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American Journal of Medical Genetics (Neuropsychiatric Genetics) 81:296–301 (1998)
A Schizophrenia Locus May Be Located in
Region 10p15–p11
Richard E. Straub,1* Charles J. MacLean,1,2 Rory B. Martin,1 Yunlong Ma,1 Maxim V. Myakishev,1
Carole Harris-Kerr,1 Bradley T. Webb,1 F. Anthony O’Neill,3 Dermot Walsh,4 and
Kenneth S. Kendler1,2
1
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Medical College of
Virginia/Virginia Commonwealth University, Richmond, Virginia
2
Department of Human Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Medical College of
Virginia/Virginia Commonwealth University, Richmond, Virginia
3
Department of Psychiatry, The Queens University, Belfast, Northern Ireland
4
Health Research Board, Dublin, Ireland
In our genomic scan of 265 Irish families
with schizophrenia, we have thus far generated modest evidence for the presence of
vulnerability genes in three chromosomal
regions, i.e., 5q21–q31, 6p24–p22, and 8p22–
p21. Outside of those regions, of all markers
tested to date, D10S674 produced one of the
highest pairwise heterogeneity lod (H-LOD)
scores, 3.2 (P = 0.0004), when initially tested
on a subset of 88 families. We then tested a
total of 12 markers across a reagion of 32 centimorgans in region 10p15–p11 of all 265
families. The strongest evidence for linkage
occurred assuming an intermediate phenotypic definition, and a recessive genetic
model. The largest pairwise H-LOD score
was found with marker D10S2443 (maximum 1.95, P = 0.005). Using multipoint HLODs, we found a broad peak (maximum
1.91, P = 0.006) extending over the 11 centimorgans from marker D10S674 to marker
D10S1426. Multipoint nonparametric linkage analysis produced a much broader
peak, but with the maximum in the same location near D10S2443 (maximum z = 1.88, P =
0.03). Based on estimates from the multipoint analysis, this putative vulnerability
locus appears to be segregating in 5–15% of
the families studied, but this estimate
should be viewed with caution. When evaluated in the context of our genome scan re-
Contract grant sponsor: National Institute of Mental Health;
Contract grant numbers: MH41953, MH52537, MH45390.
*Correspondence to: Richard E. Straub, Ph.D., Director, Molecular Genetics Laboratory, Department of Psychiatry, Virginia
Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, 800 East Leigh St., Suite 110, Richmond,
VA 23219-1534. E-mail: [email protected]
Received 18 February 1998; Revised 30 March 1998
© 1998 Wiley-Liss, Inc.
sults, the evidence suggests the possibility
of a fourth vulnerability locus for schizophrenia in these Irish families, in region
10p15–p11. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:296–301, 1998.
© 1998 Wiley-Liss, Inc.
KEY WORDS: schizophrenia; linkage; Irish;
chromosome 10
INTRODUCTION
Schizophrenia is a relatively common, often chronic,
and debilitating mental illness. Evidence from a variety of studies has clearly demonstrated that genetic
factors contribute substantially to the etiology [Gottesman and Shields, 1982; Kendler et al., 1993]. For example, a recent study of a national twin sample from
Finland estimated the heritability of schizophrenia to
be in excess of 80% [Cannon et al., 1998]. Several lines
of evidence suggest that the mode of transmission is
complex, including multiple, possibly interacting
genes, along with genetic heterogeneity and incomplete
penetrance [O’Rourke et al., 1982; Kendler and Diehl,
1993; Prescott and Gottesman, 1993; Cloninger, 1994].
Given these complexities of the ‘‘genetic architecture,’’ in combination with the difficulty of characterization of the phenotype, it is not too surprising that
with current sample sizes and analytical methods,
genes have yet to be identified. A tremendous amount
of work, however, has gone into linkage and association
studies, and incremental progress is being made [Karayiorgou and Gogos, 1997]. Initial positive linkage reports on chromosomes 22q [Pulver et al., 1994], 6p
[Wang et al., 1995; Straub et al., 1995], and 8p [Pulver
et al., 1995] have been tentatively supported by subsequent worldwide collaborative efforts [Gill et al., 1996;
Schizophrenia Linkage Collaborative Group for Chromosomes 3 and 6 and 8, 1996]. More importantly, a
number of complete genome scans are now being fin-
Schizophrenia Locus in 10p15–p11
ished. A careful and systematic tabulation of the most
positive regions from these scans (regardless of whether the lod scores from individual markers are deemed
‘‘significant’’ or not) should be a productive way to prioritize more detailed follow-up studies.
The Irish Study of High-Density Schizophrenia
Families (ISHDSF) contains 1,408 individuals, with
DNA available in 265 families, systematically ascertained from psychiatric facilities in Ireland and Northern Ireland. In previous studies with these families we
generated support for the presence of three loci influencing the vulnerability to schizophrenia on chromosomes 5q21–q31 [Straub et al., 1997b], 6p24–p22
[Straub et al., 1995], and 8p22–p21 [Kendler et al.,
1996a]. We employ a split-sample design that allows us
to attempt to discriminate true from false positives by
‘‘replicating’’ our initial findings internally before communicating our best results to other investigators. We
test three equal, randomly divided, and unchanging
subsets (n 4 87 or 88) of families for the first pass scan,
rank order the results, and then follow up as many of
the best regions as possible by testing the same marker(s) on additional subsets and by testing flanking
markers. For our genome scan and follow-up work, we
have tested 620 markers to date: 131 on all 265 families, 29 markers on two subsets each, and 460 on one
subset each.
Our interest in 10p14–p13 was first raised in May of
1997 when marker D10S674 produced a heterogeneity
lod H-LOD of 3.2 (P 4 0.0004) on a single subset (n 4
88) of families, one of the best results we have found.
We have followed this observation up with additional
genotyping and have evaluated the results in the context of the distribution of lod scores we have observed
across the genome. We conclude that the results on 10p
are relatively noteworthy, and here we report the evidence suggesting a possible fourth schizophrenia vulnerability locus in these Irish families.
MATERIALS AND METHODS
Pedigree Ascertainment
As detailed elsewhere [Kendler et al., 1996b], the
Irish Study of High-Density Schizophrenia Families
(ISHDSF) is a collaborative project between the Medical College of Virginia, the Health Research Board,
Dublin, and Queen’s University, Belfast. The linkage
sample contained 1,408 individuals from 265 systematically ascertained multiplex schizophrenia families
collected in Ireland and Northern Ireland. Our entry
‘‘field’’ criteria were: two or more first-, second-, or
third-degree relatives who, according to the field psychiatrists, met DSM-III-R criteria for schizophrenia
[American Psychiatric Association, 1987] or poor outcome schizoaffective disorder (PO-SAD) [Kendler et al.,
1995]. No exclusion criteria were used, so families were
screened neither for bilineal descent of schizophrenia
spectrum illness, nor for the presence of other forms of
psychopathology, such as bipolar illness. However, the
rates of affective illness in relatives from the ISHDSF
were not increased above that found in the relatives of
unselected schizophrenia probands from a case registry
[Kendler et al., 1993a]. For inclusion into the linkage
297
sample, each pedigree had to have two or more first-,
second-, or third-degree relatives with a diagnosis of
D1–D5 (see below), one or more of whom had a D1–D2
diagnosis; 98.6% of cases diagnosed with schizophrenia
or schizoaffective disorder had psychiatric records.
Diagnostic Assessment
The diagnostic instruments included the Structured
Interview for DSM-III-R Diagnosis (SCID) [Spitzer et
al., 1992] for selected axis I disorders (psychosis, major
depression, mania, cyclothymia, dysthymia, alcohol
abuse/dependence, panic disorder, and generalized
anxiety disorder) and the Structured Interview for
Schizotypy (SIS) [Kendler et al., 1989] for putative
schizophrenia spectrum personality disorders (schizotypal, paranoid, schizoid, and avoidant personality disorder). Diagnosis was made, using DSM-IIIR criteria,
based on all available information (personal history,
hospital record, and family history report) by individuals blind to knowledge of genotypes and to the psychopathology of relatives. Final diagnostic review was
done by K.S.K. and D.W., whose agreement on diagnostic category was 74% (weighted k: 0.94 ± 0.05). The
diagnostic categories are as follows.
Categories D1–D2 (narrow; 577 affecteds, 285 affected sib pairs) included ‘‘core schizophrenic phenotypes:’’ schizophrenia, poor outcome schizoaffective disorder (PO-SAD), and simple schizophrenia [Kendler et
al., 1994].
Categories D1–D5 (intermediate; 700 affecteds, 420
affected sib pairs) involved a narrow definition of the
schizophrenia spectrum, including disorders which
have been repeatedly shown to coaggregate in families
with narrowly defined schizophrenia [Kendler et al.,
1993c]. This category added to the narrow definition
schizotypal personality disorder, and all other nonaffective psychotic disorders (i.e., schizophreniform disorder, delusional disorder, atypical psychosis, and good
outcome SAD).
Categories D1–D8 (broad; 754 affecteds, 505 affected
sib pairs) involved a broad definition of the schizophrenia spectrum and included all disorders which significantly aggregated in relatives of schizophrenic probands in the Roscommon Family Study [Kendler et al.,
1993b–d], an epidemiologic, controlled family study
conducted in parallel in the west of Ireland. This category added to the intermediate definition mood incongruent and mood congruent psychotic affective illness,
and paranoid, avoidant, and schizoid personality disorder.
Categories D1–D9 (very broad; all psychiatric disorders; 961 affecteds) included all other psychiatric disorders (e.g., nonpsychotic affective disorders, anxiety
disorders, alcoholism, and other nonschizophrenia
spectrum personality disorders).
Genotyping
DNA was extracted directly from blood, as well as
from lymphoblastoid cell lines which were established
by standard methods. PCR amplification and gel analysis of microsatellite markers were performed as described elsewhere [Straub et al., 1993].
298
Straub et al.
Linkage Analysis
Pairwise lod scores were calculated under the assumption of heterogeneity (which we term H-LODs),
using the admixture test as implemented in the program MENDEL [Lange et al., 1988], with modifications
made by C.J.M. and L. Ploughman. The parameters
used have been published [Straub et al., 1995] and we
have kept these parameters constant for all work except where noted. We used four genetic models: dominant (Dom), intermediate heterozygotic on the penetrance scale (Pen), additive on the liability scale (Lia),
and recessive (Rec). We present only the maximum HLOD score for each marker. Estimates of the recombination fractions (u) and proportions of families segregating the disease locus (a) are available on request.
Using the GENEHUNTER program [Kruglyak et al.,
1996], multipoint H-LODs and nonparametric linkage
(NPL) scores were generated over the entire region
(where results are expressed in lod and normal deviate
(z) units, respectively). We report only the NPLall statistic, which is calculated based on groupwise S(all)
allele sharing among affecteds in sibships. When information is missing, the NPL test has been found to be
overly conservative [Kong and Cox, 1997; Davis and
Weeks, 1997]. However, this inaccuracy will be smaller
in multipoint tests when dense maps are employed
than when pairwise NPL scores are calculated. With
multipoint analysis, information content is about 70%
for most of the region reported on here (data not
shown). We have not corrected for multiple testing, for
reasons given in a previous publication [Straub et al.,
1995].
Both the lod and the H-LOD statistics approximate
the chi-square distribution, with one and two degrees
of freedom, respectively. Splitting the total sample of
265 families into three equal subsets undoubtedly
weakens the accuracy of this approximation, but given
the relatively large subsets (n 4 87 or 88) involved, we
do not expect this loss to be significant. We have analyzed a number of the variables likely to be important
(e.g., family size distribution, number of affecteds, phe-
notypic classifications, and geographical location) and,
as would be expected since the families were randomly
assigned to the subsets, we have not found any notable
differences.
Estimates of the Fraction of Families Linked
Estimates were taken from the multipoint (GENEHUNTER) H-LOD and NPL output files.
RESULTS AND DISCUSSION
The markers used and genetic map are shown in
Table I. The number of alleles, heterozygosity, and
polymorphism information content (PIC) were those
observed in the ISHDSF, and the map was constructed
using the genotyping data. Twelve microsatellite markers spanning 32 centimorgans (cM: sex averaged,
Kosambi mapping function) were tested. The distances
in our map agree reasonably well with the Marshfield
genetic map (http://www.marshmed.org/genetics/), although our intermarker distance between D10S611–
D10S1426 is 0.4 cM and not 4.8 cM. The largest gap in
the sex averaged map is 10 cM, between D10S2325–
D10S674. The marker order also agrees with the MIT
physical maps (http://www-genome.wi.mit.edu). Estimates of the physical distance for the 11 cM between
D10S674–D10S183 vary considerably. The three estimates we made were: 16 megabases (data from the
LDB: http://cedar.genetics.soton.ac.uk/public_html/),
18.7 megabases (data from the SHGC radiation hybrid
map; http://www-shgc.stanford.edu/), and 23 megabases (data from the MIT radiation hybrid map).
Table II shows the maximum pairwise lod scores
(found at any recombination fraction and proportion of
families linked) calculated under the assumption of
heterogeneity (which we term H-LODs), using an admixture test [Smith, 1963] as implemented by the program MENDEL [Lange et al., 1988]. Four diagnostic
categories [Kendler et al., 1996b] were used: D1–D2
(narrow), D1–D5 (intermediate), D1–D8 (broad), and
D1–D9 (very broad). Under each diagnostic category,
we used four genetic models [Straub et al., 1995]: dom-
TABLE I. Chromosome 10p15–p11 Genetic Markers and Map*
Distances (Kosambi cM)
Sex-averaged
Name
AFM063xf4
ATA31G11
GGAA8G02
GAAT5F06
GATA6E06
GATA70E11
MFD248
GAAT13D02
GGAA7H02
GATA3G07
GATA73E11
MFD200
Locus
Number
of alleles
HZ
PIC
Female
Male
Ratio
Intermarker
distance
Map position
D10S189
D10S1412
D10S1216
D10S2325
D10S674
D10S1423
D10S245
D10S2443
D10S1215
D10S611
D10S1426
D10S183
6
9
10
10
9
7
9
6
25
6
7
17
0.68
0.74
0.74
0.86
0.78
0.77
0.73
0.64
0.89
0.66
0.75
0.87
0.63
0.70
0.70
0.85
0.75
0.74
0.69
0.59
0.88
0.59
0.71
0.86
5.8
3.5
3.6
11.9
3.7
2.2
2.2
4.1
1.4
0.3
0.3
6.8
3.9
2.0
4.2
3.3
0.9
0.9
1.7
0.7
0.4
0.4
0.85
0.90
1.80
2.83
1.12
2.44
2.44
2.41
2.00
0.75
0.75
6.3
3.7
2.8
10.0
3.5
1.5
1.6
2.9
1.0
0.4
0.3
0
6.3
10.0
12.8
20.8
24.3
25.8
27.4
30.3
31.3
31.7
32.0
*The number of alleles, heterozygosity (Hz), and polymorphism information content (PIC) for each marker are derived from ISHDSF genotyping data,
as is the map which was constructed and error-checked with the program CRI-MAP [Donis-Keller et al., 1987].
Schizophrenia Locus in 10p15–p11
299
TABLE II. Pairwise H-LOD Scores for Schizophrenia and Chromosome 10p15–11 Markers*
D1–D2
D10S189
D10S1412
D10S1216
D10S2325
D10S674
D10S1423
D10S245
D10S2443
D10S1215
D10S611
D10S1426
D10S183
D1–D5
D1–D8
D1–D9
Dom
Pen
Lia
Rec
Dom
Pen
Lia
Rec
Dom
Pen
Lia
Rec
Dom
Pen
Lia
Rec
0.00
0.07
0.00
0.05
0.36
0.54
0.02
0.69
0.28
0.00
0.67
0.43
0.00
0.00
0.00
0.04
0.40
0.42
0.03
0.67
0.31
0.00
0.69
0.34
0.05
0.00
0.00
0.03
0.45
0.31
0.06
0.57
0.46
0.00
0.92
0.43
0.26
0.00
0.00
0.01
0.25
0.22
0.01
0.58
0.45
0.03
0.65
0.58
0.03
0.36
0.13
0.98
1.08
0.81
0.25
1.69
0.60
0.52
0.56
0.94
0.02
0.12
0.07
0.75
1.16
0.83
0.36
1.56
0.63
0.45
0.67
0.99
0.00
0.17
0.16
0.97
1.38
1.22
0.40
1.77
0.79
0.52
0.99
1.27
0.19
0.06
0.87
0.98
1.30
1.46
0.31
1.95
1.31
0.69
1.07
1.65
0.26
0.86
0.16
0.65
0.88
0.61
0.02
0.85
0.29
0.15
0.36
0.54
0.12
0.45
0.10
0.47
0.86
0.68
0.06
0.74
0.31
0.09
0.45
0.50
0.03
0.54
0.10
0.34
0.88
0.68
0.03
0.91
0.37
0.08
0.75
0.59
0.14
0.93
0.85
0.36
1.18
1.10
0.04
1.33
0.97
0.35
1.21
1.15
0.06
0.38
0.00
0.19
0.15
0.28
0.27
0.35
0.27
0.20
1.14
1.04
0.10
0.36
0.00
0.27
0.27
0.23
0.18
0.45
0.34
0.13
0.92
0.92
0.15
0.43
0.00
0.21
0.32
0.06
0.03
0.55
0.35
0.12
0.86
0.61
1.22
1.27
0.23
0.08
0.62
0.27
0.00
0.11
0.12
0.26
0.38
0.35
*The program MENDEL [Lange et al., 1988] was used to calculate lod scores under the assumption of locus heterogeneity (H-LODs), which are presented
as the maximum lod scores at any recombination fraction and proportion-linked. Diagnostic categories and genetic models are as described in Materials
and Methods.
inant (Dom), additive (Pen and Lia), and recessive
(Rec). For most markers, under a given diagnostic category, the H-LOD scores were quite similar for all four
genetic models. The largest pairwise H-LOD score was
1.95 (P 4 0.005) with marker D10S2443, under diagnostic category D1–D5 and the recessive genetic model.
While the results under D1–D5 and D1–D8 were fairly
similar, expanding the disease definition to D1–D9 or
restricting it to D1–D2 produced substantially smaller
scores, with a number of markers failing to yield positive values at any recombination fraction.
Table III shows the pairwise NPLall z scores. As we
observed on chromosomes 5, 6, and 8, compared to the
lod score analysis, the nonparametric results are in
general considerably weaker: only two markers,
D10S674 (P 4 0.062) and D10S2443 (P 4 0.066) (under diagnostic category D1–D5), yielded P values less
than 0.1. When the data are not fully informative, as is
the case in this pairwise analysis, the NPL test has
been shown to be overly conservative [Kong and Cox,
1997; Davis and Weeks, 1997].
Figure 1 shows the multipoint H-LODs generated
using the software GENEHUNTER [Kruglyak et al.,
1996] for the diagnostic category D1–D5 and all four
genetic models. D10S189 is placed at map position
zero, and proximal (centromeric) is to the right. For all
genetic models, there is a broad peak extending over
the 11 cM from D10S674–D10S1426, with the recessive
model strongest and maximizing at 1.91 (P 4 0.006).
The information content, as estimated by GENEHUNTER, is about 70% for most of the region (data not
shown).
Figure 2 shows multipoint H-LODs under the recessive genetic model for the four diagnostic categories.
Concordant with the pairwise results, the support for
linkage is the greatest under D1–D5 (as in Fig. 1). Diagnostic categories D1–D8 and D1–D9 produced a second, smaller peak about 27 cM distal to the primary
peak near D10S2443.
Figure 3 shows the multipoint nonparametric linkage (NPLall) results from GENEHUNTER. The largest
peak (maximum 1.88, P 4 0.03) is in the same location
near D10S2443 as in the parametric analyses, but the
positive evidence is spread distally over a much
broader region. Based on the parametric multipoint results, a tentative guess of the most likely location of the
putative gene is the 11 cM region between D10S674–
D10S1426.
Estimates from the multipoint analysis by GENEHUNTER of the proportion of families linked range
from 5–15% (data not shown). However, while we have
developed evidence supporting multiple genes for
schizophrenia in these Irish families, using linkage results alone, we have not been able to derive much use-
TABLE III. Pairwise NPL Scores for Schizophrenia and Chromosome 10p15–11 Markers*
D1–D2
D1–D5
D1–D8
D1–D9
Locus
NPL
P value
NPL
P value
NPL
P value
NPL
P value
D10S189
D10S1412
D10S1216
D10S2325
D10S674
D10S1423
D10S245
D10S2443
D10S1215
D10S611
D10S1426
D10S183
0.23
0.09
0.12
0.32
0.74
0.73
0.12
1.01
0.73
0.06
0.82
0.90
0.40
0.46
0.44
0.36
0.21
0.21
0.44
0.13
0.21
0.47
0.18
0.16
0.18
0.58
0.54
1.04
1.50
1.10
0.59
1.47
1.16
0.48
1.09
1.67
0.42
0.27
0.29
0.14
0.06
0.13
0.27
0.07
0.12
0.31
0.13
0.04
0.13
0.72
0.49
0.61
1.06
0.79
0.16
1.15
0.98
0.10
0.89
1.25
0.44
0.23
0.30
0.26
0.14
0.21
0.43
0.12
0.16
0.45
0.18
0.10
0.13
0.23
−0.33
0.44
0.45
0.13
0.38
0.71
0.53
0.18
1.07
1.16
0.44
0.40
0.62
0.32
0.32
0.44
0.35
0.23
0.29
0.42
0.14
0.12
*The program GENEHUNTER [Kruglyak et al., 1996] was used to calculate pairwise NPLall z scores.
300
Straub et al.
Fig. 1. Multipoint heterogeneity lod scores based on 12 markers in the
10p15–p11 region for the intermediate (D1–D5) disease definition and all
four genetic models. Marker D10S189 is arbitrarily set at map position
zero, and the locations of the labels for the markers are approximate. See
Table I for locations and intermarker distances. Calculations were performed by the GENEHUNTER program [Kruglyak et al., 1996], and are
expressed in lod units. Right is proximal (centromeric).
ful information about the nature of their interaction.
Since such interaction effects have the potential to confound the relationship between gene effects and lod
score, we caution against the overinterpretation of
these GENEHUNTER values of ‘‘fraction-linked.’’ With
the exception of the regions of interest on 5q, 6p, and
8p, our maximum multipoint H-LOD of 1.91 on 10p is
higher than for any other region that we have tested.
Although the statistical support for this region is modest, when viewed in the context of our genome scan, it
probably deserves attention.
There have not been, to our knowledge, any previous
publications of positive linkage findings for schizophrenia in this chromosomal region. During preparation of
this manuscript, in October 1997, we presented some of
our preliminary positive results [Straub et al., 1997a]
and learned of positive results in this region [Faraone
and NIMH Genetics Initiative—Millennium Schizophrenia Consortium, 1997]. In complete genome scan
Fig. 3. Multipoint nonparametric linkage (NPLall) scores for the narrow
(D1–D2), intermediate (D1–D5), broad (D1–D8), and very broad (D1–D9)
diagnostic categories. Calculations were performed by the GENEHUNTER
program [Kruglyak et al., 1996], and are expressed as normal deviates (z
scores).
of the 48 European-American schizophrenia families
from the NIMH Genetics Initiative, the region containing markers D10S1423 (NPL z 4 3.4, P 4 0.003) and
D10S582 (NPL z 4 3.3, P 4 0.0005) yielded the greatest evidence of linkage. The most positive markers in
the two studies are in similar locations, but our primary multipoint peak covers a much more limited region, indicating a target region of less than 20 cM. In
addition, we have since learned that D. Wildenauer
(Univeristy of Bonn) has generated positive results
with markers D10S582 (mean IBD sharing of 61.5%; P
4 0.0058) and D10S1423 (mean IBD sharing of 59%; P
4 0.029) in 72 families (59 German and 13 nonAshkenazi Israeli). Taken together, these three studies
suggest that an additional vulnerability locus for
schizophrenia may be located in 10p15–p11.
ACKNOWLEDGMENTS
Data collection was conducted under the supervision
of S. Humphries, M. Healy, and A. Finnerty. Additional
interviews were conducted by J. Burke, B. Murphy, F.
Duke, R. Shinkwin, M. Ni Nuallain, F. McMahon, J.
Downing, T. Hebron, B. Hanratty, E. Crowe, M.
Doherty, J. Bray, and L. Lowry. This project would not
have been possible without the cooperation of the families themselves and the staffs of the many psychiatric
hospitals and units in Ireland and Northern Ireland,
and their efforts are gratefully acknowledged. We also
acknowledge the assistance of B. Kadambi, B. Wormley, H. Sadek, and R. McClelland.
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