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LETTERS TO THE EDITOR
First family-based test for association of neuregulin with
bipolar affective disorder
Molecular Psychiatry (2006) 11, 706–707.
doi:10.1038/sj.mp.4001836
The neuregulin gene (NRG1) has generated a great
amount of interest in recent years as a highly
replicated susceptibility gene for schizophrenia.
1
As
a result of the genetic overlap between schizophrenia
and bipolar affective disorder (BPAD) that has been
revealed by linkage studies
2
and the location of NRG1
within one such overlapping linkage region (8p21),
variants within this gene were tested for association
with BPAD in a case–control sample of English/Welsh
origin.
3
A three-marker haplotype comprised of the
alleles from the core makers of the schizophrenia-
associated haplotype, HAP
ICE
, exhibited a marginal
association with BPAD, an effect which became
highly significant when the analysis was restricted
to cases with mood incongruent psychotic episodes.
Here, we report the results of the first family-based
association analysis of NRG1 with BPAD. The three
core markers from HAP
ICE
(SNP8NRG221533, 478B14-
878, 420M9-1395) and two additional markers
(SNP8NRG243177 and D8S1810) were genotyped,
using standard methods, in a collection of 92 BPAD
type I trios from the Irish population. All families
were interviewed using the Schedule for Affective
Disorders and Schizophrenia (Lifetime version:
Table 1 Results of association analysis of NRG1 polymorphisms
Marker Allele T/NT w
2
P-value Global
a
w
2df
Global
a
P-value
SNP8NRG221533 (M1:C/T) C (2) 42:39 0.12 0.74
SNP8NRG243177 (M2:G/A) G (1) 41:39 0.05 0.82
478B14-848 (M3) 1 20:12 2.00 0.16
*Allele 0 of Hap
ICE
2* 31:41 1.39 0.24
3 23:24 0.02 0.88
4 34:36 0.06 0.81
5 26:23 0.18 0.67
6 0:1 — —
7 3:0 — — 8.41
6
0.21
420M9-1395 (M4) 1 7:2 — —
2 35:33 0.01 0.81
*Allele 0 of Hap
ICE
3* 51:46 0.26 0.61
4 32:41 1.11 0.29
5 1:5 — —
6 0:1 — —
7 9:8 0.06 0.81
8 1:0 — — 10.41
7
0.17
D8S1810 (M5) 1 2:3 — —
2 30:41 1.70 0.19
3 0:3 — —
4 11:17 1.29 0.26
5 49:31 4.05 0.04
*Allele 18 of HapB
IRE
6* 34:30 0.25 0.62
7 2:4 — —
8 14:13 0.04 0.84 9.62
7
0.21
Haplotypes
M1-M2 2 2 0.01 0.91 0.23
2
0.89
M2-M3 1 2 1.90 0.17 4.76
8
0.78
M3-M4 1 3 2.13 0.14 5.07
6
0.53
M4-M5 [HapB
IRE
] 3 6 0.01 0.90 3.91
6
0.69
M3-M4-M5 1 3 5 4.23 0.04 7.15
6
0.31
M1-M3-M4 [Hap
ICE
] 2 2 3 0.07 0.79 5.44
6
0.49
M1-M2-M3-M4 1 1 2 3 2.71 0.10 5.52
6
0.48
Abbreviations: T = Transmitted, NT = Not Transmitted.
a
Calculated from haplotypes with frequency > 5%. (df) = degrees of freedom. P-values < 0.05 are indicated in bold.
Molecular Psychiatry (2006) 11, 706– 713
&
2006 Nature Publishing Group All rights reserved 1359-4184/06
$
30.00
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SADS-LB) and diagnoses met DSM-IV criteria. Asso-
ciation analyses were performed using the TDT,
4
ETDT
5
and Transmit
6
programmes.
From the single marker association analysis, there
was no evidence of association of NRG1 with BPAD in
our sample (Table 1). D8S1810 did exhibit a signi-
ficant over transmission of allele 5 to bipolar probands
(uncorrected P= 0.04) but the global P-value for this
marker was not significant (Table 1: P=0.212). Inter-
estingly, this marker was selected based on its presence
within an Irish schizophrenia-associated haplotype,
HapB
IRE
.
7
A range of two to three marker haplotypes,
including HAP
ICE
and HapB
IRE
, also failed to exhibit
any evidence of association with BPAD (Table 1). A
haplotype comprised of alleles from the three micro-
satellite markers (M3-M4-M5) did exhibit a marginal
association (Table 1, haplotype 1, 3, 5, uncorrected
P= 0.04) which was not significant at the global
haplotype level (Table 1: P= 0.31). We hypothesized
that if NRG1 is principally a gene for schizophrenia, a
stratified analysis restricted to trios with probands that
have experienced at least one psychotic episode may
reveal an association with BPAD, similar to the
findings of Green et al.
3
However, restriction of the
association analysis to the subset of 59 trios with
psychosis did not reveal any evidence for association
of NRG1 with BPAD (data not shown).
To conclude, we have failed to replicate the findings
of Green et al.
3
in a family-based collection which is not
subject to the population substructure effects of case–
control association studies. These findings suggest that
NRG1 is not a susceptibility gene for BPAD in the Irish
population. Interestingly, despite a plethora of positive
associations of NRG1 with schizophrenia in diverse
populations, the two Irish schizophrenia investigations
have also been negative.
8,9
Although a two-marker
NRG1 haplotype (HapB
IRE
) was initially reported to be
associated with schizophrenia in an Irish case–control
sample,
7
the association was no longer evident after
further investigation within an extended sample.
9
We
cannot rule out the possibility that our collection had
insufficient power to replicate the association of NRG1
with BPAD. Indeed, there are moderate differences in
the allele frequencies for SNPs surrounding the core
haplotype in European populations, which would
impact the power of replication studies, particularly
for rarer alleles/haplotypes.
10
However, geographical
variationisunlikelytobeanissueinthiscaseasthe
estimated frequency of the core haplotype in our
samples (7.7%) was very similar to that reported by
Green et al.
3
(7.8% in controls). To elucidate whether
NRG1 is truly a susceptibility gene for BPAD, addi-
tional studies in family-based collections are required.
F Cassidy
1
, S Roche
1
, E Claffey
2
and P McKeon
2,3
1
Smurfit Institute of Genetics, Trinity College,
Dublin, Ireland;
2
Depression Research Unit,
St Patrick’s Hospital, Dublin, Ireland and
3
Department of Psychiatry, Trinity College,
Dublin, Ireland.
E-mail: siobhan.roche@tcd.ie
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Serotonin transporter
polymorphism and
LDL-cholesterol
Molecular Psychiatry (2006) 11, 707–709.
doi:10.1038/sj.mp.4001837
The short allele of the serotonin transporter poly-
morphism (5HTTLPR) has been linked to psychiatric
disorders, including depression or anxiety. Our
analyses concerning the impact of 5HTTLPR on late-
onset depression in a large community-based age-
cohort unexpectedly detected that 5HTTLPR strongly
influences low-density lipoprotein (LDL)-cholesterol
levels.
The serotonin transporter (SERT) regulates the
serotonergic system via modulation of extracellular
fluid serotonin concentrations. Transcriptional acti-
vity of human SERT is modulated by a repetitive
Letters to the Editor
707
Molecular Psychiatry
