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Bipolar disorder in the Bulgarian Gypsies Genetic heterogeneity in a young founder population.

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RESEARCH ARTICLE
Neuropsychiatric Genetics
Bipolar Disorder in the Bulgarian Gypsies: Genetic
Heterogeneity in a Young Founder Population
Radka Kaneva,1 Vihra Milanova,2 Dora Angelicheva,3 Stuart MacGregor,4 Christian Kostov,2
Rositza Vladimirova,2 Spiridon Aleksiev,2 Mina Angelova,1 Vessela Stoyanova,2 Angeline Loh,3
Joachim Hallmayer,5 Luba Kalaydjieva,3 and Assen Jablensky6*
1
Molecular Medicine Centre and National Genetic Laboratory, Medical University of Sofia, Sofia, Bulgaria
Department of Psychiatry, Medical University of Sofia and First Psychiatric Clinic, Alexandrovska University Hospital, Sofia, Bulgaria
2
3
Centre for Medical Research and Western Australian Institute for Medical Research, The University of Western Australia, Perth, Australia
4
Genetic Epidemiology, Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, Australia
Department of Psychiatry and Behavior Sciences, Stanford, California
5
6
School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Australia
Received 9 December 2007; Accepted 27 March 2008
We report the results of follow-up analyses of 12 genomic
regions showing evidence of linkage in a genome-wide scan
(GWS) of Gypsy families with bipolar affective disorder
(BPAD). The Gypsies are a young founder population comprising multiple genetically differentiated sub-isolates with strong
founder effect and limited genetic diversity. The BPAD families
belong to a single sub-isolate and are connected by numerous
inter-marriages, resulting in a super-pedigree with 181 members. We aimed to re-assess the positive GWS findings and
search for evidence of a founder susceptibility allele after the
addition of newly recruited subjects, some changes in diagnostic assignment, and the use of denser genetic maps. Linkage
analysis was conducted with SimWalk2, accommodating the
full complexity of pedigree structure and using a conservative
narrow phenotype definition (BPAD only). Six regions were
rejected, while 1p36, 13q31, 17p11, 17q21, 6q24, and 4q31
produced nominally significant results in both the individual
families and the super-pedigree. Haplotypes were reconstructed and joint tests for linkage and association were done
for the most promising regions. No common ancestral haplotype was identified by sequencing a strong positional and
functional candidate gene (GRM1) and additional STR genotyping in the top GWS region, 6q24. The best supported region
was a 12 cM interval on 4q31, also implicated in previous
studies, where we obtained significant results in the superpedigree using both SimWalk2 (P ¼ 0.004) and joint Pseudomarker analysis of linkage and linkage disequilibrium
(P ¼ 0.000056). The size of the region and the characteristics
of the Gypsy population make it suitable for LD mapping.
Ó 2008 Wiley-Liss, Inc.
Key words: bipolar disorder; linkage; genetic isolate; haplotypes;
linkage disequilibrium
Ó 2008 Wiley-Liss, Inc.
How to Cite this Article:
Kaneva R, Milanova V, Angelicheva D,
MacGregor S, Kostov C, Vladimirova R,
Aleksiev S, Angelova M, Stoyanova V, Loh A,
Hallmayer J, Kalaydjieva L, Jablensky A. 2009.
Bipolar Disorder in the Bulgarian Gypsies:
Genetic Heterogeneity in a Young Founder
Population.
Am J Med Genet Part B 150B:191–201.
INTRODUCTION
Bipolar affective disorder, BPAD, (lifetime risk 1%; heritability
>80%) is a severe mood disorder, characterized by early onset,
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.
Radka Kaneva, Vihra Milanova, Luba Kalaydjieva, and Assen Jablensky
contributed equally to this work.
Grant sponsor: National Health and Medical Research Council of Australia;
Grant number: 353648; Grant sponsor: National Science Fund, Ministry of
Education and Science, Bulgaria; Grant number: G2/2003.
Christian Kostov’s present address is Pfalzklinikum, Klinik fuer Psychiatrie
und Psychotherapie, Rockenhausen, Germany.
*Correspondence to:
Prof. Assen Jablensky, School of Psychiatry & Clinical Neurosciences,
University of Western Australia, MRF Building, 50 Murray Street, Mail
Bag Delivery Point M571, Perth, WA 6000, Australia.
E-mail: assen@cyllene.uwa.edu.au
Published online 28 April 2008 in Wiley InterScience
(www.interscience.wiley.com)
DOI 10.1002/ajmg.b.30775
191
192
alternation of manic/hypomanic and depressive episodes, partial or
complete remissions between the episodes, significant functional
impairment and high risk of suicide [Thomas, 2004; Cheng et al.,
2006]. Despite recent attempts at identifying cognitive, neurophysiological or neuroimaging endophenotypes [Bearden and Freimer,
2006; Savitz and Ramesar, 2006; Antila et al., 2007] there is no
validated biological marker and the diagnosis rests on clinical
observation and detailed history.
The genetic basis of BPAD is poorly understood despite general
agreement that genetic factors play a major role in susceptibility
[Tsuang and Faraone, 2000; Smoller and Finn, 2003]. Individual
linkage studies have identified a number of candidate loci [Baron,
2002; Craddock and Forty, 2006], however replication attempts and
meta-analyses [Badner and Gershon, 2002; Segurado et al., 2003;
McQueen et al., 2005] have produced inconsistent results. While
recent genome-wide association studies, made possible by new
genotyping technologies and large case–control samples, have been
remarkably successful in identifying susceptibility genes for disorders with well defined phenotypes [Easton et al., 2007; Frayling,
2007; Todd et al., 2007; WTCCC, 2007], they have been less
productive in BPAD [WTCCC, 2007; Baum et al., 2008], reinforcing the concept of extensive genetic heterogeneity and the need for
biologically anchored phenotype definitions.
The presumed advantages of founder populations for genetic
research include a relatively uniform genetic background, shared
environment, phenotype definitions that are easier to standardize,
and large intact traditional families. BPAD is among the disorders
most investigated in such populations, for example, in the Old
Order Amish, Costa Rican, French Canadian, and Finnish, etc.
[Pekkarinen et al., 1995; Freimer et al., 1996; Ginns et al., 1996;
Morissette et al., 1999; Ekholm et al., 2003; Venken et al.,
2005; Herzberg et al., 2006], with a common pattern of failure of
follow-up studies to replicate initial evidence of linkage, interand intra-family heterogeneity and lack of shared founder
haplotypes [Egeland et al., 1987; Kelsoe et al., 1989; McInnes
et al., 1996; Ekholm et al., 2002, 2003; Ophoff et al., 2002; Shink
et al., 2003].
In the last decade, genetic studies of the Roma/Gypsies have
placed them among the most interesting isolates of Europe
[Kalaydjieva et al., 2001, 2005]. The Gypsies are a young founder
population of Asian ancestry, whose history is a string of population
fissions generating multiple endogamous, culturally divergent
groups with genetic profiles shaped by demographic bottlenecks,
random drift and differential admixture [Kalaydjieva et al., 2005].
A common primary founder effect, limited diversity, and a substructure resulting from the genetic differentiation of the endogamous Gypsy groups [Gresham et al., 2001; Morar et al., 2004]
hold promise for genetic research comparable or even superior
to some of the better known isolated populations. In a previous
study, we conducted a genome-wide scan and initial fine
mapping in three Gypsy families as part of a larger linkage study
of BPAD [Schumacher et al., 2005]. In that study, the Gypsy
families produced the most promising results, with significant
evidence of linkage to 4q31 and at least borderline significance
for 1p36-p34 and 6q24 [Schumacher et al., 2005]. Nine
further regions showed suggestive evidence of linkage in the Gypsy
families.
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
Here we describe the follow-up investigations, putting our initial
positive findings to the standard test of additional family members,
changes in affection status and denser genetic maps. In addition, to
analyze the data within the intact and complex structure of the three
inter-related Gypsy families, we used the MCMC-based (Markov
Chain Monte Carlo) linkage program SimWalk2 v.2.91 [Sobel and
Lange, 1996].
METHODS
The Families
The three families (Fig. 1) are part of the Gypsy community,
currently numbering 7,000 individuals, in a small town in the
southwest of Bulgaria. Similar to the entire Gypsy population of
Eastern Europe, this community has been strongly affected by the
socio-economic changes of the 1990s, with high unemployment
rates, widespread alcoholism and drug abuse, and rising somatic
morbidity and mortality. The community belongs to a sub-isolate
whose estimated time of founding (based on Y chromosome
haplotype diversity) is 300 years or 10–12 generations back, with
size of the founding male population estimated at 300 to 500
individuals (Chaix and Kalaydjieva, unpublished work). Our previous population genetic studies of this sub-isolate have shown
limited diversity and relative homogeneity [Kalaydjieva et al.,
2005]. Since no formal genealogical records are available, we used
narrative histories by multiple informants to reconstruct the family
trees. Independently confirmed data, going up to 7 generations
back, revealed a number of inter-marriages between the three
families, leading to a super-pedigree with a total of 181 members
(a 3D representation of the super-pedigree can be found at http://
www.waimr.uwa.edu.au/bipolar.html). The small founding size
and the traditional marriage patterns suggest that the relatedness
between the founders of the affected families is likely to be closer
than revealed by the super-pedigree structure.
Our study thus focuses a large affected kindred from a young,
genetically restricted sub-isolate, within an isolated founder population. Therefore our assumption is of genetic homogeneity and we
define the best candidates for further studies in the Gypsy population as regions where evidence of linkage obtained in the analysis of
the individual families is supported by the joint pedigree, with allele
sharing across families.
Ascertainment and Diagnostic Assessment
Two of the families were first brought to the attention of the
research team by the regional mental health service in 1993. The
third affected family was identified in 1996.
Family members were interviewed with the Schedules for Clinical Assessment in Neuropsychiatry [Wing et al., 1990] and the
Diagnostic Interview for Psychoses [Castle et al., 2006]. Ongoing
management of the case finding process over the 14 years of this
project, and monitoring of the diagnostic assessment was provided
by VM. Case records were provided by local psychiatrists who had
followed up the affected individuals from the onset of the disease.
Regular contact with the families and with the local mental health
services allowed prompt detection of new cases and of changes in
KANEVA ET AL.
193
FIG. 1. Pedigrees used in the linkage analysis.
the clinical course of the disorder. SCAN/DIP data and case records
were independently reviewed by two senior psychiatrists (AJ and
VM), blinded to the positions of the subjects in the pedigree.
Reference diagnoses, according to DSM-IV and ICD-10 criteria,
were generated using the OPCRIT computerized diagnostic
algorithm [McGuffin et al., 1991]. Any discrepancies between the
OPCRIT diagnoses and the clinicians’ judgment were reviewed
until a final research diagnosis (lifetime) was established, using a
194
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
TABLE I. Affected Subjects From the Three Gypsy Families Included in the Initial Genome Wide Scan and Fine Mapping
[Schumacher et al., 2005] and in the Current Study
GS þ initial FM, n (n genotyped)
Family
35
41
114
All affected
BPAD (BP I þ BP II)
14 (10)
2 (2)
2 (1)
18 (13)
This study, n (n genotyped)
BPAD þ UPR
26 (21)
8 (8)
7 (6)
41 (35)
BPAD (BP I þ BP II)
16 (11)
5 (5)
6 (5)
27 (21)
BPAD þ UPR
30 (27)
16 (16)
11 (10)
57 (53)
BPAD, bipolar affective disorder; BP I, bipolar disorder, type 1; BPII, Bipolar disorder type 2; UPR, unipolar recurrent depression.
The changes in the number of affected individuals are the compound result of newly diagnosed cases, recruitment of additional family branches, and changes in affection status.
best estimate consensus procedure based on all available sources of
information.
A total of 92 living members of the three families participated in
the current study, with a larger number of affected subjects compared to the earlier genome-wide linkage scan (Table I). Written
informed consent was obtained from all individuals. The project
was approved by the human research ethics committees of The
University of Western Australia, the Medical University of Sofia and
the Alexandrovska University Hospital.
Since the previous study [Schumacher et al., 2005], the diagnosis
of 11 affected subjects out of total 57 (35 cases included in the
genome scan) underwent revision. In 3 cases it was changed from
recurrent depressive disorder (RDD) to BPAD, in 2 cases from
BPAD to RDD, and in 6 from RDD to unknown. The latter group
included 5 individuals affected by epilepsy. Epilepsy, including
temporal lobe epilepsy (TLE), was diagnosed in members of some of
the family branches and in individual cases scattered across the
extended kindred (the super-pedigree at http://www.waimr.uwa.
edu.au/bipolar.html). Since depression is common and can be a
secondary phenomenon in TLE patients, these 5 subjects were reclassified as unknown. In addition, 2 RDD cases with history of
severe head injury, and one with thyroid dysfunction were also reclassified as unknown. In view of such co-morbidity, which could
confound the diagnosis of mood disorders, and the concept that for
research purposes bipolar and unipolar depressive disorder should
be treated as separate entities [Kendell, 1987; Farmer and McGuffin,
1989], this study focuses on bipolar affective disorder. Considering
the widespread impact of psychosocial and economic adversity on
this community, the numerous cases of depressive disorder in the
families were conservatively treated as unknown in the linkage
analyses.
The total number of family members with BPAD was 27 (21 with
BP I and 6 with BP II), of whom 21 were genotyped. The age of the 21
cases of BP I (14 females) at the time of diagnostic assessment was in
the range between 17 and 69 years (mean 42.7 years), and the
estimated mean age at onset was 28.8 years (<20 years of age in
9 cases and >40 years of age in 5 cases). In the 6 cases of BP II
(3 females), the mean age at onset was 23.7 years (<20 years of
age in 3 cases and >40 years of age in 1 case). Only 4 patients in
the BP I group had ever experienced psychotic symptoms, and
the overall course of the disorder was one of moderate severity
(ICD-10 criteria). There were no atypical features in either the
manic/hypomanic or depressive episodes, and the commonest
comorbidity was with anxiety disorder, especially panic attacks.
Substance abuse was relatively uncommon, with only 2 male
patients diagnosed with alcohol dependence. Suicide attempts
(including one consumed suicide) had been recorded in 13 out of
the total of 27 patients in the three families. The majority of the
patients had experienced multiple affective episodes, with good
response to standard carbamazepine treatment and nearly complete remissions between the episodes.
Genetic Analyses
Genetic markers and genotyping. The analyses included 12
regions on 10 chromosomes, where significant or suggestive NPL
values had been obtained in our previous genome-wide scan
[Schumacher et al., 2005]. A summary of the regions and the
number of markers is given in Supplementary Table I.
Microsatellite markers, previously used in the genome scan or
first round of fine mapping, were genotyped in the additionally
recruited family members, and newly added microsatellites were
genotyped in the whole sample. The microsatellites were chosen
from the UCSC database (http://genome.ucsc.edu/). PCR amplification was done under standard conditions. Electrophoretic length
separation was performed on an ABI377 DNA Analyzer or a Hitachi
FMBI0II fluorescent scanner. Genotypes were checked for Mendelian inconsistencies using the PedCheck program [O’Connell and
Weeks, 1998]. Inconsistencies were resolved by retyping the
markers for the specific subjects.
Sequencing analysis of GRM1. The coding sequence of GRM1
gene (Ref Seq NM_000838) including the 50 and 30 UTRs, all exons
and the exon–intron boundaries, was covered by 23 PCR fragments
ranging from 270 to 543 bp (primer sequences available upon
request). Sequencing of the PCR products was performed following
the standard protocols for BigDye 3.1 and was analyzed on ABI 377
DNA Sequencer.
Linkage analysis. We used the integrated genetic map
(available at www.qimr.edu.au/davidd/davidd.html). Allele frequencies were calculated by maximum likelihood estimates
(MLE) using the full pedigree structure. These estimates impute
the marker genotypes for untyped individuals and take into account
the pedigree structure. The estimates were computed in SOLAR,
which in turn uses the external program Allfreq, an extension of the
MENDEL software [Almasy and Blangero, 1998]. Input files were
generated with the Mega2 Version 3.0 software [Mukhopadhyay
KANEVA ET AL.
195
et al., 2005]. Non-parametric linkage analysis was performed using
SimWalk2 v.2.91 [Sobel and Lange, 1996; Sobel et al., 2001].
SimWalk uses a Markov Chain Monte Carlo (MCMC) approach
to sample from the complete distribution of underlying inheritance
patterns proportional to their likelihood, which is calculated from
the observed genotype data. Empirical P values are obtained by
comparing the observed value of the statistics to that estimated
under the null hypothesis by repeated sampling of marker data
simulated with a gene dropping algorithm without linkage to
phenotype. Haplotypes were reconstructed using the HAPLOTYPE
module of SimWalk2, under the assumption of linkage equilibrium
between markers. To test jointly for linkage and association, we
used PSEUDOMARKER, a linkage analysis software which is more
powerful than the conventional ‘‘model-free’’ tests when both
linkage and LD are present and remains powerful for detection of
either of the two phenomena in the absence of the other [Goring and
Terwilliger, 2000].
RESULTS
Out of the 12 regions selected for follow-up analysis, 6 met our
criterion of positive results in both the individual families
and the combined super-pedigree with nominally significant
results (P < 0.05, log 10(p) > 1.3). The data are summarized in
Table II.
Regions Not Supported by the Follow-Up Analyses
The 8p21-p12, 9p24-p22, 11p13-p11, and 18q12-q21 regions did
not show significant results in any of the SimWalk2 statistics,
neither in the individual families nor in the combined super-family.
In two chromosome 2 regions, 2p23-p13 (D2S352–D2S286) and
2q21-q31 (D2S368–D2S376) we re-analyzed the previous genome
scan data [Schumacher et al., 2005] using SimWalk2 and the full
family structure. Positive results were obtained only for the 14 cM
interval on 2q (D2S368–D2S2275) when the three families were
analyzed separately. The nominally significant values in the
NPL_ALL statistic, with a maximum of log 10(p) ¼ 1.88 at
D2S2367, were contributed by one of the three families. The analysis
of the combined super-family failed to produce any positive results.
Weakly Positive Regions
Four regions with initially suggestive evidence of linkage remained
nominally significant in the follow-up analysis: 1p36-p34, 13q22q32, 17p11-q12, and 17q21-q24.
A total of 10 markers were analyzed on 1p36-1p34, three newly
added to the D1S2732–D1S493 interval and seven from the previous fine mapping study [Schumacher et al., 2005]. Nominally
significant results were obtained in the analysis of both the individual families and the combined pedigree over the 6 cM
D1S458–D1S2693 interval. The highest values were produced
by the NPL_PAIR statistic in the analysis of the joined superpedigree at markers D1S2885 (log 10(p) ¼ 1.65) and D1S2749
(log 10(p) ¼ 1.61).
The fine mapping of chromosome 13 was done with nine STR
markers. Nominally significant P values were obtained for several
statistics and markers in the region between D13S1804 and
D13S265, encompassing 9 cM. The highest results were observed
at D13S170 (log 10(p) ¼ 1.93) for NPL_PAIR in the families
analyzed separately. A lower but still significant value was obtained
at the same marker and the neighboring D13S790, both showing
log 10(p) ¼ 1.4 for NPL_PAIR in the joint super-pedigree.
Two regions were analyzed on chromosome 17, where a total of
11 markers were genotyped. On 17p11-q12, the best values were
obtained in the analysis of the joint super-pedigree with the
BLOCKS statistic (based on the number of different founder alleles
contributing to the affected) over a 5 cM region, with a maximum
TABLE II. Results of the SimWalk2 Linkage Analyses in the Three Separate Gypsy Families and in the Joint Super-Pedigree
This study
Chr
1
2
4
6
8
9
11
13
17
17
18
Genome scan
and initial
fine mapping
resultsa
þ
þ
þþ
þþ
þ
þ
þ
þ
þ
þ
þ
Three ‘‘unrelated’’ families
Significance
(P)b
0.03
0.01
0.004
0.003
NS
NS
NS
0.012
0.03
0.03
NS
Marker region
D1S478–D1S2639
D2S368–D2S2275
D4S420–D4S2999
GATA184A08–D6S494
Interval (cM)
39.22–47.61
147.49–161.26
137.57–149.32
150.28–155.85
D13S1804–D13S265
D17S2196–D17S1294
D17S1820–D17S790
72.66–80.80
47.40–52.78
78.15–82.15
One joint super-pedigree
Significance
(P)b
0.01
NS
0.007
0.02
NS
NS
NS
0.04
0.03
0.04
NS
Marker region
D1S458-D1S2639
Interval (cM)
41.81–47.61
D4S420–D4S1606
GATA184A08–D6S494
137.57–145.12
150.28–155.75
D13S1812–D13S265
D17S2196–D17S1294
D17S1820–D17S790
74.15–80.80
47.40–52.78
78.15–82.15
NS, non-significant (P > 0.05).
a
Suggestive genome scan and 1st round fine mapping data are denoted with ‘‘þ’’, while results at significant or close to significant level with ‘‘þþ’’.
b
Scores obtained with SimWalk2 [Sobel and Lange, 1996].
The bolded figures are the significance values.
196
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
FIG. 2. SimWalk2 analysis (MAX-TREE and NPL_PAIR statistics) of chromosome 6q24 in the three separate Gypsy families and in the joint superpedigree. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
at D17S1871 (log 10(p) ¼ 1.69). On 17q21-q24, the best supported area spans 4 cM between D17S1820 and D17S790, with the
highest result at marker D17S1820, again for the joint superpedigree and the BLOCKS statistic (log 10(p) ¼ 1.5).
The 6q23-q24 region was a strong candidate for follow-up. The
NPL values at 6q24 were the highest in the genome-wide scan and
initial fine mapping, with maximum scores of 3.46 at 147.75 cM and
4.87 at 152.00 cM, suggesting the possibility of more than one
susceptibility gene on 6q [Schumacher et al., 2005] The follow-up
SimWalk2 analysis was performed on a set of nine markers (Fig. 2),
with an average inter-marker distance of 3.08 cM. The analysis of
the three separate families supported the telomeric peak, between
markers GATA184A08 and D6S494 (Fig. 2) with both the MAXTREE and NPL_PAIR statistic producing P values < 0.01. The
maximum (log 10(p) ¼ 2.53) was obtained at D6S960 for the
NPL pair statistic. All families contributed to these results. In the
combined super-family, the findings were less convincing with a
maximum (log 10(p) ¼ 1.58) produced by NPL_PAIR still at
D6S960.
Haplotype analysis showed three segments that were shared
by different subsets of affected individuals from the three families:
a 3-marker haplotype D6S1587–D6S403–D6S970 haplotype
(alleles 3-4-4) and two 2-marker haplotypes formed by
D6S970–GATA184A08 (alleles 5-2) and by D6S960 and D6S494
(alleles 5-1). These regions were examined further, with the addition of microsatellite markers and sequencing of a strong candidate
gene, the Glutamate Receptor Metabotropic 1 (GRM1). Five additional microsatellites were genotyped in the D6S1587–D6S970
interval, seven in the D6S970–GATA184A08 interval (also containing GRM1), and one between D6S960 and D6S494. In all three
regions, the additional markers revealed that the seemingly conserved 2- and 3-marker haplotypes were in reality non-identical,
with diversification introduced by the newly added microsatellites,
as well as by the SNPs in GRM1. The addition of five microsatellites
to the 4.8 cM interval D6S1587–D6S403–D6S970 specified four
unrelated haplotypes. The sequencing analysis of the coding regions, flanking introns and UTRs of GRM1 identified polymorphic
nucleotide positions only in the largest exon 8. All were common
polymorphisms represented in dbSNP (www.ncbi.nlm.nih.gov/
projects/snp/). Their analysis in the chromosomes that carried the
same (5-2) D6S970–GATA184A08 haplotype, revealed four different haplotypes over the 0.9 kb sequence of GRM1 exon 8 (Fig. 3). In
the weakly supported telomeric region (152 cM), the addition of
marker D6S1687 in-between D6S960 and D6S494 led to the differentiation of the 5-1 haplotype into three haplotypes: 5-4-1, 5-3-1,
and 5-5-1.
Best Supported Region
Chromosome 4q28-q32 (D4S1615–D4S2982) was the most promising result emerging from the genome scan and the following initial
fine mapping in the Gypsy families [Schumacher et al., 2005]. In the
present study, the large linked region (28 cM) was saturated with a
total of 24 markers genotyped in the enlarged family sample. Both
the analyses in the three separate families and in the joint superpedigree produced significant results for the BLOCKS and
NPL_PAIR statistics. The best supported linkage area was between
markers D4S420 and D4S2976 (Fig. 4), reducing the size of the
region of interest to 12 cM. The highest value obtained in
the analysis of individual families was at marker D4S2999
KANEVA ET AL.
197
FIG. 3. Haplotype analysis of GRM1 Exon 8 on Chromosome 6q24, located within the ‘‘conserved’’ haplotype D6S970–GATA184A08 (5-2). [Color figure
can be viewed in the online issue, which is available at www.interscience.wiley.com.]
(log 10(p) ¼ 2.4, P ¼ 0.004) for the NPL_PAIR. The joint superpedigree showed significant results for all markers in the
D4S420–D4S2962 region (log 10(p) 2, P < 0.01) for the
BLOCKS statistic. PSEUDOMARKER also produced positive
two-point LOD scores with a maximum of 3.18 at D4S2999 under
a recessive model (Table III). The PSEUDOMARKER [Goring and
Terwilliger, 2000] analysis showed in addition evidence of association, with P-values for some of the markers ranging between 0.01
and 0.03 (Table III), which however did not withstand correction
for multiple testing. Haplotype analysis identified the 4-4 haplotype, formed by markers D4S2999 and D4D2976, as significantly
different in frequency between affected and unaffected individuals
in all three families (44.44% of chromosomes in affected subjects
and 26.74% in unaffected; Fisher’s exact test P ¼ 0.019). The
D4S3014–D4S2962 (4-2) haplotype, by contrast, was more common in unaffected family members (22.5%), compared to just 7.6%
in affected (Fisher’s exact test P ¼ 0.019).
DISCUSSION
The main aim of the current study was to re-assess the BPAD linkage
findings in three large inter-related Gypsy families. Since the
genome scan producing these findings [Schumacher et al.,
2005], our sample has undergone the kind of changes that have
contributed to non-replication in other studies, such as addition of
more family members and re-evaluation of affection status. We
FIG. 4. SimWalk2 analysis (BLOCKS and NPL_PAIR statistics) of chromosome 4q31 in the three separate Gypsy families and in the joint superpedigree. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
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AMERICAN JOURNAL OF MEDICAL GENETICS PART B
TABLE III. PSEUDOMARKER Analysis for Linkage and Association on 4q31 Under a Recessive Model
Marker
D4S420
D4S1644
D4S424
D4S1625
D4S2981
D4S1604
D4S1586
D4S3014
D4S2962
D4S1606
D4S1548
D4S1588
D4S2934
D4S2999
D4S2976
Two-point LOD
1.63
0.70
0.46
2.78
1.31
0.26
0.50
1.04
2.59
0.38
0.50
2.24
1.62
3.18
0.30
Linkage
0.003048
0.035829
0.073771
0.000172
0.006951
0.134938
0.066555
0.014312
0.000276
0.091799
0.063856
0.000665
0.003201
0.000065
0.118645
LD|Linkage
0.249896
0.035973
0.172117
0.043070
0.531488
0.166867
0.016871
0.381349
0.779549
0.427078
0.031700
0.083871
0.041856
0.011476
0.086875
Linkage|LD
0.017944
0.002520
0.059955
0.000007
0.007387
0.016464
0.008227
0.022948
0.000400
0.516976
0.026122
0.000183
0.002933
0.000004
0.092412
LD þ linkage
0.027700
0.014375
0.111223
0.000391
0.061843
0.139180
0.010016
0.085804
0.019196
0.298751
0.018875
0.002333
0.002762
0.000056
0.070057
The bolded figures are the significance values.
have also adopted a conservative approach to linkage analysis by
assigning all unaffected individuals to the ‘‘unknown’’ category and
by using a statistical package which takes into account, and can
handle, the true and complete family structure. Based on the
characteristics of the sample and of the population from which it
is derived, we searched for evidence of sharing of ancestral alleles
between affected subjects to define candidate regions likely to be
productive in future studies of BPAD in the same and genetically
related sub-isolates.
The rejection of the 8p21-p12, 9p24-p22, 11p13-p11, and 18q12q21, based on negative results in both individual families and the
super-pedigree, could be due to the changes introduced at this stage
of the study, or simply to false positive previous findings.
The new data on chromosome 2, produced by re-analysis
(without additional genotyping) of the initial data on 2p23-p13
and 2q21-q31, also failed to meet the homogeneity and sharing
criteria. Weak evidence was obtained for the 2q locus in the separate
families, but no significant values were produced by the joint
pedigree. While a recent re-analysis of the family sample used in
our initial linkage study [Schumacher et al., 2005] suggests that
epistatic interactions between the 2q22-q24 and 6q23-q24 loci play
a role in susceptibility to BPAD [Abou Jamra et al., 2007], our
results do not support 2q (as well as 6q, see below) as candidate
regions for further studies in the Gypsy population.
Chromosomes 1p36-p34, 13q22-q32, 17p11-q12, and 17q21q24 remained weakly positive, with nominally significant P values
(0.05–0.01) obtained in both the individual families and in the joint
super-pedigree. These regions have been implicated in previous
studies [Detera-Wadleigh et al., 1999; Cichon et al., 2001; Ewald
et al., 2003; Liu et al., 2003; Potash et al., 2003; McGuffin et al., 2005]
in other populations and cannot be rejected in the Gypsy population. Their further investigation will require much larger sample
sizes.
The results of our 6q analysis tell a cautionary tale. The long arm
of chromosome 6 has attracted a lot of interest in psychiatric
genetics, with positive findings in linkage and association studies
of both affective disorder and schizophrenia [Kohn and Lerer,
2005] and is one of the few regions supported by meta-analysis
[McQueen et al., 2005]. At least five sub-regions have been implicated in the different studies, making it difficult to assess the
significance of these findings. In the genome scan of the Gypsy
families, the best NPL result of 3.65 was obtained for a 13 cM
region on 6q24, where the initial fine mapping [Schumacher et al.,
2005] outlined two peaks, at 147.75 and 152 cM. Analyzed separately and broken down into smaller pedigrees that can be handled
by standard linkage packages, all three Gypsy families contributed
to these results, with no evidence of heterogeneity. Overlapping
positive findings were reported from a study of BPAD families in an
isolated Swedish population, with a LOD-1 region between D6S310
and D6S1654 (144–147 cM) [Venken et al., 2005], and a genome
scan of Arab schizophrenia families, with the linkage region overlapping the centromeric peak in our study [Lerer et al., 2003].
Our follow-up analysis of the separate families supported the
previously identified peak(s), however the combined pedigree
provided only weak support limited to the telomeric region
(152 cM) (Fig. 2). We did not identify an extended ancestral
haplotype and the fragmented 2- or 3-marker haplotypes, in
different parts of the region and shared by different combinations
of affected members of the three families, did not support the
concept of a founder mutation. We allowed for the possibility of an
old variant, where haplotype decay via recombinations and microsatellite mutations could have resulted in a small conserved region.
Our previous studies have shown that, even in the case of rare
Mendelian disorders, the size of the conserved ancestral segment
surrounding a Gypsy founder mutation can be limited to 150 kb
[Kalaydjieva et al., 2000; Varon et al., 2003] and studies in the
Finnish population have documented a smaller size of the conserved segment around common susceptibility alleles compared to
single-gene disorders [Hovatta et al., 1998; Peltonen, 2000]. Such a
scenario was ruled out by the genotyping of additional markers,
microsatellites, and SNPs, which led to the disintegration of the
seemingly shared segments into distinctly different haplotypes.
KANEVA ET AL.
The initially most promising locus at 4q31 remained so in the
follow-up study. In the genome scan and first round of fine
mapping, we obtained significant evidence of linkage with an NPL
of 5.49 at 148.4 cM. The MOD-score analysis of all families included
in that study [Schumacher et al., 2005] showed the highest value of
4.24 at 147.2 cM for a phenotype including BP I and BP II as affected,
an estimated disease allele frequency of 0.045 and a near-additive
mode of inheritance. Our follow-up examinations provide further
support for this region, with significant results obtained in both the
three separate families and the joint super-pedigree for the BLOCKS
and NPL_PAIR statistics. The initial large (28 cM) size of the
linked interval was reduced to the 12 cM between D4S420
and D4S2976 (Fig. 4). The joint super-pedigree showed significant
results for all markers in the D4S420–D4S2962 region (log 10(p)
above 2, P < 0.01) for the BLOCKS statistic, supported by the
PSEUDOMARKER results (Table III) which also favored a recessive
model. The best value in the separate families (P ¼ 0.004) was at the
more telomeric marker D4S2999. In the telomeric 0.65 cM part of
the region, we also observed a 2-marker (D4S2999-D4S2976)
haplotype present in a large proportion of the chromosomes of
affected subjects (44.44%), compared to 26.74% of unaffected
(P ¼ 0.019). The 4q31 region thus appears to be the best candidate
locus, meeting the criteria of this study. This region has been
implicated in previous studies of different psychiatric disorders.
In the genome scan of 41 Finish families with BPAD, the best
evidence for linkage was produced at D4S1629 (151.84 cM)
[Ekholm et al., 2003]. In a genome scan of 65 multiplex bipolar
families under broad diagnostic criteria including unipolar recurrent depression, suggestive evidence of linkage (NPL 2.8) was
obtained for a 10 cM region around D4S1629 [McInnis et al.,
2003]. In the investigation of 40 American BPAD families of
European and Israeli ancestry, a two-point LOD score of 3.16 was
obtained at marker D4S1625 (140.08 cM) [Liu et al., 2003]. Evidence of linkage of 4q31 with other mental disorders includes
schizophrenia in an isolated Finish population [Hovatta et al.,
1999] and anxiety disorder in 19 extended American families [Kaabi
et al., 2006].
Our broad 4q31 region of linkage contains 12 positional and
functional candidate genes, for example, the lithium-sensitive
phosphatidylinositol calcium second messenger system (inositol
polyphosphate-4-phosphatase, type II, INPP4B), the endothelin
receptor type A, (EDNRA), genes encoding Ca2þ binding and
signaling cascades (TBC1D9 and DCHS2), and genes related to
ubiquitination (SMAD1 and the ubiquitin-specific protease
USP38), shown by gene expression studies to be involved in the
pathophysiology of BPAD [Ryan et al., 2006]. The narrow candidate region, where we have observed haplotype sharing, contains
only one gene, DCHS2. A systematic screening of single nucleotide
polymorphisms in the region is underway.
ACKNOWLEDGMENTS
Special thanks to Dr. T. Milenska, a senior psychiatrist in the town
of Kyustendil, Bulgaria, who provided invaluable information on
the pedigrees and the clinical history of the affected members. We
thank all the patients and families for participation and George
Onchev and Amelia Nikolova-Hill for initial contribution with
199
family recruitment. The assistance of Vesselin Chorbov with DNA
isolation, Michael Hunter and Kate Hollingsworth with the genotyping, and Veneta Popova with the preparation of figures is
gratefully acknowledged. The study was supported by project grant
353648 of the National Health and Medical Research Council of
Australia and research grant G2/2003 from the National Science
Fund, Ministry of Education and Science, Bulgaria.
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