VOL. 21, NO.
1, 1995
Twins With Schizophrenia:
Genes or Germs?
by James O. Davis and Abstract
Jeanne A. Phelps
High concordance for schizophre-
nia in monozygotic (MZ) twins
is often cited as evidence for the
etiological influence of genetics;
however, even if twins are sepa-
rated at birth, MZ twin concord-
ance is influenced by the shared
prenatal environment. Study of
the placentation status of MZ
twins provides a way to investi-
gate some prenatal influences,
including the possible role of
viral infections. The probability
of shared infections is likely to
be greater in monochorionic MZ
twin pairs than in dichorionic
pairs because of shared fetal cir-
culation in the monochorionic
pairs. We drew from published
twin studies and used reported
concordance for handedness as a
retrospective marker of placenta-
tion status. We found that MZ
twin pairs with opposite-hand
preferences were concordant for
psychosis in 9 of 15 cases (60%),
while only 18 of 56 twin pairs
(32%) with same-hand prefer-
ences were concordant for psy-
chosis. These results suggest that
shared prenatal viral infection
may account for much of the
high concordance for schizophre-
nia in identical twins.
Schizophrenia Bulletin, 21(1):
13-18, 1995.
The high concordance for schizo-
phrenia in monozygotic (MZ)
twins is usually interpreted as evi-
dence of genetic influence. Some
who study twins through pedigree
or population strategies have main-
tained that MZ twins reared apart
(MZA) "share essentially no en-
vironmental influences, and the
MZA correlation is a direct esti-
mate of heritabiliry" (Waller et al.
1990, p. 139). This widely cited
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position is untenable, however, be-
cause it discounts the influence of
the shared prenatal environment of
all twins. Smotherman and Robin-
son (1990) recently noted an unfor-
tunate tendency for researchers to
ignore the importance of the pre-
natal period: "[T]he behavioral lit-
erature is replete with examples of
experimental design, reasoning,
and conclusions that convey the
implicit assumption that the prena-
tal period is irrelevant to the
postnatal expression, function, or
development of behavior" (p. 97).
Few researchers, particularly
those concentrating on schizophre-
nia, have taken advantage of the
fact that MZ twins offer a special
opportunity to study prenatal in-
fluences. The placenta is a crit-
ically important determinant of the
prenatal environment: "It is a
physical and physiological link be-
tween mother and child, and it ex-
hibits variations with regard to
membrane type, size, shape, and
circulation which may be impor-
tant in themselves or may affect
the nutrition of the embryo or the
transport of drugs, toxins, and
other agents which can influence
brain development" (Melnick et al.
1978, p. 426). Because MZ twin-
ning produces a variety of placen-
tation arrangements or chorion
types, different types of MZ twins
may experience very different in-
trauterine environments. We con-
tend that these variations in pla-
centation, described below, are
especially relevant to investigations
of the intriguing viral hypothesis
of schizophrenia.
Reprint requests should be sent to
Dr. J.O. Davis, Dept. of Psychology,
Southwest Missouri State University,
Springfield, MO 65804-0027.
14
In approximately 40 percent of
MZ twins, twinning occurs early,
and so separate blastocysts arrive
in the uterus independently, attach
separately, and develop their own
separate placentas, chorion, and
amnions. These twins are dichori-
onic monozygotic (DC-MZ). The
fetal circulation of DC-MZ twins
is almost never connected (Bulmer
1970). On the other hand, approx-
imately 60 percent of MZ twinning
occurs in the early blastocyst
stage, with the inner cell mass
splitting into two separate cell
masses within the same blastocyst
cavity, resulting in a shared pla-
centa and chorion (and occasion-
ally one amnion). These twins are
monochorionic monozygotic (MC-
MZ). In about 90 percent of MC-
MZ twins, there is shared fetal cir-
culation (Bulmer 1970).
The placenta acts as a barrier to
infection, but it is an imperfect
barrier. Because MC twins share
blood circulation while DC twins
generally do not, MC-MZ twins
would be likely to share any in-
fection that crosses their single
shared placenta. On the other
hand, an infection might cross the
placenta of one member of a DC-
MZ twin pair (or a dizygotic pair,
all of whom are dichorionic), but
not the placenta of the cotwin. If
it can be shown that MC-MZ
twins are more concordant for
schizophrenia than DC-MZ twins,
this finding would be consistent
with the growing evidence that the
mother's exposure to infectious
disease, especially during the sec-
ond trimester of pregnancy, in-
creases the risk of later schizo-
phrenia in her child (Torrey et al.
1988; Bracha et al. 1992; Pulver et
al. 1992; Sham et al. 1992; Adams
et al. 1993).
It is important to note that
shared circulation can lead to
problems for some MC twins.
From 15 to 30 percent develop
"twin-transfusion syndrome"
(Bulmer 1970), a condition that can
cause mild to marked differences
in weight and appearance between
the twins at birth (Tan et al. 1979;
Scerbo et al. 1986). Twin-transfusion
syndrome occurs when there is a
significant degree of arteriovenous
anastomosis between the placental
circulations of the twins, such that
the twin on the arterial limb in-
fuses blood into the circulation of
the cotwin, leaving the infused
twin plethoric and the donor twin
anemic (Fanaroff and Martin 1987).
The infused twin may be larger
(up to 1,000 grams) and jaundiced
and may suffer cardiac atrophy or
polycythemia, among other health
problems, while the donor twin
may appear very pale and may
suffer from hypoglycemia, de-
creased muscle mass, and cardiac
atrophy, as well as other problems
(Scerbo et al. 1986).
Despite these intrapair differ-
ences in the 15 to 30 percent of
MC-MZ twins who suffer from
twin-transfusion syndrome, more
intrapair similarity in MC twins
than in DC twins has been found
on measures of plasma cholesterol
(Corey et al. 1976) and on meas-
ures of behavioral characteristics.
Reed et al. (1991), using dermato-
glyphics to estimate placentation
retrospectively, found that MC-MZ
pairs were more similar than DC-
MZ pairs on measures of type A
characteristics but not on measures
of cognitive function and hostility.
Munsinger (1977), using birth-
weight differences to estimate plac-
entation retrospectively, claimed
that twin-transfusion syndrome de-
creased the intrapair similarity of
IQ in MC twins, but Kamin (1978)
reanalyzed Munsinger's own data
and found the opposite effect. In
SCHIZOPHRENIA BULLETIN
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perhaps the strongest study in
terms of methodology, Melnick et
al. (1978), who worked with twin
pairs of known placentation, found
that with respect to IQ, members
of DC-MZ pairs were significantly
more discordant than members of
MC-MZ pairs. Their findings led
them to discount the influence of
twin-transfusion syndrome on in-
trapair variation in IQ: "Appar-
ently, either the frequency or the
degrees of severity of the con-
sequences of the transfusion syn-
drome or both have been over-
estimated" (Melnick et al. 1978,
p. 430).
We found no schizophrenia
studies that considered placentation
in twins. While it would be desir-
able to contrast the schizophrenia
concordance rates of MZ twins of
known placentation, the data for
this type of investigation are not
yet available. So we adopted an
interim strategy for assessing pla-
centation status retrospectively to
determine whether there is any
evidence of differences in MC-
MZ/DC-MZ concordance for
schizophrenia. For this study, we
based our strategy on hand prefer-
ence in MZ twins. The logic un-
derlying our use of handedness as
a marker and our findings are re-
ported below, followed by recom-
mendations for future research.
A variety of placentation ar-
rangements are produced by MZ
twinning. DC placentation is gen-
erally associated with twinning
that occurs up to the 4th day after
fertilization; MC placentation de-
velops in twinning that occurs
from the 4th day on. Finally, even
later twinning results in mirror
imaging (Macgillivray et al. 1975;
Springer and Deutsch 1981; Lohr
and Bracha 1992; Torrey et al.
1993), and if twinning is very late
(e.g., after the 13th day), conjoined
VOL. 21, NO. 1, 1995
twins can occur (Scerbo et al.
1986). Approximately one-fourth of
MZ twins are mirrored (Springer
and Deutsch 1981). Although it is
clear that mirroring is the result of
late twinning, the embryological
mechanisms are not completely un-
derstood. Springer and Deutsch
(1981) offer this speculation:
At some point early in develop-
ment, chemical gradients that
establish an axis of bilateral
symmetry are established in the
embryo. If the division that
forms two individuals occurs af-
ter that point (and in the proper
plane), one embryo will develop
from what was to be the left
half of the original embryo, and
one will develop from wnat was
to be the right half. [p. 112]
Mirroring is usually confined to
the ectodermal layer and only
rarely involves internal organs. MC
twins can mirror for hand prefer-
ences, birthmarks, hair swirls, and
dermal ridge patterns on hands
and feet (Springer and Deutsch
1981). Because both mirroring and
sharing a single placenta occur
as a result of late twinning, mir-
roring is a special case of MC
placentation.
Mirrored handedness is undoubt-
edly an imperfect marker of pla-
centation status, and we realize
there may be a number of prob-
lems associated with its use. First,
although there is a logical basis
for positing an association between
mirrored handedness and MC pla-
centation (i.e., both are the result
of late splitting), no one has tested
the accuracy of this marker with
samples of twins of known
placentation.
Second, statistical power would
be compromised if left-handedness
is caused by other factors. Ge-
netics, brain pathology (especially
that caused by prenatal and peri-
natal stressors), and learning all
have been proposed as other fac-
tors that could lead to the emerg-
ence of left-handedness (Halpern
and Coren 1990). However, Hal-
pern and Coren (1990) conclude
that genetic theories fail to explain
handedness patterns in twins, and
Torrey (1994) points out that, al-
though insult to the brain is
widely cited as a cause of left-
handedness, there are remarkably
few research data to support this
claim. Further, if learning reduces
the incidence of left-handedness,
then twins who were originally
mirrored for handedness would be
misclassified, once again decreasing
our statistical power.
A third problem with using
handedness as a marker is that
only MC twins who split very late
are mirror imaged, so mirroring
for handedness will fail to cor-
rectly identify the placentation
status of nonmirrored MC twins.
Thus, handedness is a very conser-
vative marker in the sense that it
reduces the number of twin pairs
that can be used, which makes
statistical significance harder to
achieve. Although we can be rea-
sonably certain that mirrored MZ
twins are indeed MC, not all MC-
MZ twins are mirrored, and non-
mirrored twins will be classified
into the DC group by this marker.
In summary, studies of placenta-
tion status in MZ twins provide a
way to assess the possible effects
of prenatal influences and particu-
larly the role of infections. While
other retrospective strategies for
estimating placentation have been
used (Munsinger 1977; Reed et al.
1978, 1991), we are fortunate that
MC placentation and mirroring for
handedness are both explained by
late division in the early blastocyst
stage, so that hand preferences
provide a readily accessible, albeit
imperfect, marker for placentation.
15
We reanalyzed information on
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handedness from three recent stud-
ies on samples of twins in which
one or both twins had schizophre-
nia (Lewis et al. 1989; Lohr and
Bracha 1992; Torrey et al. 1993).
Lewis et al. (1989) reported on 30
pairs drawn from the Maudsley
Hospital Twin Register collected
since 1967, after the older
Maudsley series used by Boklage
(1977), which was collected before
1967. Torrey et al. (1993) provided
40 more pairs of twins for this
study with their data from the
National Institute of Mental Health
(NIMH) Twin Study Unit. Lohr
and Bracha (1992) were able to re-
port one more pair that had been
recruited for the NIMH project but
had been unable to travel in order
to participate. Together, the three
studies provided 71 pairs of MZ
twins.
We did not include twin sam-
ples from older studies that relied
on fingerprints or subjective judg-
ments of appearance to determine
zygosity. Lohr and Bracha (1992)
contend that such studies of twins
were conducted before researchers
had knowledge about the effects
of mirroring and viral infections
on skin patterns, which likely re-
sulted in MC-MZ twins' being
incorrectly assigned to the DZ
group. Twin-transfusion syndrome
is another factor that can lead to
misclassification of MZ twins as
DZ, because this syndrome leads
to marked differences in weight
and appearance between the mem-
bers of the pair (Tan et al. 1979).
These and other concerns led us
to exclude one of the better
known and more controversial
studies of handedness in twins
with schizophrenia conducted by
Boklage (1977). First, Boklage re-
lied on the older Maudsley Hospi-
tal twin series reported by Gottes-
16
man and Shields (1972). In their
57 pairs, zygosity was determined
only by fingerprinting in 5 cases
and by appearance alone in 21
pairs. Second, there were problems
with the determination of handed-
ness. Boklage decided that any
left-foot preferences or ambidex-
terity would qualify as "not right
handed." This is a decision not
followed by subsequent re-
searchers, who have relied instead
on writing preferences and stand-
ardized tests. Third, and perhaps
most disturbing, were the com-
ments of Lewis et al. (1989), who
found evidence that fewer than
half of the proband cases in the
Maudsley series who received con-
sensus diagnoses of schizophrenia
would match current criteria for
schizophrenia. Finally, a number
of attempts to replicate Boklage's
findings have failed (Luchins et al.
1980; Lewis et al. 1989; Torrey et
al. 1993).
Based on the 71 cases reviewed,
twin pairs who preferred opposite
hands were more often concordant
for schizophrenia or psychosis. Of
15 pairs that included a left-
handed and a right-handed twin, 9
(60%) were concordant for schizo-
phrenia or psychosis, while only
18 of 56 (32.1%) twin pairs with
same-hand preferences were con-
cordant (x2 = 3.90, p < 0.025, di =
1, one-tailed test). Because only 21
percent (15 of 71) of our cases
were opposite-handed, and because
the expected rate of MC twinning
is 60 percent, we can assume that
many of those in the same-hand-
preference condition must be MC.
In that case, the 32.1 percent con-
cordance rate for same-hand-
preference pairs would be too
high an estimate of the schizo-
phrenia concordance rate for DC-
MZ twins, as it would likely be
inflated by the presence of hand-
concordant MC-MZ twins.
Additional data from the NIMH
twins provided convergent valida-
tion for handedness as an indi-
cator of mirror imaging and/or
placentation. First, following
Munsinger (1977), who used
weight differences to retrospec-
tively assess placentation, we an-
alyzed all NIMH twins' birth
weights to determine whether dis-
cordance for handedness would be
associated with larger within-pair
birthweight differences and greater
between-pair variance, which
would be expected in cases of
twin-transfusion syndrome in MC
placentation (Munsinger 1977). The
birthweight difference of hand-
discordant twin pairs averaged
14.9 percent, compared with 9.4
percent for same-hand-preference
pairs (t = 2.10, p = 0.05, df = 59).
There was also greater variance in
birth-weight differences in the
hand-discordant twins (F = 2.75; df
= 9,45; p = 0.05), which is consis-
tent with reports on twin transfu-
sion (Tan et al. 1979). Skre et al.
(1992) also reported similar birth-
weight differences for concordant
and discordant twins with
schizophrenia.
Second, we also inquired
whether hand-discordant twins in
the NIMH series showed any ad-
ditional signs of mirroring. Dr.
Torrey (personal communication
October 1993) reported that 10 of
the 15 twin pairs with opposite-
hand preferences reported in Tor-
rey et al. (1993) showed additional
signs of mirror imaging for ap-
pearance. Because mirror imaging
is expected in 25 percent of MZ
twins (Springer and Deutsch 1981),
the 67 percent of hand-discordant
twins who were mirror-imaged in
Torrey et al.'s study contrasts sig-
nificantly (z = 3.723, p < 0.001)
with the overall expected rate.
SCHIZOPHRENIA BULLETIN
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Based on these suggestive find-
ings, we intend to employ der-
matoglyphics analysis as a more
refined way to estimate placenta-
tion retrospectively. This strategy
(Lohr and Bracha 1992) also relies
on the relationship between mir-
roring and placentation and avoids
some of the problems discussed
above. We hope dermatoglyphics
will provide confirmation of these
findings and spur further research
on placentation effects.
Of course, the best method of
determining placentation is direct
examination of the placenta in
twin births, an avenue of inves-
tigation that we strongly recom-
mend. Research on placentation
takes on greater significance in
light of the increasing support for
the influence of viral infections on
schizophrenia (Torrey et al. 1988;
Pulver et al. 1992; Sham et al.
1992; Adams et al. 1993).
In the National Advisory Mental
Health Council's Report to Con-
gress on the Decade of the Brain
entitled Approaching the 21st Cen-
tury: Opportunities for NIMH
Neuroscience Research (National In-
stitute of Mental Health 1988), the
Council posed "a challenge for
neuroscience: 50 important ques-
tions to answer in the decade
ahead." We feel research on pla-
centation effects in schizophrenia
can shed light on these questions:
1. What role do viruses play in
mental illness? (p. vi)
2. What factors account for the
lack of complete concordance in
identical twins? (p. vii)
3. How do physical illnesses
cause psychopathology? (p. viii)
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VOL. 21, NO. 1, 1995 17

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Acknowledgment
This article is based in part on a
presentation at the Fifth Annual
Convention of the American Psy-
Nominations are being sought for
the 1995 Psychological Founda-
tion/Gralnick Award for schizo-
phrenia research. Candidates for
this award of $2,000 must demon-
strate an exceptional contribution
to schizophrenia research with
emphasis on the discovery and /or
treatment of the earliest signs of
schizophrenia, emphasizing the
psychological aspects of the dis-
ease process. Preference will be
given to individuals working in
SCHIZOPHRENIA BULLETIN
chological Society, Chicago, IL,
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June 1993.
The Authors
James O. Davis, Ph.D., is Pro-
fessor, Department of Psychology,
and Jeanne A. Phelps, Ph.D., is
Assistant Professor, Department of
Psychology, Southwest Missouri
State University, Springfield, MO.
a psychiatric facility.
Individuals must submit applica-
tions to the American Psychologi-
cal Foundation by April 1, 1995.
To request an application or addi-
tional information, please contact:
Cynthia Garber
The American Psychological
Foundation
750 First St., NE.
Washington, DC 20002
Telephone: (202) 336-5814