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Association study of CREB1 and childhood-onset mood disorders.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 137B:45 –50 (2005)
Association Study of CREB1 and Childhood-Onset
Mood Disorders
I. Burcescu,1 K. Wigg,1 N. King,2 Á. Vetró,3 E. Kiss,3 L. Katay,3 J.L. Kennedy,2 M. Kovacs,4 C.L. Barr,1,5*
and The International Consortium for Childhood-Onset Mood Disorders
1
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
3
Department for Child and Adolescent Psychiatry, Szeged University, Szeged, Hungary
4
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
5
The Hospital for Sick Children, Toronto, Ontario, Canada
2
Several lines of evidence suggest that the cellular
pathways involved in synaptic plasticity contribute to the risk of depression. These findings
include the evidence that chronic antidepressant
treatment upregulates the cAMP signal transduction cascade resulting in increased expression
and function of the cAMP responsive element
binding protein (CREB), a transcription factor
that increases the expression of key growth
factors involved in synaptogenesis and neurogenesis. Recently, linkage to CREB1 was reported for
early-onset depression in families recruited from
the Pittsburgh area. This finding was significant
only in female sibling pairs from those families. Two specific DNA variants, 656G/A and a C
insertion/deletion in intron 8, were identified in
CREB1 that co-segregated with depression in two
of the families. We sought to investigate the
relationship of CREB1 to childhood-onset mood
disorders (COMD) using a sample of 195 nuclear
families (225 affected children) collected in Hungary. We genotyped the two CREB1 DNA variants
previously identified as linked to depression as
well as three additional polymorphisms spanning
the gene. In addition, we genotyped the 656G/A
DNA change and the intron 8 polymorphism in a
Members of the International Consortium for Childhood-Onset
Mood Disorders: István Benák, Viola Kothencné Osváth, Edit
Dombovári, Emı́lia Kaczvinszky and Andor Kanka, Szeged
University Medical Faculty, Department of Child and Adolescent
Psychiatry, Szeged. Júlia Gádoros, Ildikó Baji, Zsuzsa Tamás,
Márta Besnyo, and Judit Székely, Vadaskert Hospital, Budapest.
László Mayer, Margit Hospital, Csorna. Heads of the Units and
Departments where the patients were collected: Rózsa Hasuly, MD,
Szent Rókus Hospital, Outpatient Unit of Child Psychiatry,
Budapest; Ilona Riegler, MD, Márta Fohn, MD, Heim Pál Hospital
Outpatient Unit of Child Psychiatry, Budapest; Katalin Benko,
MD, Outpatient Unit of Child Psychiatry; Szeged. Mária Mojzes,
MD, Outpatient Unit of Child Psychiatry, Baja; Róza Oláh, MD,
Kenézy Gyula Hospital, Department of Child and Adolescent
Psychiatry, Debrecen; Mária Károlyfalvi, MD, Gyöngyi Farkas,
MD, Zsuzsa Bánk, MD, Outpatient Unit of Child Psychiatry,
Debrecen. Ferenc Dicso, MD, Dénes Kövendy, MD, Jósa András
Hospital Outpatient Unit of Child Psychiatry, Nyı́regyháza;
Mária Gyurcsó, MD, Petz Aladár Hospital, Outpatient Unit of
Child Psychiatry, Gyor; Zsuzsanna Fekete, MD, Mariann Vados,
MD, Szent György Hospital, Outpatient Unit of Child Psychiatry,
Székesfehérvár; Zsuzsa Takács, MD, Szekszárd Hospital, Outpatient Unit of Child Psychiatry, Szekszárd; Eszter Gyenge, MD,
Mária Palaczky, MD, Ágnes Horváth, MD, Outpatient Department of Child Psychiatry, Pécs; Ilona Mógor, MD. Péter
ß 2005 Wiley-Liss, Inc.
sample of 112 probands with mood disorders
collected in the Pittsburgh area and matched
controls, and examined the distribution of alleles.
The 656A allele was not observed in our samples
and there was no evidence for association of the
intron 8 polymorphism in either the sample from
Pittsburgh (x2 ¼ 0.061, 1 d.f., P ¼ 0.803) or Hungary
(x2 ¼ 0.040, 1 d.f., P ¼ 0.842). We found no evidence
for an association with the other three polymorphisms or with the haplotypes of these markers.
Further, we found no sex-specific relationship.
Our results, therefore, do not support the previous evidence for this gene as a major factor
contributing to depression.
ß 2005 Wiley-Liss, Inc.
KEY WORDS: CREB1; depression;
mood disorders; gene
genetics;
INTRODUCTION
Mood disorders that onset in childhood have a significant
impact on subsequent adjustment, and present challenges
to conventional treatments. In young patients, an episode of
major depressive disorder (MDD) has a recurrence rate of
approximately 70%, indicating that many young patients
Steiner, MD, Csolnoky Ferenc Hospital, Outpatient Unit of Child
Psychiatry, Veszprém. Eniko Juhász Szolnok Hospital Outpatient
Unit of Child Psychiatry, Szolnok; Mária Révhelyi, MD, Petz
Aladár Hospital Department of Child and Adolescent Psychiatry,
Gyor; Éva Gyulai, MD, Baja Hospital Outpatient Unit of Child
Psychiatry, Baja; Katalin Bense, MD, Edina Farkas, MD,
Kecskemét Hospital Outpatient Unit of Child Psychiatry, Kecskemét; Sörfozo Zsuzsanna, MD, Kaposi Mór Hospital, Outpatient
Unit of Child Psychiatry, Kaposvár. Interviewers: Judit Tömöri,
Tünde Horváth M., Eszter Szamosi. Regional research office
members: Cserép Melinda, Edit Sitkei, Noémi Takács. Central
research office members: Zoltán Széll, László Tóth-Soma Ph.D,
Márta Dobó, and Éva Lehoczky.
Grant sponsor: National Institute of Mental Health Program
Project; Grant number: MH 56193; Grant sponsor: National
Alliance for Research on Schizophrenia and Depression.
*Correspondence to: C.L. Barr, 399 Bathurst St. Toronto
Western Research Institute, University Health Network, Toronto,
Ontario, Canada. E-mail: CBarr@uhnres.utoronto.ca
Received 22 October 2004; Accepted 21 April 2005
DOI 10.1002/ajmg.b.30201
46
Burcescu et al.
remain at significant risk for depressive disorders [Kovacs
and Devlin, 1998]. Mood disorders and depressive symptoms
are estimated to have a heritable component (31–42%)
[Sullivan et al., 2000] and probands with early-onset, including
childhood-onset, carry a higher familial risk [Orvaschel, 1990;
Kovacs et al., 1997], and have higher heritiability estimates
(70–82%) [Thapar and McGuffin, 1994].
Extensive research has established that population base
rates of depression are higher in women than in men [Weissman
and Klerman, 1977; Nolen-Hoeksema, 1987; Kessler et al.,
1993]. However, prior to around 14 years of age, depression
appears to affect boys and girls equally [Wade et al., 2002].
Further, in psychiatrically referred depressed children, there
is no evidence for significant sex differences in clinical presentation in terms of age of onset, severity, risk of recurrence,
episode length, or comorbid disorders [Kovacs, 2001]. The sex
differences in depression become apparent following puberty:
almost twice as many adolescent girls as boys present with
MDD [Lewinsohn et al., 1993; Angold et al., 1998]. Some twin
studies have suggested a greater heritability of depression in
women than in men [Bierut et al., 1999; Kendler et al., 2001],
with evidence that women and men, for the most part, share
common genetic influences for depression, but with some
gender specific genes contributing to the risk [Kendler et al.,
2001].
Evidence has been reported for linkage of the 2q33–35
chromosomal region to mood disorders among women, but not
men, in families with recurrent (2 episodes) early onset (onset
age 25) major depressive disorders (MDD) [Zubenko et al.,
2003b]. A particularly strong candidate for depression located
in this region, the gene for cAMP responsive element binding
protein, CREB1, was investigated in an additional study that
implicated CREB1 as a potential sex-limited susceptibility
gene for MDD [Zubenko et al., 2003a]. In that study, two
sequence variants in CREB1 were identified, one located in the
promoter region (656A/G) and one in intron 8 (cytosine
insertion/deletion located 16 bp 50 to exon 9) that yielded
significant linkage scores (P ¼ 0.002 and 0.01, respectively) for
mood disorders, or their absence, among the women in 2 of a
total of 81 families in the study.
The CREB1 gene encodes a 43 kDa, 341 amino acids
nuclear phosphoprotein, cAMP-responsive element (CRE)binding protein (CREB), which is a member of the basic leucine
zipper family of DNA binding proteins [Mayr and Montminy,
2001]. Alternate splicing of the gene’s exons (spanning 68.9 kb)
results in two transcript variants encoding different isoforms
with distinct properties in different tissues and during development [Walker et al., 1996; Rudolph et al., 1998]. Phosphorylation at Ser133 by several protein kinases in response to,
amongst others, cAMP, activates CREB. Once activated, the
protein binds as a homodimer to the CRE site (an octameric
palindrome) of a number of gene promoters, thereby inducing
transcription. Several reports on the synergistic interaction of
CREB with nuclear estrogen receptors have suggested mechanisms by which CREB facilitates sex-specific patterns of gene
expression [Lazennec et al., 2001; McEwen, 2001].
This gene is a strong candidate for depression based on the
hypothesis that cellular pathways involved in synaptic plasticity contribute to the risk of depression [Duman et al., 1999;
Vaidya and Duman, 2001]. Recurrent major depression has
been associated with significant hippocampal damage, and
chronic (but not acute) antidepressant treatment upregulates the cAMP signal transduction cascade involved in
synaptic plasticity. Upregulation of cAMP results in increased
expression and function of CREB1, increasing the expression
of target genes including brain-derived neurotropic factor
(BDNF), leading to neuronal sprouting and neurogenesis.
Chronic stress has been demonstrated to decrease hippocampal neurogenesis and to induce atrophy and death of
hippocampal and cortical neurons. Genetic variability in the
components of this system may result in an inherent decrease
in the ability to make adaptive cognitive changes to stressful
events and decreased resilience to negative thoughts. Directly
relevant is our previous genetic studies of BDNF that provides
evidence for this gene as a susceptibility gene in COMD in the
samples used in this study, specifically supporting the role of
the cAMP pathway in the genetic risk for COMD [Strauss et al.,
2004].
These converging lines of evidence and the study by Zubenko
et al. [2003a] prompted our group to investigate whether the
CREB1 gene was associated with COMD, and whether this
association was related to sex. To test for such an association,
we genotyped the two CREB1 DNA variants described above
[Zubenko et al., 2003a] as well as three additional polymorphisms in a sample of 195 small nuclear families with 225 affected
children that had been collected in Hungary. The transmission
disequilibrium test (TDT) was then used to test for biased
transmission of alleles and of haplotypes from heterozygous
parents to their affected offspring. Using an independent
sample of 112 probands with early-onset mood disorders
collected in Pittsburgh and matched controls, we also
genotyped the two DNA variants identified in the Zubenko
et al. [2003a] study and then examined the distribution of the
alleles.
MATERIALS AND METHODS
Subjects
The subjects enrolled in this study were part of a multidisciplinary Program Project to study risk factors in childhoodonset mood disorders (COMD) and have been previously
described in detail [Adams et al., 2005]. We used two samples
for this study: (i) family-based association study: The sample
consisted of 195 families with 225 affected children recruited
from 21 mental health facilities across Hungary. The probands
were diagnosed using the Interview Schedule for Children and
Adolescents-Diagnostic Version (ISCA-D), an extension and
modification of the ISCA [Sherrill and Kovacs, 2000]. The
probands met DSM-IV criteria for a mood disorder (unipolar
major depression or bipolar disorder), with the onset of the first
episode by age 14. Probands were interviewed twice, approximately 1 month apart. Consensus diagnosis of two independent
child psychiatrists was used as final diagnosis. (ii) Case-control
association study: An extensive description of the subjects
enrolled in this study was published previously [Adams et al.,
2005]. Briefly, the 112 proband sample consisted of young
adults from the Pittsburgh, PA area that met DSM-III or DSMIV criteria for depression (major depressive and/or dysthymic
disorder) by age 14 or bipolar spectrum disorder (bipolar I, II or
cyclothymic disorder) by age 17. Psychiatric assessments were
conducted and verified by experienced and trained clinical
evaluators and independent best-estimate psychiatrists. Each
proband was individually matched to a control with no history
of mental illness, of the same sex, and of the same ethnic
background. The sample consisted of 69 (62%) females and
43 (38%) males. For both probands and controls, ethnicity
matching was based on detailed self-reported description of
ancestry. Proband and control groups consist of 83% EuropeanNorth American, 16% African-North American, and 1% mixed
ethnicity. Previously, genomic control testing [Devlin and
Roeder, 1999] was performed with 17 biallelic markers distributed randomly across the genome. The distribution of the w2
values for the COMD probands versus controls showed no
deviation from that expected by chance indicating that the
controls were of similar ethnic background as the COMD
probands and no correction for stratification was required for
this sample [Strauss et al., 2004].
0.602
0.273
0.842
0.040
0.442
0.591
0.478
b
30 UTR
208432020
rs6785
Creb1-9224
Intron 8
208425646
Creb1-int8del
Intron 4
208395853
rs2551920
Creb1-9089
Intron 1 (untranslated region)
208376555
rs2709357
Creb1-7093
a
71
63
73
64
12
13
69
63
1.000
0.000
0.763
0.237
0.762
0.238
0.967
0.033
0.768
0.232
1
2
1
2
1
2
1
2
1
2
G
A
A
G
C
G
Ins C
Del C
G
A
Promoter
Based on genomic contig NT005403, S53722 (and using NCBI information regarding location on chromosome 2 for the SNPs with reference sequence number).
Intron structure based on NCBI Build 33, the April 2003 UCSC human reference sequence.
63
71
64
73
13
12
63
69
Non-transmissions
Transmissions
Allele
frequency
Allele
DNA
variant
Locationb
Nucleotide
numbera
Reference
sequence number
208358054
For this study we genotyped five markers (Table I), two of
which had been reported previously [Zubenko et al., 2003a].
Creb1-pro
RESULTS
Polymorphism
Statistical Analysis
The degree of linkage disequilibrium (LD) between marker
alleles in this study was evaluated using the ldmax program
(available in the GOLD software package [Abecasis and
Cookson, 2000] at http://www.sph.umich.edu/csg/abecasis/
GOLD). LD was expressed as the coefficient of LD D0 [Devlin
and Risch, 1995] and the square of the standardized measure,
r2 [Hill and Weir, 1994]. Hardy–Weinberg equilibrium was
tested using the program PedStats (http://www.sph.umich.
edu/csg/abecasis/PedStats/index.html). All markers were found
to be in Hardy–Weinberg equilibrium. The extended TDT
(ETDT) program [Sham and Curtis, 1995] was used to test for
biased transmission of alleles in the family-based association
study (Hungarian samples). The transmission of haplotypes
was analyzed using the TRANSMIT program [Clayton, 1999]
with the robust estimator option, and where only haplotypes with frequencies greater than 0.10 were used in the
analysis. For the case-control association study, chi-square
analyses were performed to compare the distribution of alleles.
TABLE I. CREB1 Polymorphisms, Allele Frequencies in the Hungarian Sample Parental Chromosomes, and TDT Results
Blood, or in some cases, buccal samples, were collected from
subjects and genomic DNA was extracted using a standard
high salt method or NaOH and Proteinase K (QIAmp DNA
Mini Kit, Qiagen, Inc., Mississauga, ON, Canada), respectively. Genotypes for the two Zubenko et al. [2003a] DNA
variants, a G to A change in the promoter region (marker
CREB1-pro) and a C insertion/deletion in the CREB1 intron 8
(marker CREB1-int8del), were determined by PCR amplification of 60–100 ng DNA, followed by restriction enzyme
digestion of the PCR products, as described previously
[Zubenko et al., 2003a]. The promoter region polymorphism
was genotyped with the following primers: F: GTA GGA TGG
GGC ATA TTT CCA G and R: CGG GTT TTC CTT TCC GAG
ACT CC amplified at 608C and digested with MspI. The intron 8
insertion/deletion polymorphism was initially genotyped with
restriction enzymes as previously described but was then
converted into a TaqMan1 50 nuclease assay for allelic
discrimination assay (Applied Biosystems, Foster City, CA)
for more efficient genotyping. The primers for amplification
(608C) were F: TAT GTG GAA ATC ATT TGC AT and R: TTT
TCA AGC ACT GCC ACT CTG T with probes VIC: TCC CGT
CTC TTT TG and FAM: CCG TCC TCT TTT G.
The remaining three single nucleotide polymorphisms
(SNPs; CREB1-7093, CREB1-9089, CREB1-9224) were genotyped using the TaqMan1 50 nuclease assay with primers
and probes available commercially (Applied Biosystems). The
PCR primers and allelic discrimination probes were designed (CREB1-int8del) and/or obtained from ABI (assays-ondemand1) based on published reference sequence numbers.
Five microliters PCR reactions contained 30 ng of genomic
DNA, 5 mmol of TaqMan1 Universal PCR Master Mix (Applied
Biosystems), and 0.125 ml of allelic discrimination mix, which
contained 36 mM of each primer and 8 mM of each probe. The
thermal cycling conditions for the Assays-on-Demand1 obtained from Applied Biosystems were 958C for 10 min, then
50 cycles of 928C for 15 sec and 1 min at 608C. For CREB1int8del, an initial 2 min step of 508C was added. Negative
controls were included with each 96-well plate. Plates were
read on the ABI 7900-HT Sequence Detection System using
the allelic discrimination end-point analysis mode of the
software package version 2.0 (Applied Biosystems).
w2
Genotyping
0.489
P-value
Association of CREB1 and Childhood-Onset Mood Disorders
47
48
Burcescu et al.
The first of these, a G to A transition is predicted to eliminate a
consensus-binding motif for AP-2, a transcriptional activator,
and a potential CpG methylation site in the CREB1 promoter
(Creb1-pro). The second is a C insertion/deletion in intron 8 of
the gene (Creb1-int8del). We selected the remaining polymorphisms from the NCBI SNP database (http://www.
ncbi.nlm.nih.gov/SNP/index.html), located either in introns,
or in the 30 untranslated region (30 UTR) of the gene, and thus
we were able to genotype polymorphic markers across the gene
from intron 1 to the 30 UTR. The location of the polymorphisms
and allele frequencies in the Hungarian parental chromosomes
are listed in Table I.
We did not observe the A allele of the promoter DNA variant
in any of 376 probands (n ¼ 124) affected siblings (n ¼ 21) or
parents (n ¼ 231) screened in the Hungarian family sample,
nor in the 112 COMD probands collected in Pittsburgh.
To test for association of the CREB1 gene to COMD, we used
the TDT to analyze the inheritance of four polymorphisms,
both individually and as haplotypes, in the families from
Hungary. We found no evidence of biased transmission of
individual marker alleles (Table I). For the intron 8 C insertion/
deletion polymorphism, the number of informative transmissions was low (25) therefore not to be considered definitive;
however, there was no evidence of even a trend for transmission of either allele. We also genotyped this marker in the
sample of COMD probands collected in Pittsburgh as this
sample would be of similar ethnic background to the families
previously identified with evidence for linkage of this marker.
The frequency of the intron 8DC allele in the probands (0.040)
collected in Pittsburgh did not differ significantly from the
frequency observed in the control sample (0.036) and therefore
we find no evidence for association to COMD (w2 ¼ 0.06, 1 df, Pvalue ¼ 0.803). Further, the frequency did not differ significantly from the frequency observed in the Hungarian parental
(0.033) or probands’ chromosomes (0.039).
We also examined the transmission of haplotypes in the
Hungarian sample, since haplotypes may be more informative
than single markers alone. The four-marker haplotype frequencies were determined from the parental chromosomes,
and as Table II shows, only two haplotypes were found at
haplotypes frequencies greater than 10% and therefore at a
high enough frequency to be used meaningfully in TDT analysis. We found no evidence of biased transmission of haplotypes in our nuclear family sample.
Since Zubenko et al. [2003a] identified sex differences in the
risk conferred by the intron 8DC insertion/deletion and
promoter variants, we analyzed our female and male probands
separately in an attempt to determine whether this would
indicate biased allele transmission. As Table III shows, even
when sex of the subjects was considered separately, we found
no biased mode of transmission in our Hungarian family
sample for any of the markers. The previous report by Zubenko
and colleagues of linkage for the intron 8 insertion/deletion
polymorphism indicated that the DC allele was a protective
factor in women but not men. It would then be predicted that
there would be evidence for biased non-transmission of this
allele in the sample of female subjects, but this was not supported in our sample. There was also no significant difference
in the allele frequencies for the intron 8 marker between
males (0.046) and females (0.036) in the Pittsburgh probands
(w2 ¼ 0.146, 1 d.f., P ¼ 0.703).
D0 [Devlin and Risch, 1995] and r2 [Hill and Weir, 1994] are
commonly used measures for describing the degree of LD
between alleles at two markers. Strong LD (>0.90 between all
markers) as measured by D0 is evident across the gene in the
Hungarian sample. r2 can be used as an indication of the power
to detect an association with r2 values greater than 0.80 considered a stringent threshold, able to detect 80% of the existing
haplotypes [Carlson et al., 2004]. With the exception of
the relatively uninformative intron 8DC insertion/deletion
marker, the remaining three markers have r2 values greater
than 0.93 indicating that we would have high power to detect
an association using these three markers if this gene is a major
susceptibility factor contributing to depression as indicated
from the previous linkage studies of this region.
DISCUSSION
In this study, we failed to find support for the CREB1 gene
recently reported as a candidate gene for susceptibility to
early-onset mood disorders [Zubenko et al., 2003a]. The
evidence that this gene is related to mood disorders was based
on an initial linkage study that yielded a peak multipoint LOD
score of 3.77 at D2S2208 for female relative pairs affected by
recurrent, early-onset, unipolar mood disorders [Zubenko
et al., 2002]. Subsequent studies [Zubenko et al., 2003a]
identified two DNA changes in the CREB1 gene that cosegregated with mood disorders (or their absence). The first of
these variants was a possible functional G to A transition at
position 656 in the promoter region (Creb1-pro); heterozygosity for the CREB1 promoter variant was linked with mood
disorders among women (w2 ¼ 9.76, df ¼ 1, P ¼ 0.002) in one
early-onset MDD family (family A) that previously revealed a
positive LOD score with the 2q33–35 locus. This change was
also observed to segregate in a nuclear family with four affected
children, two males and two females (family B). The second
DNA change was a C deletion in intron 8 (Creb1-int8del).
Unlike the promoter variant, heterozygosity for the intron 8
TABLE II. CREB1 Common Haplotype Frequencies and TRANSMIT Analyses
CREB1 marker alleles
Haplotype
number
1
2
3
4
5
6
7
8
2
Transmission
7093
9089
Int8Del
9224
Haplotype
frequency
1
2
1
1
1
1
1
2
1
1
2
1
2
1
2
2
1
1
1
2
2
1
1
1
1
1
1
1
1
2
2
2
0.72
0.01
0.00
0.03
0.00
0.00
0.00
0.23
2
Obsa
Expb
w2
P-value
(two-sided)
324.00
317.37
1.16
0.28
100.00
103.47
0.37
0.55
Global w ¼ 7.350, 7 d.f., P ¼ 0.3934; common haplotypes (those with frequencies >10%) w ¼ 1.778, 2d.f., P ¼ 0.411.
Only haplotypes with frequencies >0.01 are listed. Others were found with frequencies <0.01.
a
Test statistic representing the observed number of transmissions.
b
Expected value of the test statistic under the null hypothesis of no linkage or association.
0.502
0.450
1.000
0.000
0.502
0.450
0.317
1.000
36
45
37
43
7
7
37
43
1.000
0.000
0.763
0.091
0.158
0.691
45
36
43
37
7
7
43
37
0.890
0.019
27
26
27
30
6
5
26
26
26
27
30
27
5
6
26
26
One degree of freedom.
a
Creb1-9224
Creb1-int8del
Creb1-9089
1
2
1
2
1
2
1
2
Creb1-7093
Non-transmissions
Polymorphism
Allele
Transmissions
Non-transmissions
w2
P-valuea
Transmissions
Female subjects
Male subjects
TABLE III. TDT Results of CREB1 Markers in the Sample of Hungarian Families According to Sex
w2
P-value
Association of CREB1 and Childhood-Onset Mood Disorders
49
polymorphism yielded a protective effect against mood disorders in women but not men in family A (P ¼ 0.01).
In our sample of Hungarian families, the promoter polymorphism was not observed and we did not find significant
evidence for biased transmission of the alleles of the intron 8 polymorphism, nor any significant sex-biased results.
Because ethnic variation could result in different alleles
contributing to the phenotype in different populations, we
genotyped the promoter DNA variant and the DC DNA changes
in a sample of probands drawn from the Pittsburgh population.
We did not observe the promoter DNA change in the Pittsburgh
sample, therefore, although possibly functional due to the predicted change in the consensus binding site for the transcription factor AP-2, this DNA variant is too rare to be a major
susceptibility allele contributing to the COMD phenotype. We
also did not observe any difference in allele frequencies for the
intron 8DC allele in the Hungarian and Pittsburgh samples
and there was no evidence for an association.
The Zubenko and colleagues study found that these two
CREB1 sequence variants contributed to the susceptibility
of mood disorders in only 2 of 31 early-onset MDD families
(or 2.5% of a total of 81 recurrent early-onset unipolar mood
disorders families in their collection). Further analysis
indicated that the 79 remaining families generated a statistically significant LOD score of 4.24 that occurred in the 451 kb
region between adjacent markers D2S2321 and D2S2208 that
contained CREB1 indicating that the remaining families are
linked to this region. This allows for the possibility that as yet
unidentified DNA variants in CREB1 contribute to the disorder. Results in our sample did not support this as a possible
explanation as we did not find any evidence for an association
using markers spanning the gene. There is strong LD across
this gene, therefore in our sample, we should be able to detect
an association if this gene is a major genetic factor contributing
to depression as suggested by the results of the linkage studies.
Different factors influence power in linkage versus association studies thus it is difficult to compare power between these
different methods of analysis. The high LOD scores for this
region indicate that the locus in this region is a gene of major
effect contributing to depression. Therefore, using an association approach which is much more powerful, and multiple
markers spanning the gene with high LD across the gene, our
sample of 195 nuclear families should have sufficient power to
detect an association. We can estimate power for the DC allele
specifically, assuming complete LD (this allele is the causative
change) and allele frequency of 0.03. Based on these assumptions, the Hungarian sample will have 80% power at the alpha
0.05 level to detect an association if this allele carries a relative risk of 2.6 or greater (Genetic Power Calculator, http://
statgen.iop.kcl.ac.uk/gpc/qtlassoc.html).
Linkage analysis based on sharing of alleles within families
generally results in positive LOD scores over large chromosomal regions. Association studies, however, rely on LD and
therefore association can generally only be detected over small
chromosomal regions generally under 1 Mb. The genome scan
results provided the highest evidence for support spanned a
region of 451 kb with significant multipoint LOD scores spanning a much larger region of 15 cM. Based on the evidence
supporting genes involved in synaptic plasticity in mood disorders, particularly CREB1 [Duman et al., 1999, 2000], this
gene was by far the strongest candidate in the 2q33–35 region.
However, linkage to another gene in this region co-segregating
with the CREB1 DC and the promoter variant in the families
previously linked to CREB1 cannot be ruled out on the basis
of the linkage data, and other genes in the region should be
considered.
Lastly, differences in the definition of the phenotype
between the previous study of CREB1 and ours may be a factor
in the findings. For example, different mechanisms may
50
Burcescu et al.
contribute to childhood-onset depression, defined here as onset
before 14 compared to early-onset defined as onset prior to
25 years of age defined in the Zubenko and colleagues study.
Further, the sample from Pittsburgh used here consists of both
early-onset unipolar as well as bipolar cases whereas the
previous study used only unipolar cases. Phenotypic, or clinical
features, as contributing factors to the differential findings
cannot be ruled out at this time.
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