which can determine phase unambiguously in
rare cases), the EM algorithm was used to deduce haplotype
frequencies in the combined sample creating a potential for
lost information. However, EM is a validated, widely-used
algorithm for determining phase in case-control datasets and
combining the two samples produced a study of sufficient
power due to the increase in sample size.
The BDNF val66met polymorphism has been reported to be
associated with many other psychiatric conditions, especially
schizophrenia and bipolar disorder. However, these association studies appear to be far from conclusive as seen by
recent meta-analyses [Kanazawa et al., 2007; Xu et al.,
2007b; Zintzaras, 2007]. Subjects who met the criteria for
comorbid psychiatric disorders were excluded from our study
to maintain homogeneity of the sample in respect to their Adult
ADHD diagnosis and remove the possibility of a confounding
effect. It has been suggested that socio-economic status (SES)
plays a moderating role on the effect of BDNF SNPs on ADHD
etiology [Lasky-Su et al., 2007]. The lack of SES data in our
analysis is a limitation of our results.
The previous association reported by Xu et al. [2007a]
showed a decreased transmission of the haplotype containing
the Val allele of val66met and T allele of C270T to ADHD
patients, indicating they are protective. Contrarily, our study
found an increased frequency of the haplotype containing those
same two alleles in Adult ADHD patients, and the study by
Kent et al. [2005] also found increased Val transmission to
ADHD patients. It is possible to find association between a
disease and different alleles when the SNP studied is not
functionally involved in the disease, but is in LD with an
adjacent disease causing locus. Unfortunately, due to the LD
discovered between the SNPs we genotyped, we are unable to
950
Lanktree et al.
discern whether the signal we are detecting is from within
LIN-7 or BDNF.
In conclusion, we have detected association between
both BDNF and LIN-7 polymorphisms and adult ADHD in a
combined family and case-control sample. Two other studies
have reported associations between childhood ADHD and
BDNF polymorphisms, while three other studies reported no
association, and thus our results need to be interpreted with
measured caution. Our observation of association between
LIN-7 polymorphisms and Adult ADHD suggest that future
investigations should include the investigation of LIN-7.
ACKNOWLEDGMENTS
The authors would like to graciously thank the Vincenzo
De Luca, Daniel Műller, Takahiro Shinkai, and Natalie
Bulgin for their thoughtful assistance and encouragement.
ML is supported by the Canadian Institute of Health Research
MD/PhD studentship award.
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