GENETIC FACTORS IN AFFECTIVE
ILLNESS zyxwvutsrqponmlkjihgfedcb
WADE H. BERRETTINI, LYNN R. GOLDIN, JOHN I. NURNBERGER, JR.
and
ELLIOT S. GERSHON
Sectionon Psychogenetics,BiologicalPsychiatryBranch, National Institute
Building 10, Room 3N220, Bethesda, MD 20205, U.S.A.
of Mental Health,
Summary-Research
strategies for determining
genetic vulnerability
markers in affective illness
are delineated.
Using these strategies,
recent developments
in the biology of manic-depressive
illness are discussed,
including
results from association
and linkage studies, pharmacologic
challenge protocols, and cerebrospinal
fluid (CSF) data. Several lines of evidence suggest that one
genetically determined
vulnerability
to affective disorder may be a cholinergic
supersensitivity,
possibly mediated through increased numbers of cholinergic receptors.
INTRODUCTION
THIS paper will attempt to review some recent developments in the search for genetic
vulnerability factors in affective illness. Research strategies used in this search will be
delineated. Recent studies of association and linkage of affective illness to chromosomal
markers will be reviewed. Finally, some clinical neurobiological studies will be presented
to suggest promising putative genetic markers for vulnerability to affective illness.
For the purposes of this paper, it is assumed that some forms of affective illness are
associated’with genetic vulnerability to the disease. The issue of genetic transmission in
affective illness has been reviewed recently in detail elsewhere (NURNBERGER and zyxwvutsrqponmlkjihgfedc
GERSHON,
1982). Briefly, the evidence in favor of genetic transmission of vulnerability factors in
affective illness is quite strong.
RESEARCH
STRATEGIES
In any periodic illness, genetic vulnerability implies that episodically ill individuals
possess at least one continuously heritable (constitutional) factor which increases the risk
of developing the illness in question. A genetic vulnerability factor for affective illness
should have the following characteristics (RIBDER and GERSHON, 1978): (1) stable and
heritable; (2) state independent (present regardless of whether the individual is currently in
an episode of illness); (3) differentiates those with affective illness from the general
population; and (4) within a pedigree in which the proband has the marker, the marker
should differentiate relatives with the illness from those without. This is not an absolute
differentiation because of decreased penetrance and possible genetic heterogeneity of the
illness.
In the progress of research in affective disorders, several studies must be done before
a biological parameter can be considered as a putative genetic vulnerability marker. The
parameter should be stable in individuals over time. If the parameter is highly concordant
in monozygotic twins and less concordant in dizygotic twins, then the parameter is most
likely under some degree of genetic control. That is, it is heritable. The mean value of the
329
330
WADE
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHG
H. BERRETTINI
et zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQP
al.
parameter for euthymic (well-state) patients must be significantly
different from controls.
Finally,
and most importantly,
the putative
marker must be associated
with illness
within a family in which the ill proband has the marker. If some biological parameter
fulfils these criteria then it may be considered a genetic vulnerability
marker for affective
illness.
Two different research strategies have been employed in the search for genetic vulnerability markers in affective illness. One can study biological
parameters
of theoretical
interest in affective illness (such as receptor function,
enzyme activity, etc.) to determine
whether the parameter satisfies criteria for a genetic vulnerability
marker. Alternatively,
one can study known chromosomal
markers, such as ABO blood types or human leukocyte
antigens (HLA) in individuals
with the illness. This latter strategy refers to association
and linkage studies. The object of these studies is to determine
whether a particular
allele at a chromosomal
locus is associated with illness in the general population
of ill
individuals,
or chromosomally
linked to a susceptibility
gene for development
of illness
within given pedigrees.
In the first strategy
one commonly
studies biological
parameters,
which reportedly
differentiate
affectively
ill from well populations
(that is, the means for ill and well
groups are significantly
different),
in an attempt to prove that the parameter is heritable
and is associated with a greater risk for illness within certain pedigrees. In the second
strategy one studies parameters which are known to be transmitted
by a single major locus
(ABO blood groups for example) in an attempt to determine whether the marker locus is
related to susceptibility
for illness. If ill populations
have a significantly
higher incidence
of an allele at a marker locus than do control populations,
this suggests that the allele
plays some role in disease susceptibility.
However, if alleles at a marker locus co-segregate
with the illness in families, this is evidence that the disease locus is chromosomally
linked
to the marker locus. Linkage will generally not lead to the association
of illness with
particular
alleles at the marker locus at the population
level. However, in some cases,
(such as loci in the HLA region) associations
of alleles at closely linked loci are found,
presumably
due to disequilibrium.
Separate methodologies
exist for studying linkage and association,
depending
on the
type of data obtained.
The association
of a genetic marker trait (such as an HLA antigen or an ABO blood
type) with a disease is tested by comparing
the frequency of the trait in populations
of
patients and controls. This is illustrated in the 2 x 2 table below.
Marker
Disease
Trait
Present
a
Present
Absent
C
Absent
b
d
In this table, a, 6, c and d are the numbers of individuals
falling into each category.
The most commonly
used measure of association
is the relative risk (R) given below,
which describes the increased risk for an individual
to have the disease when he has the
marker trait:
R=
ad
-.
bc
GENETICS AND
AFFECTIVE
ILLNESS
331
Other measures of association
and techniques
for combining
results across studies are
described in detail in THOMSON(1980).
The significance of an association can be determined by a chi-square statistic from the
2x2 table. However, if more than one marker trait is tested (e.g. large series of HLA
antigens) then the significance
level must be multiplied
by the number of tests. SMOUSE
and WILLIAMS (1982) have developed an alternative
method for the analysis of HLA
antigens which yields a single chi-square test for each locus and an overall test for the
whole complex. This takes into account allelic correlations
within and between HLA loci.
Two methods of detecting linkage can be used depending on the type of data available
and the assumptions
that can be reasonably made. If the data consist of complete nuclear
families or larger pedigrees, then it is possible to apply the lod score method of MORTON
(1955). Methods have also been developed to detect linkage in samples of affected sibpairs. These two methods will be discussed in terms of the underlying
assumptions
and
relative advantages and disadvantages.
Lod score method
The lod score method developed by MORTON (1955) is a means of testing the hypothesis
of linkage between two loci when the mode of transmission
of each locus is known. The
underlying
assumptions
are that: (1) the parameters
(gene frequency
and genotypic
penetrances)
for the disease locus and marker locus are known; (2) there is no population
association between the disease locus and marker locus; (3) mating is random. Under these
assumptions
one compares the probability
of observing the pattern of segregation of the
two traits in a family if there is linkage to the probability
of observing the family, if there
is no linkage. The probability
of linkage is expressed as a function of the recombination
fraction (0) where Clis some value between 0 and l/2. The probability
of no linkage is the
probability
that the two loci are segregating independently
(i.e. 8 = l/2). This odds ratio t3
is expressed by a statistic called the lod score (or log of the odds ratio) and is defined as
follows:
probability
of observing a family for 8 < l/2
lod score = log,,
probability
of observing a family for t3= l/2’
A lod score of 1.0 means that linkage is 10 times more likely than no linkage. The lod
scores for small families can be done by hand (LEVITAN and MONTAGU, 1971) or using
tables in simple cases. For larger or more complex families, a widely available computer
program LIPED (OTT, 1974) performs the calculations.
In practice, for each family the
lod score is evaluated
for several values of 8. Since the scores represent independent
probability
ratios (the scores are in log,, units), they can be summed across families. If
linkage is true, the best estimate of 0 is that value of 8 which results in the highest lod score.
Data can be evaluated sequentially
after each sample of pedigrees is collected. MORTON
(1955) originally proposed lod scores of 3.0 being the cut-off value for acceptance
of
linkage and -2.0 being the cut-off value for rejection of linkage. If the score is intermediate,
then more families should be collected until the hypothesis
can either be accepted or
rejected. This convention
has generally been followed in linkage studies. However, use
of these absolute cut-off points may not always be appropriate;
when tests of linkage of a
332
disease locus to many marker
in a single study.
WADE
H. BERRETTINI
et al.
loci are made,
significant
lod scores may occur by chance
Sib-pair method
The use of samples of affected sib-pairs for linkage analysis may be desirable because
fewer assumptions
are required.
The method used currently
derives from Penrose’s
sib-pair method (PENROSE, 1935, 1953). The idea behind the method is that if a marker
locus is linked to a disease locus, then affected pairs of siblings will have the same phenotype at the marker locus more often than expected by chance. Since only affected sibs
are used, this method is especially useful for disease susceptibility
loci that are thought to
have low penetrance.
Although general in theory, this method has been mainly developed
to apply to problems of detecting linkage to the HLA loci. Because there is so much
polymorphism
in the HLA region, each parental chromosome
has a different set of HLA
alleles (or haplotype).
Thus, it is usually possible to determine whether affected sib-pairs
share exactly 2, 1 or 0 haplotypes identical by descent (IBD) at the marker locus. If there is
no linkage, then the proportion
of affected sib-pairs sharing 2, 1, and 0 haplotypes is l/4,
l/2, l/4, respectively.
If linkage is present, then this distribution
is skewed so that more
than 25% of affected sib-pairs have identical haplotypes. The simple hypothesis of linkage
can be tested by comparing
the observed IBD distribution
in a sample of independent
affected sib-pairs with that expected when there is no linkage. The affected sib-pair
method has been further developed by several investigators
(SUAREZ et al., 1978; SUAREZ,
1978; DAY and SIMONS, 1976; THOMSON and BODMER, 1977a, b; GREEN and WOODROW,
1977) in order to make some inferences about the mode of inheritance
of the disease trait
and the recombination
fraction
between the disease and marker loci. For example,
THOMSON and BODMER (1977a, b) have derived tables of the expected IBD distribution
for
simple dominant
and recessive models with varying gene frequency. In addition, methods
have been developed (GREEN and WOODROW, 1977; SUAREZ and CROUGHAN, 1982) to
evaluate the degree of haplotype sharing when more than two affected sibs in a sibship are
available for study. In theory, it is also possible to use unaffected
pairs and unaffectedaffected pairs of siblings for this test; however, SUAREZ et al. (1978) have shown that these
types of sib-pairs do not contribute
very much information
about linkage. It should be
noted that although the sib-pair method has been developed and applied largely to the HLA
locus, it is general and can be applied to other marker loci (e.g. ABO, Rh, etc.). However,
because most other loci are not as polymorphic as HLA, not all sib-pairs will be informative
and a larger sample size will be needed in order to detect linkage.
This method has been widely applied to testing of linkage to HLA in samples of affected
sib-pairs with juvenile diabetes (see review in CLERGET-DARPOUX, in press) and multiple
sclerosis. Later we will review sib-pair studies of HLA and major affective disorder.
Comparison of methodoiogies of linkage analysis
The choice of methods to use for linkage analysis will depend on several factors. For
some diseases, it may be easier to collect data on a sample of affected sib-pairs than on
complete families. While the lod score method is easily applied to small nuclear families, it
is most powerful for larger multigenerational
families (which are generally more difficult
to study). On the other hand, as stated previously,
the affected sib-pair method is most
GENETICS
ANDzyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHG
AFFECTIVEIILNES
333
efficient for highly polymorphic loci such as HLA and will require larger sample sizes in
the case of other loci. Most importantly, the underlying assumptions required for these
methods are different. For the lod-score method, the underlying genetic parameters (gene
frequency, penetrances) must be specified. Unfortunately, for many diseases studied, the
mode of transmission is not known and is often guessed in order to calculate lod scores.
However, incorrect specification of the model can give the wrong results (SUAREZand
VAN EERDEWEGH,1981). MORTONand KIDD (1980) and KRUGERetzyxwvutsrqponmlkjihgfedcbaZYXW
al. (1982) have also
shown how variation in unknown model parameters can affect the results of linkage
analysis using real data.
As stressed previously, no such assumptions are needed to test the hypothesis of linkage
in affected sib-pairs, and this method is therefore most appropriate when the exact mode
of transmission of the disease locus is unknown. If preliminary evidence for linkage is
obtained from sib-pairs, it is possible to estimate genetic parameters under certain models
and thereby make some inferences about the mode of transmission of the disease.
Another problem that needs to be considered is possible genetic heterogeneity of the
disease under study. Since families are pooled for both methods, it is assumed that the
same disease locus is segregating in each family. If there is heterogeneity then such pooling
of families will lead to erroneous results. It is possible to test for heterogeneity of linkage
(MORTON,1956); however, large families are generally needed to be able to detect significant
heterogeneity.
The presence of association of alleles at the disease and marker locus can bias the results
of linkage. CLERGET-DARPOUX
(1982) has shown that ignoring associations in a lod score
analysis biases the estimate of the recombination fraction (slightly upward) and decreases
the lod score. However, in theory, it is possible to calculate lod scores taking association
of phenotypes into account.
These deviations from simplifying assumptions must be taken into account when
performing linkage analyses (see SPENCE, 1980). This is especially true for psychiatric
disorders where the validity of most of the simplifying assumptions are not known, i.e.
the mode of transmission of illness is unknown, the illnesses may be genetically heterogenous and assortative mating may exist (see GERSHONet al., 1973; DUNNERet al., 1976;
NEGRI et al., 1981). In addition, the “ill” phenotype cannot be exactly defined since
there are numerous theories with regard to which diagnoses should be included in a
particular “spectrum”.
Association and linkage studies in affective disorder
Association studies
ABO locus. Several studies have reported the frequencies of ABO types in patients with
affective disorder (or sub-groups of patients) as compared to control populations. Results
from most of these studies are conflicting. A few studies (e.g. PARKER et al., 1961;
MENDLEWICZet al., 1974; R~NIERISet al., 1979) have found a higher frequency of blood
type 0 in manic-depressive patients than in controis. In contrast, FLEMENBAUM
and
LARSON(1976) found type A to have a higher frequency in patients and BECKMANet al.
(1978a) found the frequency of type B to be increased in unipolar (UP) and bipolar (BP)
patients. Other studies have found no differences between patients and controls (TANNA
WADEH. BERRETTINI
et al.
334
and zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
WINOKUR, 1968; JAMES et al., 1979). SHAPIRO et al. (1977a) found no overall difference
in patients but found bipolars to have a higher frequency of type 0 and unipolars to have
a higher frequency of type A.
Clearly, there is no consistency in these reports. FLEMENBAUMand LARSON (1976) suggest
that many of the significant
results reported in the literature,
including
their own, are
artifacts due to skewed patient population
samples. In their own study, they found that
the entire population
of psychiatric
patients had different
ABO frequencies
than the
control population.
If manic-depressives
were compared to all other psychiatric patients,
there were no significant ABO differences. They present evidence to suggest that this is true
in some of the other published studies of ABO types in psychiatric disorders and conclude
that psychiatric
patients may be different
from the overall population
with respect to
ABO types. This demonstrates
the potential
effect of population
stratifications
on
association studies.
HLA loci. Ten studies of HLA types in patients with affective disorders and controls
are summarized
in Table 1. This table presents the results of whole samples of patients
and only the latest study of each group of investigators. One of the first studies by SHAPIRO
et al. (1976, 1977b) reported that HLA BW16 had a significantly
higher frequency in a
sample of Danish patients than in controls.
The difference
was significant
@=0.046)
after statistical correction for multiple tests and was more pronounced
(although not significant) in patients without a family history of affective disorder. This finding generated
some excitement; unfortunately,
subsequent studies were not able to replicate the association.
Associations
with other antigens were reported but none were statistically significant after
correction for the number of antigens tested. The fact that HLA BW16 was found to be
higher in the Danish study is interesting
since this antigen is found with much higher
frequency in Ashkenazi Jewish populations than in other European Caucasian populations. zyxwvutsrqponm
TABLE 1. ASSOCIATION
STUDIES:HLA AND MAJORAFFECTIVE
DISORDER
No.
Study
SHAPIKO et al.
(1977b)
of patient!,
107
STEMBERand FEVE (1977)
50
Results
f BWl6
t BS, 813,
i BlZ
Significance
@ < 0.05)
after statistical
correction
t BW16
BW35
t B13
t B5
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
No difference
118
GOVAERTSei al. (1977)
1 B1.S
SMERALDIet al. (1978~1)
91
BECKMANet al. (1978b)
168
JOHNSON (1978)
TEMPLF et al.
(1979)
TARGUM eI a/. (1979)
.IAMES et al. (1980)
M~NDLE WICZ et al.
( 198
I)
~~--~--_-_
t A29, BW22
1 AlO, A30
No difference
t A10
1 B7
No difference
36
No difference
38
t BW22
C AY, CW3
1 cw3
92
t BW14
? BW27
No difference
I14
No difference
47
No diffrrznce
GENETICSANDAFFE~TIVE
ILLNESS
335
Ashkenazi
Jews also have a higher frequency
of manic-depressive
illness than other
European
populations
(GERSHON and LIEBOWITZ, 1979). Two studies (TEMPLE et al.,
1979; TARGUM et al., 1979) compared HLA types in Ashkenazi Jewish patients to ethnically
matched controls and found no differences.
In most of the HLA studies reported, BW16
is slightly higher in patients than in controls. This may be another example of population
stratification
if the samples of patients are enriched with individuals
of Ashkenazi Jewish
origin. TARGUM et al. (1979) have shown how a spurious association
can be found if
comparisons
are made between heterogeneous
populations.
Linkage studies
Studies of linkage of affective disorder to genetic markers have included loci both on
the X-chromosome
and the autosomes.
The X-chromosome
studies were motivated
by
the findings of WINOKUR et al. (1969) that in BP families there was a high rate of motherson transmission
of illness, virtually no father-son
transmission
and a higher proportion
of females affected than males. These findings are consistent
with the pattern of an
X-linked dominant gene. Other family studies (GOETZL et al., 1974; GERSHON et al., 1975)
have not found these differences in transmission
but the results of linkage studies with
X-chromosome
markers have stirred up considerable
controversy.
Other autosomal
marker loci have been studied with special emphasis on the HLA loci. In the next two
sections, we shall review studies of linkage to X-chromosome
and autosomal
markers.
X-chromosome marker studies. WINOKUR et al. (1969) were the first to present evidence
to support the X-chromosome
transmission
hypothesis
by showing that the X-linked
colorblindness
(CB) locus segregated
with manic-depressive
illness in a single large
pedigree. This finding was supported in a large series reported by MENDLEWICZ et al.
(1972), in a report by MENDLEWICZ and FLEISS (1974), and in a series of families with
schizoaffective
probands (MENDLEWICZ, 1977). FIEVE et al. (1973) also reported positive
evidence for linkage of BP illness to the red cell Xg locus; however, the CB and Xg loci
are on different arms of the X-chromosome
and linkage of a gene for BP illness to both
loci is incompatible.
More recently, MENDLEWICZ et al. (1980) reported linkage between
the G6PD locus (near the CB locus) in a single multigenerational
pedigree of a BP proband.
BARON (1977) has also reported a single pedigree containing
SA and BP individuals which
supports linkage of these disorders to the CB locus. Data on 6 informative
families from
our own large series of BP pedigrees showed no evidence for linkage of affective disorder
and CB (GERSHON et al., 1979) or Xg (LECKMAN et al., 1979). These families were also
reported as part of a WHO collaborative
study (GERSHON et al., 1980). The pooled series
of 16 families was found to be heterogeneous
with one family favoring linkage (lod
score > 2.0) and the remainder being indeterminate
(lod scores between -1 and + 1). In
a preliminary
report, EGELAND (1980) found no evidence for linkage to CB in a large BP
pedigree from the Old Order Amish population.
It should be noted that there are other methodological
issues with regard to the CB
linkage studies. In the early reports, lod scores were calculated with no correction
for
variable age of onset of illness. MORTON and KIDD (1980) have demonstrated
how age
correction
can affect the results of linkage analyses.
As discussed by GERSHON and
BUNNEY (1977), affective disorder seemed to be associated with colorblindness
in the
336
WADEHzyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJI
. BERRETTINI
et al.
MENDLEWICZ et al. (1972) series. Such an association
is not expected if there is actual
linkage. This raises the possibility of a bias in ascertainment
of families. Recently RISCH
and BARON (1982) have reanalyzed all of the published X-chromosome
data incorporating
age of onset and concluded that there is heterogeneity
of the illness so that a proportion
of
families are segregating for a gene linked to the CB locus of the X-chromosome.
However,
this interpretation
is controversial
since most of the families favoring linkage are from one
group of investigators
and most of the families favoring non-linkage
are from another
group of investigators.
This issue may be resolved in the near future with the use of DNA
polymorphisms
in the CB region of the X-chromosome
(SINISCALCO et al., 1982). If
enough polymorphisms
can be identified, all families will be informative for X-chromosome
linkage.
Autosomal markers. Most studies of linkage of affective disorder to autosomal markers
have been of the HLA region of chromosome
6. However, a few studies have examined
linkage to other polymorphic
loci.
Tanna and co-workers
found positive evidence for linkage of “depression
spectrum
disease” to the Haptoglobin
locus first in sib-pairs (TANNA et al., 1976) and then by
calculating
lod scores in families (TANNA et al., 1979). [Depression
spectrum disease is
defined as unipolar illness in a proband who has at least one first degree relative with
alcoholism
or sociopathy
(WINOKUR, 1972).] However, the maximum
lod score in 14
families was 1.03 (i.e. linkage 12 times more likely than non-linkage).
In the absence of
further evidence, a score of approximately
1.0 is likely to be due to chance. A study of
30 markers in a single large UP pedigree by CROWE et al. (1981) and a study of 29 markers
in a single large UP pedigree (WEITKAMP et al., 1980) did not suggest any linkages or
provide any support for linkage to the Haptoglobin
locus. Families with BP, UP and SA
illness from our own laboratory
have recently been analyzed for linkage to 21 autosomal
loci (GOLDIN et al., 1983). There were no positive linkages, the highest lod score being
1.39 (0 = 20%) for the MNS locus in 30 informative
families.
Recently there has been considerable interest in the relationship of a possible susceptibility
gene for affective disorders to the HLA region.
Smeraldi and coworkers in Italy (SMERALDI et al., 1978b; SMERALDIand BELLODI, 1981)
found that pairs of siblings, both of whom had a major affective disorder (UP or BP),
shared HLA haplotypes more often than would be expected by chance. This suggests that
a susceptibility
locus for affecrive disorder is linked to the HLA locus, but the finding
had only borderline statistical significance in their sample of 26 sib-pairs.
WEITKAMP et al. (1981) reported data from 21 sibships (6 pairs were part of a single
large multigenerational
pedigree) from UP and BP families. The distribution
of HLA
haplotypes
in the overall sample did not deviate from random.
However, a subset of
sib-pairs, where there were only two affected sibs in the sibship (as opposed to three or
more affected) did share more HLA types than expected from chance. The authors
hypothesized
that the significant
deviation
in this particular
subset of families was
expected on the basis of an assumption that sibships with only two affected sibs represented
families where parents had “fewer” susceptibility
genes than in sibships with more than
two affected. With “fewer”
parental susceptibility
genes, the increase sharing of HLA
types would be more easily detectable.
GOLDIN et al. (1982) have observed that this
GENETI~~.~NDATFEcTIvE
ILLNESS
337
subdivision
of the data is not theoretically
justified because it does not correspond
to
any specific genetic hypothesis.
A study by TKJRNER and KING (1981) showed positive evidence for linkage of HLA to
affective disorder in several BP pedigrees that were consistent with autosomal dominant
transmission
of illness. Two of these families were recently reanalyzed by KRUGER et al.
(1982) who found that the likelihood of linkage depended to a large extent on the underlying assumptions
about the mode of transmission
of affective disorder, age of onset
correction, marker allele frequencies, and diagnostic criteria. The maximum likelihood of
linkage to HLA was found when loose criteria for affective disorders (including UP, BP
and several personality disorders) were applied. However, when the GLO locus (a marker
closely linked to HLA) was analyzed, the maximum likelihood of linkage was found when
strict criteria for affective disorder (including only UP and BP) were applied. These two
results appear to be inconsistent.
We and others have not been able to demonstrate
a relationship
of HLA to major
affective disorder, Data from our own laboratory
(TARGUM et al., 1979; GOLDIN et al.,
1982) have been analyzed by two methods. Both a sample of 19 pedigrees (UP and BP)
analyzed for linkage of HLA to affective disorders using standard methods of linkage
analysis and a sample of 21 affected sib-pairs (mostly from the same families) failed to
show evidence for an HLA role in this disorder. A recent analysis of affected sib-pairs
in 10 families by SUAREZ and CROUGHAN (1982) has also failed to provide evidence for a
susceptibility
locus in the HLA region. In addition, both our data and that of Suarez and
Croughan
are inconsistent
with Weitkamp’s
predictions
of increased haplotype sharing
in sibships with only two affected sibs.
In summary, there are conflicting reports regarding association and linkage of affective
disorders to these known chromosomal
markers. Our data do not support linkage to any
of these markers. In view of the conflicting
reports, one might conclude conservatively
that the affective disorders are not closely linked to any of these chromosomal
markers.
For each marker, there are several negative studies. If linkage to affective illness exists for
any of these chromosomal
markers, it is weak and not of primary importance
in the
development
of the disease.
Clinical neurobiological studies
The search for neurobiological
genetic vulnerability
markers in affective illness is an
important research strategy that involves two independent studies. In one, it must be shown
that the neurobiological
variable is heritable. In the second, it must be demonstrated
that,
within a family in which the ill proband has the neurobiological
variable, the variable
should differentiate
well from ill relatives (RIEDER and GERSHON, 1978). In this section
several clinical neurobiological
studies, performed as part of a search for vulnerability,
will be discussed.
CSF studies
Few studies of CSF biochemistry
have been conducted to establish CSF parameters as
genetic vulnerability
markers. However, several lines of indirect evidence are compatible
with the hypothesis that CSF 5-hydroxyindoleacetic
acid (S-HIAA) levels may be stateindependent
and genetically
determined.
SEDVALL and OXENSTIERNA (1981) found a
33x
WADE E. BERRETTINI era/.
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
significant
intraclass correlation
among monozygotic
twins but did not demonstrate
that
this concordance
is higher than that found in dizygotic twins. Additionally,
the studies
of SWANN et al. (1983) and KOSLOW et al. (1983) found elevated CSF 5-HIAA values in
14 manic and 43 depressed women compared to the 29 female normal volunteers.
The
data of POST et al. (1980) are also compatible with 5-HIAA as a state independent variable.
However,
VESTERGAARD et al. (1978) found that recovered patients had significantly
higher @ < 0.02, paired ?-test) CSF 5-HIAA levels compared to depressives. This suggests
that 5-HIAA
may be state dependent.
Additional
studies are required
to determine
whether CSF 5-HIAA levels are independent
of mood state and genetically determined.
SEDVALLet ul. (1980) found that 28 psychiatrically
healthy individuals
with a positive
family history of severe psychiatric illness showed greater variation in CSF 5-HIAA than
did 32 normals without the positive family history. Additionally,
they reported that those
with abnormally
low CSF 5-HIAA tended to have a family history of depression while
those with high 5-HIAA tended to have a family history of schizophrenia.
There was a
significant
difference between levels of CSF 5-HIAA in the realtives of schizophrenics
compared to the relatives of depressives.
These data are compatible
with, but are not
strong evidence for, the hypothesis that low CSF 5-HIAA is a familial, state-independent
vulnerability
factor for affective illness. The studies of VAN PRAAG and DE HAAN (1980)
are also compatible
with this hypothesis.
They found that 33 of 54 depressed individuals
with low post-probenecid
accumulation
of CSF 5-HIAA still showed this low accumulation
after recovery from the episode of depression.
These individuals
(VAN PRAAG, 1980)
tended to respond well to oral 5-hydroxytryptophan
treatment (only one of 13 relapsed)
compared
to those individuals
with normal
post-probenecid
5-HIAA
accumulation
(five of seven relapsed). Additionally,
VAN PRAAC and DE HAAN (1980) found a greatet
number of hospital admissions for depression among the low 5-HIAA groups and among
their relatives compared
to the normal 5-HIAA group. However,
most importantly,
there was no report of higher incidence of illness among the relatives of the low 5-HIAA
group. At present, we cannot exclude the possibility
that some affective disorders are
associated with a state-independent
low CSF 5-HIAA after probenecid.
We performed
lumbar punctures
on 25 lithium treated euthymic
bipolar patients
(12 of whom had repeat punctures
after a minimum
two weeks off lithium) and 25
carefully screened normal volunteers to determine whether various abnormalities
reported
in the ill state could be detected in the well state. That is, we attempted
to determine
whether examination
of CSF biochemistry
would yield state-independent
trait markers
for affective illness. Results are summarized in Table 2.
Monoamines
and their metabolites
(NURNBERGER et al., 1983a) were measured
by
high-performance
liquid chromatography
with electrochemical
detection.
No significant
differences (defined asp 5 0.01) were found between patients and controls for norepinephrine,
4-hydroxy-3-methoxyphenylglycol
(MHPG)
(a norepinephrine
metabolite),
homovanillic
acid (HVA) and 3,4_dihydroxyphenylacetic
acid (DOPAC) (two dopamine
metabolites), or 5-HIAA. A strong correlation was found between CSF HVA and 5-HIAA
for patients (unmedicated
and lithium-treated)
and controls (see Fig. !). A similar strong
correlation
was found by AGREN (1982) between CSF HVA and 5-HIAA (n = 97, r= 0.79,
p < 0.0001). Patients (n=6) with a history of suicide attempts did not have lower CSF
5-HIAA than other patients or controls.
GENETICS
339
ANDAFFECTIVE
ILLNESS
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQP
TABLE~.CSFBIOCHEMISTRY
INEUTHYMICBIPOLARS
Unmedicated
bipolars
n=lO
Controls
II=20
Monoamines
(pmol/ml)
NE
MHPG
HVA’
DOPAC’
5-HIAA+
Peptides/hormones
(pg/ml)
NTF
/I-LPH
a-MSH
Cortisol
VIP
SRIF*
AVP
ACTHt
/%EndorphinTrlz
GABAS
(pmol/ml)
0.32
45.3
180.0
2.6
75.0
427
77.0
8.7
5800.0
17.2
33.1
4.7
22.8
40.2
+
+
f
+
*
0.20
7.9
54.0
0.9
20.0
f 194.0
* 25.0
f
4.2
f 2000.0
k
8.4
* 14.0
zk
1.o
f
5.8
f
6.9
127.0 f
ANDCONTROLS
50.0
0.34
44.2
178.0
2.3
92.3
457.0
87.0
8.8
6700.0
20.2
43.8
4.7
22.3
39.2
+
+
f
+
k
0.21
7.0
72.0
0.9
41.4
-t 228.0
k 36.0
k
3.2
k 1600.0
k
7.6
k 18.0
k
2.1
f
5.4
k
6.8
129.0 k
36.0
Lithium-treated
bipolars
n=20
0.59
51.3
183.0
2.6
94.7
-c
+
-t
+
*
428.0
86.0
9.8
7400
15.0
29.6
4.5
21.4
37.8
k 217.0
? 27.0
?
3.0
~3100.0
k
6.6
k 10.0
k
0.9
f
5.8
f
7.5
134.0 f
0.5 1
25.6
58.0
1.0
31.7
32.0
Values are mean -CSD.
No significant (p < 0.01) group differences were found.
*Corrected for height and weight.
*Corrected for sex.
*Corrected for age.
For abbreviations. see text.
Reports of decreased CSF vasopressin
[AVP (GOLD et al., 1981)], CSF vasoactive
[SRIF (RUBINOW
intestinal
peptide [VIP (GJERRIS et al., 1982)] and CSF somatostatin
et al., 1982)] in depressed patients prompted
us (Berrettini,
W. H., Nurnberger,
J. I.,
Reichlin, S., Zerbe, R. L., Simmons-Alling,
S., Gershon, E.S., unpublished
observation)
to measure these peptides by RIA in euthymic patients. None of these substances differentiated euthymic patients from controls, suggesting that these reported abnormalities
may
be state dependent.
GJERIUS et al. (1982) reported decreased CSF VIP concentration
in a
subgroup of atypical depressed patients, while endogenously
depressed patients had values
similar to controls.
We found no differences
between euthymic unmedicated
bipolars
and controls (Table 2). Differences
in patient population
may explain these results. A
strong correlation
was found among the patients and controls between CSF SRIF and
CSF VIP (see Fig. 2). Lithium treatment seemed to decrease both CSF and plasma VIP
(see Figs 3 and 4).
A series of CSF substances associated with hypothalamic-pituitary-adrenal
(HPA) axis
function were measured, because a dysregulation
of this axis (abnormal
dexamethasone
suppression
test [DST]) commonly
occurs in depression
(CARROLL et al., 1981). This
340 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
WADE H.BERRETTINI~~~L
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFED
180
r
.
..
z
120-
1
E”
.
Sloe-
2
.
.
.
y EOIn
60
.
-
l
-
. .
l
..
.
.
.:*
l.
l.
40
. :. . -.
. ”
. . .
.
.
:
l
.
.
1,,,1,,11
20-1
50
,,,,,,,,,,j
90
130
170
210
250
WA
FIG. 1. Correlation
of CSF S-HIAA
290
330
370
410
450
(pmolimli
and CSF HVA in normal
volunteers
and bipolar
patients.
90
80
r
69
p-
Ocol
70
n = 42
.
60
.
550
.
z
.
40
. .
.
. .
.
30
20
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.. .
.
10
.
.
0
5
I
I
r
I
6
7
8
9
I1
1
10 11 12
I
I
13 14
I
I
,
15 16 17
,
18
1,
19
I
20
I
I,
21 22 23
I,
24 25 26
VIP
Fm. 2. Correlation
of CSF SRIF and CSF VIP.
,
1
27 28
I
,
29 30
I
I
31 32
,
I
33 34
I,
35 36
341
Unmedicated
Lrthrum-Treated
p=
0.01
(pafred
t
test)
FIO. 3. Lithium decreases plasma VIP,
Unmed i cat ed
Lithium-Treated
p =
(paired
0.0005
t
test)
Ra. 4. Lithium decreases CSF VIP.
WADEHzyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJ
. BERRETTINI
e t a zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQ
l.
342
abnormality
is thought to be state-dependent.
It was hypothesized
that the abnormal DST
might be the result of an underlying
genetic vulnerability
marker for affective illness.
The polypeptide pro-opiomelanocortin
(POMC) is synthesized, released and metabolized
in response to corticotropin releasing factor (CRF). POMC is cleaved to yield an N-terminal
fragment (NTF), corticotropin
(ACTH), beta-lipotropin
(beta-LPH),
alpha-melanocyte
stimulating
hormone (alpha-MSH),
beta-endorphin
and related peptides (CHR~TIEN et al.,
1979).
Plasma and CSF levels (as detemined by RIA) of substances produced by the HPA axis
(NTF, beta-LPH,
alpha-MSH,
ACTH and beta-endorphin)
were not different between
patients and controls (see Table 2; BERRETTINI et al., 1984).
These data suggest that the abnormal DST result in affectively ill patients is not associated
with an underlying
state-independent
abnormality
in HPA axis function.
However,
more work needs to be done to strengthen this argument.
GABA studies
Several measures of gamma-aminobutyric
acid (GABA) metabolism were determined in
this patient population.
GOLD et al. (1980), GERNER and HARE (1981), and KASA et al.
(1982) found low CSF GABA in unmedicated
depressed patients. PETTY and SCHLESSER
(1981) found low plasma GABA in some depressed patients on various medications.
Lithium - Tre a te d
Unm e dic a te d
I
\
p
=
,003
\
+
x=
S.D.
N=
f
p=
36.
i
i’
,001
/
L
x=
1
197.
S.D.
45.
N
x
S.D.
N
FIG.
C o ntro ls
=
f
=
197.
30.
56.
171.
Z!C
=
34.
31.
5. Plasma GABA (pmoVm1) in euthymic bipolars.
These studies prompted
measurements
of CSF GABA,
which did not differentiate
euthymic bipolars from controls (see Table 2). Platelet GABA-transaminase
[GABA-T
(BERRETTINI et al., 1982b)] and plasma GABA (BERRETTINI et al., 1982a, 1983) were
found to be lower in euthymic bipolars (Figs 5 and 6). Both these measures were con-
GENETI~SANDAFFECTIVE
Lithium-Treated
F? =
SD. f
N =
lpmol/min/mg
ILLNESS
343
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQ
Unmed i cot ed
11.8
ii =
6.0
S.D. f
28.
N =
10.6
4.1
27.
5? =
S.D. f
N =
13.5
6.2
56.
protein
FIG. 6. Platelet
GABA-T+ in euthymic
bipolars and controls.
cordant in monozygotic
twins (Fig. 7, data for GABA-T not shown). This suggests that
low plasma GABA may be a genetic vulnerability
factor. Interestingly,
we found that
lithium treatment tends to increase plasma GABA (BERRETTINI et al., 1983), which may
explain the contradiction
between our data and those of PETTY and SHERMAN (1982), who
found increased plasma GABA in lithium treated remitted bipolars, but lower plasma
GABA in unipolar depressed patients who were not taking lithium. Family studies are
required to determine
whether plasma GABA differentiates
ill from well relatives in
pedigrees in which the proband has low plasma GABA. The origin or physiologic
significance of plasma GABA is unknown.
No significant correlation
between plasma and
CSF GABA was found, although pharmacologic
blockade of GABA metabolism
leads to
increases in brain, CSF and plasma GABA (LOSCHER, 1979).
‘H-Imipramine binding to platelets
Recently several studies of 3H-imipramine
binding to platelets from depressed subjects
have reported decreased maximal binding (B,~ without any change in affinity (RAISMAN
et al., 1981; PAUL et al., 1982; ASARCH et al., 1980).
USMAN et al. (1981) reported that the B,, remained low after recovery in a group
treated with tricyclics. However, BERRETTINI et al. (1982~) and SURANYI-CADOTTE et al.
(1982) found no difference
between controls
and euthymic
patients
who had been
recovered for 2 months or more. Thus, it is controversial
whether low B,, is a stateindependent
marker. Most optimistically
it may remain low in a subgroup of recovered
patients, although all 10 depressed patients, studied by SURANYI-CADOTTE et al. (1982),
showed robust increases in B,,, 2 months after recovery. This increase seemed to be
independent
of tricyclic medication.
344
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
WADE H. BERRETTINIet al.
_B_
INTRACLASS
I= 72
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQP
P= 007
FIG. 7. Plasma GABA in monozygotic
twins.
Melatonin studies
Melatonin
is secreted by the pineal gland at high levels during dark hours. Levels are
very low during daylight hours. Bright room lighting (2500 lux) at night will suppress
melatonin secretion (LEWY et al., 1980). Normal room lighting at night (less than 500 lux)
will not suppress melatonin
secretion in most individuals,
but LEWY et al. (1981) found
suppression
with 500 lux in two manic and two depressed patients.
This led them to
speculate that affectively
ill patients are supersensitive
to light’s effect on melatonin
secretion.
NURNBER~ER et al. (1983b) showed that this supersensitivity
was detectable
in 11 euthymic unmedicated patients, compared with 24 controls. Suppression of melatonin
secretion was greater in the patients (p < 0.005).
The neuronal pathway from retina to hypothalamus
mediates this response. There is
evidence that acetycholine
may be the pertinent neurotransmitter
in this tract (ZATZ and
BROWNSTEIN, 1979). If the melatonin
response is dependent
on a cholinergic
synapse,
then this result is compatible
with a state-independent
cholinergic
supersensitivity
in
affective illness, although this may be a nicotinic (not muscarinic)
cholinergic response.
Cholinergic REM induction
A second series of studies suggests that cholinergic
supersensitivity
may be a genetic
vulnerability
marker in affective illness. SITARAM et al. (1980, 1982) showed that euthymic
unmedicated
patients entered their second REM sleep period significantly
more rapidly
@ < 0.001) than did controls
following
an intravenous
0.5 mg dose of arecoline (a
cholinergic agonist), given 25 min after the end of the first REM period. Interestingly,
this difference
disappeared
when a 1.0 mg dose of arecoline was used. At this dose
controls entered the second REM period as fast as patients.
NURNBERGER et al. (1983~) studied cholinergic
REM induction
in seven monozygotic
twin pairs. Included in this sample were four twin pairs discordant
for minor (n = 3) or
major (n = 1) depression (criteria of MAZURE and GERSHON, 1979). The REM induction
time following arecoline was concordant
in these seven twin pairs (p < 0.02). One twin
pair showed a rapid induction,
but did not have any history of minor or major depression.
In contrast to the arecoline induced second REM period, the endogenous
time from first
to second REM period was not concordant
0, = 0.44).
These studies suggest that euthymic
patients
are supersensitive
to the cholinergic
GENETICSANDAFFE~TNEILLNESS
345
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPO
induction of REM sleep, and that this phenomenon is heritable. It remains to be determined whether the cholinergic REM induction test will differentiate ill from well relatives
in pedigrees in which the probands show the cholinergic supersensitivity.
A more recent observation of cholinergic supersensitivity was made by NADI et al. (1984)
who showed that fibroblasts possess a muscarinic binding site. The number of binding
sites on fibroblasts from bipolar patients and their ill relatives is significantly greater than
the number of sites on fibroblasts from the well relatives and controls.
Tyramine conjugation
SANDLER et al. (1975) first reported that depressed patients excrete a decreased amount
of conjugated tyramine in urine after an oral dose of 100 mg of tyramine. Subsequently,
they reported that this phenomenon was detectable in recovered patients as well (BONHAM
CARTER et al., 1978a). Their finding have been recently replicated in endogenously
depressed outpatients before and after recovery (HARRISON et al., 1983). Interestingly,
a much higher incidence of affective disorder (73.3%) was found among the lowest
tyramine excreters compared to the highest excreters (26.7%) from among 77 pregnant
women screened for tyramine excretion after oral challenge (BONHAM CARTER et cd.,
1980). Platelet levels of the conjugating enzyme, phenolsulfotransferase,
do not explain
the difference (SANDLER et al.,1983), nor do changes in gastrointestinal motility seem
to be responsible (BONHAM CARTER et al., 1978b).
This deficit may be a trait marker for the illness, but demonstration of genetic control
and pedigree studies are required.
DISCUSSION
JANOWSKY et al. (1972) proposed that mania and depression might be associated with
an imbalance between cholinergic and adrenergic systems in the brain. Both the cholinergic
REM induction test reports and the melatonin studies are compatible with a stateindependent genetically-determined cholinergic supersensitivity in affective illness. The
hypothesis of cholinergic supersensitivity in affective illness has been given further
support by the recent discovery that fibroblasts of bipolar patients and their ill relatives
have significantly greater numbers of muscarinic cholinergic receptors than do controls
(NADI et al., 1984). Thus, several lines of evidence are compatible with a cholinergic
supersensitivity in affective illness. This represents a promising area of investigation in the
genetics of affective disorders.
A second promising area may be the study of euthymic patients who have low CSF
5-HIAA. Here again several lines of evidence support the possibility that low CSF 5-HIAA
may be a genetic marker for vulnerability to affective illness. There are studies indicating
that CSF 5-HIAA is heritable, that it remains low in some recovered patients and that
it may be associated with violent suicide, a relatively common occurrence in depression.
The arduous task of determining CSF 5-HIAA in pedigrees remains to be done. It would
be quite interesting to study these individuals with other serotonergic probes, such as
platelet serotonin uptake and ‘H-imipramine binding. Perhaps these are the individuals in
whom RAWUN et al. (1981) find low numbers of ‘H-imipramine binding sites even after
recovery.
346
WADE H. BERRETTINIet al.
Other promising areas of investigation include plasma GABA and tyramine conjugation.
Pedigree studies are needed for both these parameters.
This paper has presented some promising areas of investigation
in genetics of affective
illness. This review is not intended to be comprehensive;
other areas of intensive research
in genetics of affective illness, such as lithium ratio (DORUS et al., 1983; PANDEY et al.,
1979) have not been discussed.
REFERENCES
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONML
neurotransmission-state,
traits and interactions.
In Origins of
(Edited by ANGST, J.). Springer, Berlin.
ASARCH, K. B., SHIH, J. C. and KUBESAR, A. (1980) Decreased ‘H-imipramine
binding in depressed males and
females. Commun. Psychophormac.
4,425-430.
BARON, M. (1977) Linkage between an X-chromosome
marker (deutan color-blindness)
and bipolar affective
illness. Archsgen.
Psychiat. 34721-725.
BECKMAN, L., CEDEROREN, B., PERRIS, C. and STRANDMAN, E. (I978a) Blood groups and affective disorders.
AOREN, H. (1982)
Depression:
Depression
Current Concepts
and altered
ond Approaches
Hum. Hered. 28,48-55.
BECKMAN, L.,
PERRIS, C.,
STRANDMAN, E. and WAHLBY, L. (1978b)
HLA
antigens
and affective
disorders.
Hum. Hered. 28,96-99.
BERRETTPII, W. H., NURNBEROER, J. I., JR., HARE, T., GERSHON, E. S. and POST, R. M. (1982a) Plasma and
CSF GABA in affective illness. Br. J. Psych&.
141,483-487.
BERRETTINI, W. H., UMBERKOMAN-WIITA, B., NURNBEROER, J. I., JR., VOGEL, W. H., GERSHON, E. S. and
POST, R. M. (1982b) Platelet GABA-transaminase
in affective illness. Psychiot. Res. 7,255-260.
BERRETTINI, W. H., NURNBEROER, J. I., JR., POST, R. M. and GERSHON, E. S. (1982~) Platelet ‘H-imipramine
binding in euthymic bipolar patients. Psych&.
Res. 7,215-219.
BERRETTINI, W. H., NURNBEROER, J. I., JR., HARE, T., SIMMONS-ALLINO, S., GERSHON, E. S. and POST, R. M.
(1983) Reduced plasma and CSF GABA in affective illness: effect of lithium carbonate.
&of. Psych&.
18,
185-194.
BERRETTINI, W. H., NURNBEROER, J. I., JR., CHROUSOS, G., SEIDAH, N. G., GOLD, P. W., CHR~TIEN, M.,
CHAN, J., SIMMONS-ALLINO, S. and GERSHON, E. S. (1984) Proopiomelanocortin-related
peptides in CSF.
Presented at the 1984 C.I.N.P.
Meeting, Florence, 1984.
BONHAM CARTER, S. M., REVELEY, M. A., SANDLER, M., DEWHURST, J., LITTLE, B. C., HAYWORTH, J. and
PRIEST, R. G. (1980) Decreased urinary output of conjugated
tyramine is associated with lifetime vulnerability to depressive illness. Psych&.
Res. 3, 13-21.
BONHAM CARTER, S., SANDLER, M., GOODWIN, B. L., SEPPINO, P. and BRIDGES, P. K. (1978a) Decreased urinary
output of tyramine and its metabolites in depression. Br. J. Psych&.
132, 125-132.
BONHAM CARTER, S., SANDLER, M., SEPPING, G. and BRIDGES, P. K. (1978b) Decreased conjugated
tyramine
outputs in depression: gastrointestinal factors. Br. J. c/in. Phormac. 5,269-271.
CARROLL, B. J., FEINBERO, M., GREDEN, J. F., TARIKA, J. S., ALBALA, A. A., HASKELL, R. F., JAMES, N. MCI.,
KRONFOL, Z., LOHR, N., STEINER, M., DEVIONE, J. P. ard YOUNG, E. (1981) A specific laboratory test for
the diagnosis of melancholia:
standardization,
validation and clinical utility. Archs gen. Psychiot. 38, 15-22.
CH~~TIEN, M., BENJANNET, S., GOSSARD, G., GIANORLAKIS, C., CRINE, P., LIS, M. and SEIDAH, N. G. (1979)
From beta-lipotropin
to beta-endorphin
and pro-opio-melanocortin.
Can. J. Biochem. 57, 111 I-l 121.
CLEROET-DARPOUX, F. (1982) Bias of the estimated recombination
fraction and lod score due to an association
between a disease gene and a marker gene. Ann. hum. Genet. 46,363-372.
CLERGET-DARPOUX, F. (In press) Analysis for HLA-association
with diseases: terminology,
methodology
and
interpretation.
In Compendium
of Immunology, Vol. 4 (Edited by SCHWARTZ, L.). Van Nostrand, Reinhold,
New York.
CKOWE, R. R., NAMBOODIRI, K. K., ASHBY, H. B. and ELSTON, R. C. (1981) Segregation and linkage analysis
of a large kindred of unipolar depression. Neuropsychobiology
7,20-25.
DAY, N. E. and SIMONS, M. J. (1976) Disease susceptibility genes-their
identification
by multiple case family
studies. Tissue Antigens 8, 109-l 19.
DUNNER, D. L., FLEISS, J. L., ADDONIZIO, G. and FIEVE, R. R. (1976) Assortative mating in primary affective
disorders. Biol. Psychiaf. 11,43-51.
EGELAND, J. (1980) Affective disorders among the Amish: 1976-1980.
Presented at the Annual Meeting of the
American College of Neuropsychopharmacology,
Puerto Rico, December.
FIEVE, R. R., MENDLEWICZ, J. and FLEISS, J. L. (1973) Manic-depressive
illness: linkage with the Xg blood
group. Am. J. Psychiut. 130, 1355-1359.
GENETICS AND AFFECTIVE ILLNESS
FLEMENBAUM,A. and LARSEN, J. W. (1976) ABO-Rh
blood
347
groups and psychiatric
diagnosis:
a critical review.
Dis. nerv. Syst. 31,581-583.
GERNER, R. H. and HARE, T. A. (1981) CSF GABA
in normals,
depression,
schizophrenia,
mania and anorexia
nervosa. Am. J. Psychiat. 138,1098-l 101.
GERSHON, E. S., DUNNER, D. L., STURT, L. and GOODWIN, F. K. (1973) Assortative mating in the affective
disorders. Biol. Psychiat. 1,63-74.
GERSHON, E. S., MARK, A., COHEN, N., BELIZON, N., BARON, M. and KNOBE, K. E. (1975) Transmitted
factors in the morbidity of affective disorders: a controlled study. J. psychiat. Res. 12,283-299.
GERSHON, E. S. and BUNNEY, W. E., JR. (1977) The question of X-linkage in bipolar manic-depressive
illness.
J. psych&. Res. 12.301-317.
GERSHON, E. S., TARGUM, S. D., MATTHYSSE, S. and BTJNNEY, W. E., JR. (1979) Color blindness not closely
linked to bipolar illness. Archsgen. Psychiat. 36,1423-1434.
GERSHON, E. S. and LIEBO~ITZ, J. H. (1979) Affective
illness. In Genetic Diseases Among Ashkenazi Jews
(Edited by GOODM A N,R. M . and MOTULSKY, A. G.), pp. 343-352. Raven Press, New York.
GERSHON, E. S., MENDLEWICZ, J., GASTPAR, M., BECH, P., GOLDIN, L. R., KIELHOLZ, P., RAFAELSEN, 0. J.,
VARTANIAN, F. and BUNNEY, W. E., JR. (1980) A collaborative
study of genetic linkage of bipolar manicdepressive illness and red/green colorblindness.
Actapsychiat. stand. 61,3 19-338.
GJERRIS, A ., FAHRENKRUG, J., HAMMER, M., SCHAFFALITZKYDE MUCKADELL, 0. P., BOJHOLM, S., VENDSBORG,
P. and RAFAELSEN, 0. J. (1982) In Proceedings of the 3rd World Congress of Biological Psychiatry (Edited
by JANSSON, B., PERRIS, C. and STREW, G.), Abstract 237. Elsevier, Amsterdam.
GOETZL, V., GREEN, R., WHYBROW, P. and JACKSON, L. (1974) X-linkage revisited: a further family study of
manic-depressive.
Archsgen. Psychiat. 31,665-672.
GOLD, B. I., BOWERS, M. B., JR., ROTH, R. H. and SWEENEY, D. W. (1980) GABA levels in CSF of
patients with psychiatric disorders. Am. J. Psychiat. 137,362-364.
GOLD, P. W., GOODWIN, F. K., POST, R. M. and ROBERTSON, G. L. (1981) Vasopressin function in depression
and mania. Psychopharmac. Bull. 17,7-10.
GOLDIN, L. R., CLER~ET-DARPOUX, F. and GERSHON, E. S. (1982) Relationship
of HLA to major affective
disorder not supported. Psychiat. Res. 7,29-45.
GOLDIN, L. R., GERSHON, E. S., TARGUM, S. D., SPARKES, R. S. and MCGINNIS, M. (1983) Segregation and
linkage analyses in families of patients with bipolar, unipolar, and schizoaffective
mood disorders. Am. J.
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
hum. Genet. 35,274-287.
GOVAERTS, A., MENDLEWICZ, J. and VERBANK, P. (1977) Manic-depressive
illness and HLA. Tissue Antigens
10,6&62.
GREEN, J. R. and WOODROW, J. C. (1977) Sibling method for detecting HLA-linked
genes in disease. Tissue
Antigens9,31-35.
HARRISON, W. M., COOPER, T. B., QUITKIN, F. M., LEIBOWITZ, M. R., MCGRATH, P. J., STEWART, J. W.
and KLEIN, D. F. (1983) Tyramine sulfate excretion test in depressive illness. Psychopharmac. Bull. 19,
503-504.
JAMES, N. M., CARROLL, B. J., HAINES, R. F. and SMOUSE, P. E. (1979) Affective disorders: ABO and HLA.
In Genetic Aspects of Affective Zlbzess (Edited by MENDLEWICZ, J. and SHOPSIN, B.), pp. 35-44. Spectrum
Publications,
New York.
JAM ES, N. M ., SM OUSE, P. E., CARROLL, B. J. and HAINES, R. F. (1980) Affective
illness and HLA frequencies:
no compellling association. Neuropsychobiology 6,208-216.
JANOW SKY, D. S., EL-YOUSEF, M. K. and DAVIS, J. M. (1972) Cholinergic-adrenergic
hypothesis of mania and
depression. Lancet ii,632.
JOHNSON. G. F. S. (1978) HLA antigens and manic-depressive
disorders. Biol. Psychiat. 13, w-412.
KASA, K.‘, SA~JRO; ~.,‘MITSUTOSH~, Y., MITSUMOTO; S., KURODA, H. and O&WA,
N. (1982) CSF GABA and
HVA in depressive disorders. Biol. Psychiat. 17,877-884.
KOSLOW, S. H., MAAS, J. W., BOWDEN, C. L., DAVIS, J. M., HANIN, I. and JAVA~D, J. (1983) CSF and urinary
biogenic amines and metabolites in depression and mania: a controlled univariate analysis. Archs gen. Psychiat.
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
40,999.
KRUGER, S. D., TURNER, W. J. and KIDD, K. K. (1982) The effects of requisite assumptions
on linkage
analyses of manic-depressive
illness with HLA. Biol. Psychiat. 17, 1081-1099.
LECKMAN, J. F., GERSHON, E. S., MCGINNISS, M. H., TARGUM, S. D. and DIBBLE, E. D. (1979) New data do not
suggest linkage between the Xg blood group and bipolar illness. Archsgen. Psychiat. 36,1435-1441.
LEVITAN, M. and MONTAGU, A. (1971) A Textbook of Human Genetics. Oxford University Press, London.
LEWY, A. J., WEHR, T. A. and GOODWIN, F. K. (1980) Light suppresses melatonin secretion in humans.
Science210,1267-1270.
WADE H. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGF
BERRETTINIet al.
348
LEV~Y, A. J., WEHR, T. A., GOODWIN,
F. K., NEUSOME, D. A. and ROSENTHAL, N. E. (1981) Manic-depressive
patients may be supersensitive
to light. Luncet ii, 303-304.
L&CHER, W. (1979) GABA in plasma and CSF of different species. Effects of y-acetylenic GABA, y-vinyl GABA,
and sodium valproate. J. Neurochem.
32,1587-1891.
MAZURE, C. and GERSHON, E. S. (1979) Blindness and reliability in lifetime psychiatric
diagnosis. Archs gen.
P&riot.
127, l-10.
MENDLE~~CZ, J., FLEISS, J. L., FIEVE, R. R. (1972) Evidence for X-linkage in the transmission
of manic-depressive
illness. J. Am. med. Ass. 222.1624-1627.
MENDLE\KICZ, J., MA~SART-GUIOT, T., W~LMOTTE, J. and FLEISS, J. L. (1974) Blood groups in manic-depressive
illness and schizophrenia.
Dis. nerv. Syst. 35,39-41.
MENDLEWICZ,
J., FLEtss, J. L. (1974) Linkage studies with X-chromosome
markers in bipolar (manic-depressive)
and unipolar (depressive) illness. Biol. Psychiut. 9,261-264.
MENDLEWICZ, J. (1977) Genetic studies in schizoaffective
illness. In The Impact of Biology on Modern
Psychiutry (Edited by GERSHON, E. S., BELUKER, R. H., KETY, S. S. and ROSENBAUM, M. R.), pp. 229-240.
Plenum Press, New York.
MENDLEU~ICZ, J., L~KOWSKI, P. and WUMOTTE, J. (1980) Linkage between glucose 6-phosphate
dehydrogenase
deficiency and manic-depressive
psychosis. Br. J. Psychiut. 134,337-342.
MENDLE\KICZ, J., VERBANCK, P., LINKOWSKI, P. and G~VAERTS, A. (1981) HLA antigens in affective disorders
and schizophrenia.
J. &feet. Dis. 3, 17-24.
MORTON, L. A. and KIDD, K. K. (1980) The effects of variable age of onset and diagnostic
criteria on the
estimates of linkage. An example using manic-depressive
illness and color blindness.
Sot. Biol. 27, l-10.
MORTON, N. E. (1955) Sequential tests for the detection of linkage. Am. J. hum. Genet. 7,277-318.
MORTON, N. E. (1956) The detection and estimation
of linkage between the genes for elliptocytosis
and the
Rh blood group. Am. J. hum. Genet. 8,80-96.
NADI, N. S., NURNBEROER, J. I., JR. and GERSHON, E. S. (1984) Muscarinic
cholinergic
receptors on skin
fibroblasts in familial affective disorders. New Engl. J. Med., in press.
NEORI, F., MELLICA, A. M., ZULICPTI, R., GASPERINI, M., MARCIARDI, F. and SMERUDI, E. (1981) Genetic
implication in assortative mating of affective disorders. Br. J. Psychiut. 138,236-239.
NURNBEROER, J. I., JR. and GERSHON, E. S. (1982) Genetics of affective disorders.
In Hundbook of Mfective
Dborders (Edited by PA~~~EL, E.), pp. 126-145. Churchill Livingstone, London.
NURNBEROER, J. L., JR., BERRETTINI, W. H., SCHEININ, M., SIMMONS-ALLINO, S., LINNOILA, M. and GERSHON,
E. S. (1983a) CSF monoamine
metabolites in “well state” bipolar patients and normal volunteers.
Abstracts
of the 1983 Annual Meeting of the Society for Biological Psychiatry,
No. 58, p. 92.
NURNBEROER, J. I., JR., LEWY, A. J., PACK, D., BECKER, L., WEHR, T. A., POHZLL, R. L., SIMMONS-ALLINO,
S. and GERSHON, E. S. (1983b) Bipolar patients are supersensitive
to light. Abstracts
of the 1983 Annual
Meeting of the American Psychiatric Association.
NURNBEROER. J. I.. JR.. SIT&AM, N.. GERSHON, E. S. and GILLIN. J. C. (1983~) A twin study of cholinernic
REM induction. biol. Psychiut. i8, i 161-1173..
OTT, J. (1974) Estimation
of the recombination
fraction in human pedigree: efficient computation
of the
likelihood for human linkage. Am. J. hum. Genet. x.588-597.
PANDEY, G. N., TORUS, E., DALLY,J. M. and TOSTESON, D. C. (1979) Lithium transport in human red blood cells.
Genetic and clinical aspects. Archsgm. Psychiut. 36.902-908.
PARKER, J. B., THEILLIE, A. and SPIELBEROER, C. D. (1961) Frequency of blood types in an homogeneous
group
of manic-depressive
patients. J. ment. Sci. 107,936-942.
PENROSE, L. S. (1935) The detection of autosomal linkage in data which consists of pairs of brothers and sisters
of unspecified parentage. Ann. Eugen. 6,133-138.
PENROSE, L. S. (1953) The general purpose sib-pair linkage test. Ann. Eugen. 18, 120-124.
PETTY, F. and SCHLESSER, M. A. (1981) Plasma GABA in affective illness. J. clffect. Dis. 3,334-343.
PETTY, F. and SHERMAN, A. D. (1982). Plasma GABA: a blood test for bipolar affective disorder trait?
Res. Commun. Psychol. Psychiut. Behuv. 7,431-W.
PAUL, S. M., REHAVI, M., SKOLNICK, P., BALLENOER, J. C. and GOODWIN, F. K. (1982) Depressed patients
have decreased binding of tritiated imipramine
to platelet serotonin “transporter”.
Archs gen. Psychiut. 38,
1315-1320.
RAISMAN,R., SECHTER, D., BRILEY, M. S., ZARIRAN, E. and LANCER, S. Z. (1981) High-affinity
binding
in platelets
from untreated
and treated
depressed
patients
compared
to healthy
3H-imipramine
volunteers.
Psycho-
phurmucology 75,368-372.
RIEDER, R. 0. and GERSHON, E. S. (1978) Genetic
strategies
in biological
psychiatry.
Archs gen. Psych&.
35,
866-873.
P. M., STEFANIS, C. N., LYKOURAS, E. P. and VARSOU, E. K. (1979) Affective
blood types. Actu Psychiut. Scund. 60,272-278.
RINIERIS,
disorders
and ABO
GENETICS ANDAFFECTIVE
ILLNESS
349
Rrscrr, N. and BARON,M. (1982) X-linkage and genetic heterogeneity in bipolar-related major affective illness:
reanalysis of linkage data. Ann. hum. Genet. 46,153-166.
Runprow, D. R., GOLD, P. W., POST, R. M., BALLENOER,
J. C., COWDRY,R., B~LLINOER,J. and REICHLIN,S.
(1983) CSF somatostatin in affective illness. Archsgen. Psychiat. 40.409-412.
SANDLER,M., Bow
CARTER,S., CUTHBERT,M. F. and PARE, C. M. B. (1975) Is there a decrease in monoamineoxidase activity in depressive illness? Loncet 1,1045-1048.
SANDLER,M., B~NWM CARTER,S. M. and WALKER,P. L. (1983) Tyramine conjugation deficit as a trait-marker
in depression. Psychopharmac. Bull. 19,501-502.
SEDVAU,G., Fvao, B., GUL.LBERO,
B., MYBACK, H., WIESEL, F.-A. and WODE-HELOODT,
B. (1980) Relationships
in healthy volunteers between concentrations of monoamine metabolites in cerebrospinal fluid and family
history of psychiatric morbidity. Br. J. Psychiat. l&366-374.
SEDVALL, G. and OWNSTIERNA,G. (1981) Genetic and environmental influences on central monoaminergic
mechanisms in man. Abstract No. 5344, Third World Congress of Biological Psychiatry, Stockholm.
SHAPIRO,R. W., BOCK, E., RAFAELSEN, 0. J., RYDER,L. P. and
A. (1976)
Archsgen.
R. W., RAFAELSEN, 0. J.,
L. P.,
A. and SORENSEN, H. (1977a)
in
unipolar
J. Psychiut.
R. W.,
L. P.,
A. and
0.
of
SINISCALCO, M., SZABO,P., FILIPPI, F. and RnULDI, A. (1982) Combination of old and new strategies for the
molecular mapping of the human X-chromosome. In Human Genetics, Part A: The Unfolding Genome
(Edited by B~NNE-TA~QI~,
B.), pp. 103-124. Alan R. Liss, New York.
SITARAM,N., NURNBEROER,
J. I., JR., GERSHON, E. S. and GALLON,
J. C. (1980) Faster cholinergic REM sleep
induction in euthymic patients with primary affective illness. Science 208,200-202.
SITARAM,N., N~J~NBEROER,
J. I., JR., GERSHON,E. S. and GILLIN,J. C. (1982) Cholinergic regulation of mood
and REM sleep: potential model and marker of vulnerability to affective disorder. Am. J. Psychiat. 139,
571-576.
SMERUDI, E., NEO~U,F., MELICA,A. M., SCORW-SMEULDI,R., FABIO,G., BONARA,
P., BBLLODI,
L., SACCHE~,
E., S~BA~INI-VILLA,M. G., CU~JLLO, C. L. and ZANUSSI,C. (1978a) HLA typing and affective disorders: a
study in the Italian population. Neuropsychobiology 4,344352.
SME~ULDI,
E., NEORI,F., MELICA,A. M. and SCORW-SMERUDI,R. (1978b) HLA system and affective disorders:
a sibship genetic study. Tissue Antigens 12,270-274.
SMEULDI, E. and BELLODI,L. (1981) Possible linkage between primary affective disorder susceptibility locus
and HLA haplotypes. Am. J. Psychiat. 138.1232-1234.
SMOUSE,P. E. and W~L~AMS,R. C. (1982) Multivariate analysis of HLA-disease associations. Biometrics 38,
757-768.
SPENCE,M. A. (1980) Linkage methods in psychiatric disorders. In Genetic Strategies for Psychobiology and
Psychiatry (Edited by GERSHON, E. S., MATTHYSSE,S., BREAKEFIELD,X. 0. and CLUUNELLO,R. D.),
pp. 295-304. Boxwood Press, Pacific Grove, CA.
STEMBER,R. H. and Fmva, R. R. (1977) Histocompatibility antigens in affective disorders. C/in. Immunol.
Immunopath. 7,10-14.
SUAREZ,B. K. (1978). The affected sib-pair IBD distribution for HLA linked disease suspectibility loci.
Tissue Antigens 12.87-93.
SUAREZ, B. K., RICE, J. and REICH, T. (1978) The generalized sib-pair IBD distribution: its use in the detection
of linkage. Ann. hum. Genet. 42,87-94.
SUAREZ,B. K. and CROUOHAN,J. (1982) Is the major histocompatibility complex linked to aenes that increase
susceptibility to affective disorders? A critical appraisal. Psychiat. Res: 7,19127.
SUAREZ,B. K. and VAN EERDEWEOH.P. (1981) Tvue I insulin-deuendent diabetic mellitus. Diabetoloaia
_ 20.I
524-529.
SUIUNYI-CADOTTE,
B. E., WOOD, P. L., NAIR, N. P. V. and SCHWARTZ,0. (1982) Normalization of platelet
3H-imipramine binding in depressed patients during remission. Eur. J. Pharmac. 85,357-358.
SWANN,A. C., SECUNDA,S., DAMPS,J. M., ROBINS,E., HANIN,I., KOSLOW,S. H. and MMS, J. W. (1983) CSF
monoamine metabolites in mania. Am. J. Psychiot. 140,396.
TANNA,V. L. and WINOKUR, 0. (1968) A study of association and linkage of ABO blood types and primary
affective disorders. Br. J. Psychiot. 114, 1175-l 181.
TANNA,V. L., WINOKUR,G., ELSTON,R. C. and Go, R. C. P. (1976) A linkage study of depression spectrum
disease. The use of the sib-pair method. Neuropsychobiology 2,52-62.
TANNA,V. L., Go, R. C. P., WINOKUR,G. and ELSTON,R. C. (1979) Possible linkage between a-haptoglobin
and depression spectrum disease. Neuropsychobiology 5,102-l 13.
350 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
WADE H . BERRETTINIet al.
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
TARGUM, S. D., GERSHON, E. S., VAN EERDEWEGH, M. and ROOENTINE, N. (1979) Human leukocyte antigen
system not closely linked to or associated with bipolar manic-depressive
illness. Biol. Psychiat. 14,615-636.
TEMPLE, H., DUPONT, B. and SHOPSIN, B. (1979) HLA antigen and affective disorders: a report and critical
assessment of histocompatibility
studies. Neuropsychobiology
$50-58.
THOMSON, G. (1980) A review of theoretical aspects of HLA and disease associations.
Theoret. Population Biol.
20,168-208.
THOMSON, Cl. and BODMER, W. F. (1977a) The genetics of HLA and disease associations.
In Measuring Selection
in Natural Popuhtions
(Edited by CHRISTIANSEN, F. B., FENCHAL, T. and BARNDORFF-NIELSON, 0.).
pp. 545-564. Springer, Berlin.
THOMSON, G. and BODMER, W. F. (1977b) The genetic analysis of HLA and disease associations.
In HLA and
Disease (Edited by DAUSSET, J. and SVEJGAARD, A.), pp. 84-93. Williams&Wilkins,
Baltimore.
TRASKMAN, L., ASBERG, M., BERTILSSON, L. and SJOSTRAND, L. (1981) Monoamine
metabolites
in CSF and
suicidal behavior. Archsgen.
Psychiat. 38,631-636.
TURNER, W. J. and KING, S. (1981) Two genetically distinct forms of bipolar affective disorder? Biol. Psychiat.
16,417-439.
VAN PRAAG, H. M. (1980) Central monoamine
Compreh. Psychiat. 21,30-43.
metabolism
in despresions--I.
VAN PRAAG, H. M. and DE HAAN, S. (1980) Central serotonin
vulnerability. Actapsychiat.
stand. Suppl. 280, pp. 89-103.
deficiency-a
Serotonin
factor
and related compounds.
which increases
depression
VESTERGAARD, P., SORENSEN, T., HOPPE, E., RAPHAELSEN, 0. J., YATES, C. M. and NICOLAOU, N. (1978)
Biogenic amine metabolites in cerebrospinal
fluid of patients with affective disorders. Actapsychiatscand.
58,
88-96.
WEITKAMP, L. R., PARDUE, L. H. and HUNTZINGER, R. S. (1980) Genetic marker studies in a family with
unipolar depression. Archsgen.
Psychiat. 37, 1187-1192.
WEITKAMP, L. R., STANCER, H. C., PERSAD, E., FLOOD, C. and GUTTORMSEN, S. (1981) Depressive disorders
and HLA: a gene on chromosome
6 that can affect behavior. NewEngl.
J. Med. 305,1301-1306.
WINOKUR, G., CLAYTON, P. J. and REICH, T. (1969) ManicDepressive
Illness. Mosby, St. Louis.
WINOKUR, G. (1972) Depression spectrum disease: description and family study. Compreh. Psychiat. 13, 3-8.
ZATZ, M. and BROWNSTEIN, M. J. (1979) Intraventricular carbachol mimics the effects of light on the circadian
rhythm in the rat pineal gland. Science 203,358-360.