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Investigation of parent-of-origin effects in ADHD candidate genes.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:776 –780 (2007)
Investigation of Parent-Of-Origin Effects in ADHD
Candidate Genes
Jang Woo Kim,1* Irwin D. Waldman,2 Stephen V. Faraone,3 Joseph Biederman,4 Alysa E. Doyle,4
Shaun Purcell,1 Lori Arbeitman,1 Jesen Fagerness,1 Pamela Sklar,1 and Jordan W. Smoller1
1
Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital,
Harvard Medical School, Boston, Massachusetts
2
Department of Psychology, Emory University, Atlanta, Georgia
3
Department of Psychiatry, SUNY Upstate Medical University, Syracuse, New York
4
Pediatric Psychopharmacology Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Attention deficit hyperactivity disorder (ADHD)
is a common early-onset childhood disorder with
a strong genetic component. Results from previous studies have suggested that there may be a
parent-of-origin effect for ADHD candidate genes.
In particular, a recent investigation identified
a pattern of paternal over-transmission of
risk alleles for nine ADHD candidate genes.
We examined this phenomenon in a sample of
291 trios for five genes previously associated with
ADHD (HTR1B, SNAP-25, DRD5, DAT1, and
BDNF). Using a dense map of markers and two
analytic methods in this relatively large familybased sample, we do not find any evidence for
significant paternal over-transmission of risk
alleles in these candidate loci. Thus, we conclude
that a substantial parent-of-origin effect is
unlikely for these leading ADHD candidate
genes.
ß 2007 Wiley-Liss, Inc.
KEY WORDS: Attention deficit
disorder (ADHD)
hyperactivity
Please cite this article as follows: Kim JW, Waldman ID,
Faraone SV, Biederman J, Doyle AE, Purcell S, Arbeitman L, Fagerness J, Sklar P, Smoller JW. 2007. Investigation of Parent-of-Origin Effects in ADHD Candidate
Genes. Am J Med Genet Part B 144B:776–780.
INTRODUCTION
Attention deficit hyperactivity disorder (ADHD) is a common
childhood disorder with prevalence of 8–12% worldwide
[Faraone et al., 2003]. Previous epidemiological studies
provide compelling evidence that genes play a strong role in
mediating susceptibility to ADHD and candidate gene
studies have already implicated several genes in the etiology
of ADHD [Faraone et al., 2005]. Interestingly, several familybased candidate gene studies have reported paternal overtransmission of alleles to ADHD offspring [Brophy et al., 2002;
Hawi et al., 2002, 2005; Kustanovich et al., 2003; Quist et al.,
2003; Mill et al., 2004; Kent et al., 2005; Smoller et al., 2006].
For example, three studies have reported paternal overtransmission of the G861 allele of HTR1B [Hawi et al.,
2002; Quist et al., 2003; Smoller et al., 2006]. Additionally,
prior studies have suggested paternal over-transmission of
alleles of the SNAP-25 locus in ADHD [Brophy et al., 2002;
Kustanovich et al., 2003; Mill et al., 2004] and for the Val66Met
polymorphism of BDNF in which the common valine
allele showed significant paternal over-transmission [Kent
et al., 2005]. Most recently, Hawi et al. [2005] investigated 17
candidate genes and observed parent-of-origin effect in 9 of
them. When they summed the transmission of risk alleles by
parent-of-origin across these genes, they observed a significant
excess of paternal transmissions.
If a parent-of-origin effect does exist for ADHD, the
mechanism or biological basis is unclear. Whereas parentof-origin effects have been demonstrated for several rare
disorders [Mann and Bartolomei, 1999], such effects have not
been well established for more common, complex disorders.
Establishing whether such a phenomenon applies to a disorder
as complex as ADHD would therefore be of substantial interest.
Herein, we describe our examination of parent-of-origin
effects for five loci that have been associated with ADHD in
several previous studies (HTR1B, SNAP-25, DRD5, DAT1, and
BDNF), including three (HTR1B, SNAP-25, and BDNF)
that have previously been reported to show paternal overtransmission of risks alleles in ADHD families [Brophy et al.,
2002; Hawi et al., 2002; Kustanovich et al., 2003; Quist et al.,
2003; Mill et al., 2004; Kent et al., 2005; Smoller et al., 2006].
We report that, using a dense map of single nucleotide
polymorphisms (SNPs) across each gene in a sample of
291 trios, we find no significant evidence of paternal overtransmission.
MATERIALS AND METHODS
This article contains supplementary material, which may be
viewed at the American Journal of Medical Genetics website
at http://www.interscience.wiley.com/jpages/1552-4841/suppmat/
index.html.
Grant sponsor: NIH; Grant numbers: HD37694, HD37999,
MH66877.
*Correspondence to: Jang Woo Kim, M.D., Psychiatric and
Neurodevelopmental Genetics Unit, Center for Human Genetic
Research, Massachusetts General Hospital, Harvard Medical
School, 185 Cambridge Street, Boston, MA 02114.
E-mail: jwkim@partners.org
Received 14 November 2006; Accepted 31 January 2007
DOI 10.1002/ajmg.b.30519
ß 2007 Wiley-Liss, Inc.
Subjects
A total of 229 families (comprising 291 parent-affected
offspring trios) with ADHD were recruited from several
ongoing family studies of ADHD conducted at the Massachusetts General Hospital as previously described [Smoller et al.,
2006]. The largest number (90 families) was ascertained from
longitudinal case-control family studies of boys and girls with
ADHD [Biederman et al., 1992, 1999]. In these studies,
probands were recruited from either consecutive referral to
the MGH Pediatric Psychopharmacology program or by
pediatric referral from a large Health Maintenance Organization (HMO) in the Boston area. Because ascertainment
Parent-Of-Origin Effects and ADHD
occurred prior to the publication of DSM-IV, affection status for
probands and their relatives was based on DSM-IIIR criteria.
During the screening phase, mothers were administered a
telephone questionnaire containing criteria for
DSM-IIIR
ADHD and exclusionary criteria for their referred child.
Potential probands were excluded if they were adopted, if
their nuclear family was not available for study or if they had
major sensorimotor handicaps, psychosis, autism, or a Full
Scale IQ less than 70. Individuals who screened positive for
DSM-IIIR ADHD were invited to enroll in the study along with
their first-degree relatives. Probands with subthreshold
ADHD diagnoses were excluded. Those classified as having
ADHD at both the screen and the interview (described below in
diagnostic assessment) were included as index cases. Families
were also ascertained from a family study of adults with
ADHD, an affected sibling pair linkage study of ADHD, family
studies of bipolar disorder, and family studies of ADHD and
substance abuse. The screening methods for these studies were
similar to the methods for the family studies of ADHD boys
and girls with the following exceptions: (1) ADHD cases
were obtained from the psychiatry clinics at MGH (and for
the linkage study, the child psychiatry clinic at Children’s
Hospital in Boston) as well as referrals from individual
child psychiatrists in the community and advertisements;
(2) ascertainment was based on DSM-IV diagnoses; (3) the
pediatric bipolar studies ascertained cases for bipolar disorder
and did not screen out cases with psychosis. Affection status for
these studies was based on DSM-IV criteria for ADHD.
Individuals whose age were 18 years or older provided written
informed consent for themselves. Mothers provided written
informed consent for minor children, and children provided
written assent.
Diagnostic Assessment
For children, lifetime history of psychopathology was
assessed using the semi-structured K-SADS-E diagnostic
interview [Orvaschel and Puig-Antich, 1987] administered to
the mother, and, for children 12 and older, by direct assessment
of the child. Final diagnostic assignment was made after blind
review of all available information by a Diagnostic Committee
composed of three board-certified child and adolescent psychiatrists and licensed clinical psychologists. The interviewers
were instructed to take extensive notes about the symptoms for
each disorder. These data were reviewed by the diagnostic
committee and confirmed only if a consensus was achieved that
criteria were met to a degree that would be considered
‘‘clinically meaningful’’ (i.e., that the structured interview
indicated that the diagnosis should be a clinical concern due to
the nature of the symptoms, the associated impairment, and
the coherence of the clinical picture). To combine discrepant
parent and offspring reports, the most severe diagnosis from
either source was used as the consensus diagnosis, unless the
diagnosticians suspected the source was not supplying reliable
information. In addition to the ADHD diagnosis, we examined
DSM-IV diagnostic subtypes of ADHD and co-morbidities for
all subjects.
Selection of Markers
Affected offspring and their parents were genotyped at SNPs
spanning each candidate gene (HTR1B, SNAP-25, DRD5,
DAT1, and BDNF). The selected region for each gene
encompasses genomic areas of high linkage disequilibrium
(LD) in and around each gene. The average inter-marker
distance ranged from 2 to 6 kb for each gene, except for BDNF.
For BDNF, the region spans a genomic area of 210 kb which
includes BDNF iso-form a (the shortest transcribed form of the
gene) and its 30 downstream area. Although SNPs covering all
iso-forms of BDNF were not typed, the functional Val66Met
777
polymorphism [Kent et al., 2005] and surrounding areas of
high LD were included.
SNPs were selected from the National Center for Biotechnology Information (NCBI) public database (http://
www.ncbi.nlm.nih.gov/SNP), and Celera databases (http://
www.celera.com). We selected ‘‘double-hit’’ SNPs (i.e., SNPs
found either by independent submitters to dbSNP or in both
the dbSNP and Celera databases) spanning each locus as
others and we have demonstrated that these SNPs validate at a
high rate. SNPs were selected for analysis if they met the
following quality control metrics: (a) genotyping call rate
>90%; (b) genotypes in Hardy-Weinberg equilibrium; and
(c) less than 1% Mendelian errors.
Genotyping
The genotyping for SNPs was performed using a single base
extension reaction with allele discrimination by MassArray
mass spectrometry system (Bruker-Sequenom) as previously
described [Sklar et al., 2002].
Analytic Strategy
We used two approaches to examine parent-of-origin effects
in this sample. First, we applied the strategy reported by Hawi
et al. [2005] by performing a TDT analysis on the full sample
and selecting markers within each gene that demonstrated
the highest T/NT ratio (i.e., ‘‘risk’’ alleles) and for which the
TDT P-value was <0.1. This resulted in one putative risk allele
per gene by design. Then, according to the method of Hawi et al.
[2005], we performed an omnibus test combining transmissions by parent-of-origin across all five loci and compared the T/
NT ratios of paternal versus maternal alleles using a standard
Pearson’s chi square test. TDT analysis was performed using
TDTPHASE [Dudbridge, 2003]. Second, we examined whether
any of the full set of 141 SNP markers that we genotyped across
the five candidate genes show evidence of parent-of-origin
effects. This analysis also included all variants of these five
loci that have been reported to show significant paternal
over-transmission in ADHD in prior published studies
[Brophy et al., 2002; Hawi et al., 2002, 2005; Kustanovich
et al., 2003; Quist et al., 2003; Mill et al., 2004; Kent et al.,
2005; Smoller et al., 2006]. These analyses were performed
using TDTPHASE [Dudbridge, 2003] and repeated using
the PLINK package (http://pngu.mgh.harvard.edu/purcell/
plink/index.shtml) for confirmation. The P-values were essentially the same using both statistical packages and thus we
report the results of the TDTPHASE analyses.
RESULTS
Table I shows the results of the ‘‘risk allele’’ analysis based on
the method of Hawi et al. [2005]. As shown, the omnibus test of
paternal versus maternal transmission across the five genes
showed no evidence of a parent-of-origin effect (P ¼ 0.956).
When we examined the full array of SNPs (N ¼ 141), only one
(rs4813925 of SNAP-25) showed a nominally significant
parent-of-origin effect (uncorrected P ¼ 0.025) (see Fig. 1) (see
supplementary Tables 1 and 2 for full TDT results and
transmissions from each parent); however, in this case the
evidence favored maternal rather than paternal over-transmission. In addition, this result does not survive correction for
the number of markers (n ¼ 63) tested in this gene. For the
HTR1B G861 allele, which has been the most frequently
reported to show paternal over-transmission [Hawi et al., 2002;
Quist et al., 2003; Smoller et al., 2006], we observed nominally
significant association for paternally transmitted alleles
(P ¼ 0.013) as previously reported [Smoller et al., 2006], but
there was no significant difference when paternal versus
778
Kim et al.
TABLE I. Investigation of Parent-Of-Origin Effects for Alleles Chosen According to the Criteria of Hawi et al. [2005] (10)*
Paternal transmission
Gene
BDNF
DAT
DRD5
HTR1B
SNAP-25
Combined
Maternal transmission
Paternal versus maternal
transmission
SNP ID (allele)
T
NT
T
NT
P
rs1038660 (C)
rs462523 (A)
rs1818669 (G)
rs1145830 (G)
rs363026 (C)
43
51
42
48
14
198
25
44
32
29
7
137
38
64
52
41
14
209
31
41
35
31
8
146
0.332
0.301
0.708
0.502
0.841
0.956
*SNPs with the highest T/NT ratio for each gene were chosen.
maternal transmissions were compared (uncorrected
P ¼ 0.079). Other markers, which were previously reported to
show paternal over-transmission to ADHD offspring (Val66Met polymorphism of BDNF [Kent et al., 2005]; MnlI–DdeI
haplotype of SNAP-25, Mnl I polymorphism of SNAP-25[Kustanovich et al., 2003]; Dde I polymorphism of SNAP-25 [Brophy
et al., 2002]; -2015 A/T & 80609 G/A of SNAP-25 [Mill et al.,
2004]) did not yield any statistically significant results. Thus,
this more extensive examination is consistent with the first
analysis in failing to detect any parent-of-origin effect for these
five ADHD candidate loci.
We also examined how well our genotyped SNPs captured
genetic variation at each locus by evaluating their performance
as tag SNPs for each gene region. We downloaded genotype
data for each locus from the HapMap website (www.hapmap.
org; Release #19) and applied the Tagger algorithm [de
Bakker et al., 2005] as implemented in the ‘‘Haploview’’
program [Barrett et al., 2005] to calculate the mean r2 value
between our SNPs and HapMap SNPs that we did not
genotype. This analysis revealed that our SNP set captures
most of the genetic variation (mean r2 > 0.8) for four loci;
HTR1B, SNAP-25, DRD5, and BDNF. For DAT1, the mean r2
was 0.54. However, it should be noted that these estimates of
captured variation are conservative because we also genotyped
genetic markers that were not found in the HapMap dataset.
For instance, 20 of our 35 markers in and around DAT1 were
not available in the HapMap SNP data (release #19). For the
other genes which showed better performance, there were
fewer markers that were not in the HapMap data: HTR1B
(5 out of 21), SNAP-25 (14 out of 63), DRD5 (8 out of 13), BDNF
(4 out of 10)
DISCUSSION
In light of a recent report that there may be systematic overtransmission of paternal alleles at candidate genes associated
with ADHD [Hawi et al., 2005], we examined parent-of-origin
effects using a dense set of SNPs across five leading candidate
genes (HTR1B, SNAP-25, DRD5, DAT1, BDNF). We were
unable to find any evidence suggesting systematic paternal
over-transmission of risk alleles in ADHD for these loci. This
conclusion was supported by two types of analyses: first,
Fig. 1. Test of paternal versus maternal effects for whole gene. X-axis is the marker number and the Y-axis is negative log10P for the paternal versus
maternal transmissions. The cut-off value corresponding to a nominal P ¼ 0.05 is 1.3. Only marker 48 (rs4813925) at SNAP-25 exceeds this cutoff value.
Parent-Of-Origin Effects and ADHD
applying the method of Hawi et al. [2005] to identify the
strongest ‘‘risk allele’’ within each locus and second, by testing
all 141 SNPs genotyped across these genes. Several features of
our analyses suggest that our results are unlikely to represent
Type II error. First, our family sample is actually somewhat
larger than that in which Hawi et al. [2005] observed
systematic paternal over-transmission (291 trios vs. 179 trios).
Power estimates indicate that we had >80% power at
alpha ¼ 0.05 to detect association of paternal alleles under a
multiplicative genotype relative risk (GRR) model for risk
alleles with frequency of 0.1–0.8 and GRR >2. Second, we saw
no evidence of parent-of-origin effects in either analytic
approach, including an examination of a dense set of markers
encompassing each gene. Third, the full set of genetic markers
that we genotyped appear to capture most of the genetic
variation in the five candidate loci.
Of the individual markers tested, only the BDNF Val66Met
polymorphism has previously been reported to have a
statistically significant excess of paternal versus maternal
transmission in ADHD [Kent et al., 2005]. We did not observe
this effect in our analysis; however, since we examined only the
iso-form a of the BDNF gene, we cannot rule out the possibility
of parent-of-origin effects for other markers in the gene. Data
from three independent samples [Hawi et al., 2002; Quist et al.,
2003; Smoller et al., 2006] has provided some support for
paternal over-transmission of the G861 allele of the HTR1B,
although chi-square comparison of paternal versus maternal
transmissions does not support a parent-of-origin effect in
previous studies or the current analysis.
Our results appear to conflict with those of Hawi et al. [2005]
who reported paternal over-transmission when they summed
transmissions by parent-of-origin across nine candidate loci.
When we applied this method, we did not observe a significant
overall difference based on the parent-of-origin. The genes that
we examined are overlapping but not identical with those
tested by Hawi et al. [2005]. We examined an additional gene,
BDNF, for which paternal over-transmission in ADHD has
been reported [Kent et al., 2005) but which was not included in
the report of Hawi et al. [2005]. In addition, we did not examine
five genes that were included in their report (DRD4, TH, DDC,
SERT, and TPH2). Although the lack of any signal for our five
genes (P ¼ 0.956) makes it unlikely that adding the additional
five genes would produce an overall pattern of paternal
transmission, we cannot rule out that our results differed from
those of Hawi et al. [2005] due to examining this smaller set of
genes.
Our failure to replicate parent-of-origin effects of Hawi et al.
[2005] could also be related to differences in sample characteristics. For example, subtle differences in the percentage of each
ADHD diagnostic subtype (combined, inattentive, hyperactive-impulsive) or in co-morbidity status might have also
contributed to our discrepant result compared to the Hawi et al.
[2005] study.
Parent-of-origin effects have been determined to be the cause
of several rare disorders such as Prader-Willi syndrome (PWS)
and Angelman syndrome (AS) [Mann and Bartolomei, 1999].
PWS and AS result from molecular defects in 15q11-q13 that
cause loss of expression of paternally transcribed (PWS) and
maternally transcribed genes (AS), respectively. Whether it
plays a substantial role in the etiology of more complex
disorders has not been established. Linkage studies of several
psychiatric disorders including autism [Lamb et al., 2005],
bipolar disorder [McInnis et al., 2003], and alcoholism
[McInnis et al., 2003; Liu et al., 2005] have provided some
evidence for such effects, however, these remain to be
confirmed.
In sum, using two analytic methods in a relatively large
family-based sample, we do not observe evidence for systematic
paternal transmission of risk alleles of five candidate loci for
779
ADHD. We conclude that a robust parent-of-origin effect in
ADHD is unlikely for these genes.
ACKNOWLEDGMENTS
This work was supported by National institute of Health
(NIH) Grants HD37694, HD37999, and MH66877 to SVF
and NARSAD Young Investigator Award to JWK. JWK is a
NARSAD Sidney R. Baer, Jr. Foundation Investigator.
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