American Journal of Medical Genetics (Neuropsychiatric Genetics) 74:353–360 (1997)
Schizophrenia in the Genetic Isolate of Finland
Iiris Hovatta,1,2 Joseph D. Terwilliger,3 Dirk Lichtermann,1,2 Taru Mäkikyrö,2,4 Jaana Suvisaari,2
Leena Peltonen,1* and Jouko Lönnqvist2
1
Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland
2
Department of Mental Health, National Public Health Institute, Helsinki, Finland
3
Department of Psychiatry and Columbia Genome Center, Columbia University, New York, New York
4
Department of Psychiatry, University of Oulu, Oulu, Finland
We compared the features of schizophrenia
in the homogeneous population of Finland
(population about 5,000,000) and in an inter-
nal isolate in northeastern Finland inhab-
ited in the 1680s by a small group of
founders (current population about 18,000)
in a register-based epidemiological study.
We identified all cases with a diagnosis of
schizophrenia in Finland born between
1940–1969 using three national computer-
ized registers and found a total of 267
schizophrenia patients in the internal iso-
late and 29,124 in Finland. The lifetime
prevalence was 2.21% in the internal isolate
and 1.21% in Finland, respectively. The age-
corrected lifetime risk was 3.2% in the inter-
nal isolate and 1.1% in the whole country.
The risk of schizophrenia to siblings in the
internal isolate was 6.4% (95% confidence in-
terval 0.052, 0.078), 9.1% (95% CI 0.062, 0.130),
and 6.8% (95% CI 0.028, 0.135) given 1, 2, or 3
affected siblings, and for all Finland 4.2%
(95% CI 0.036, 0.043), 6.4% (95% CI 0.058,
0.071), and 8.7% (95% CI 0.068, 0.107) given 1,
2, or 3, affected siblings, respectively. The
mean number of children in schizophrenia
families and thus the number of families
having at least two affected individuals
were clearly higher in the isolate (24.9% vs
9.2%). We did not find any other epidemio-
logical features differing between these two
regions. It seems that the family material
collected from the internal isolate is a rep-
Contract grant sponsor: Jalmari and Rauha Ahokas Founda-
tion; Contract grant sponsor: Research and Science Foundation of
Farmos; Contract grant sponsor: Sigrid Juselius Foundation;
Contract grant sponsor: Paulo Foundation; Contract grant spon-
sor: Academy of Finland; Contract grant sponsor: NIH; Contract
grant number: HG00008; Contract grant sponsor: Burroughs-
Wellcome Fund, Hitchings-Elion Fellowship.
*Correspondence to: Dr. Leena Peltonen, Department of Hu-
man Molecular Genetics, National Public Health Institute, Man-
nerheimintie 166, FIN-00300 Helsinki, Finland.
Received 22 October 1996; Revised 7 February 1997
© 1997 Wiley-Liss, Inc.
resentative subsample from the entire coun-
try and hopefully it enables easier identifi-
cation of at least some predisposing genes
for schizophrenia due to its unique popula-
tion structure. Am. J. Med. Genet. 74:353–
360, 1997. © 1997 Wiley-Liss, Inc.
KEY WORDS: genetic epidemiology; lifetime
prevalence; age-corrected life-
time risk; risk for siblings
INTRODUCTION
The process of identifying genes underlying mental
disorders faces many difficulties due to complex pat-
terns of inheritance and the strong confounding influ-
ence of environmental factors. One way to facilitate the
search is to focus the analysis on genetic isolates. In
such a setting there may be fewer genes predisposing
to a given complex disease than in more mixed popu-
lations. Focusing on a highly restricted population may
also offer advantages for eventual positional cloning
because one may be able to exploit linkage disequilib-
rium for fine-structure genetic mapping. [Lander and
Schork, 1994]. One source of evidence for the accumu-
lation of certain genes is the Finnish Disease Heritage
[Norio et al., 1973], which consists of some 30 mostly
autosomal-recessive disorders. It provides evidence of a
genetic founder effect and subsequent isolation which
has resulted in the enrichment of some disease muta-
tions and in a total lack of others in this relatively
small population of 5,000,000 inhabitants [Norio,
1981].
The first archaeological evidence of human inhabit-
ants in Finland dates from the last postglacial period,
some 11,000 years ago [Edgren, 1992], but the major
expansion of the population began only later after a
population bottleneck, approximately 3,900 years ago
[Sajantila et al., 1996]. Since then, Finland has been
isolated for geographic, linguistic, and cultural rea-
sons, and the original relatively small ancestor popu-
lation slowly invaded the southern and western coast-
line of the country. The northern and eastern parts of
Finland were inhabited later, in the 16th and 17th cen-
turies, and this has resulted in internal isolates inside
354 Hovatta et al.
this isolate. We have chosen one internal isolate, a mu-
nicipality in the northeastern part of Finland, to inves-
tigate the genetic epidemiology of schizophrenia.
The municipality was originally populated by the
Lapps when the first Finns, some 40 families, moved
there in the 1670s from the south. The Finnish popu-
lation expanded locally; in 1750, when the official reg-
isters were established, 1,208 inhabitants were already
recorded [Ervasti and Vasari, 1978]. The population
increased further and is 18,281 at the present time.
There have been several periods when mortality was
high due to years with crop failures. However, the
population of this municipality has been extremely
stable throughout the centuries. People have usually
found spouses from the same village and even mar-
riages between people living in northern and southern
parts of the same municipality have been rare. Only
after World War II has emigration from the municipal-
ity increased towards the southern parts of Finland,
whereas immigration into the municipality has re-
mained limited.
We performed a nationwide epidemiological survey
in Finland to search for differences in the geographical
distribution of schizophrenia. We specifically wanted to
compare the epidemiological features of schizophrenia
in the well-characterized internal isolate with those in
the whole population.
MATERIALS AND METHODS
Three registers were used to identify all probands
with a diagnosis of schizophrenia. The National Hos-
pital Discharge Register was established in 1968. All
admission and discharge dates and primary diagnoses
for inpatient stays at public and private facilities are
indexed in this register. In addition, we used two reg-
isters of the Social Insurance Institution of Finland,
i.e., the Pension Register and the Free Medicine Reg-
ister. The Pension Register indexes beginning and end-
ing dates and primary diagnosis justifying disability
pensions. The Free Medicine Register indexes primary
diagnoses for state-subsidized medications.
All three registers have been computerized since
1968. Before 1987 the International Classification of
Diseases, Version 8 (ICD-8) descriptions were used as a
basis for diagnosis. Thereafter, psychiatric diagnoses
have been coded according to the Finnish version of
ICD-9 [Kuoppasalmi et al., 1989], using the criteria of
the Diagnostic and Statistical Manual of Mental Dis-
orders, Version III Revised (DSM-III-R).
In the registers of the Social Insurance Institute only
the first three digits of the diagnostic codes are re-
corded. Therefore, we identified probands having a
‘‘295’’ diagnosis according to the ICD-8 numbering
scheme. This means that schizophreniform disorder,
schizoaffective disorder, and ICD-8 simple and latent
schizophrenia diagnoses are included in our definition
of schizophrenia.
Probands born between 1940–1969 were included in
this study, since it was possible to reliably identify
first-degree relatives of these patients. Also, inclusion
of probands born earlier than 1940 would have intro-
duced a bias because of changes in diagnostic systems
and treatment over time.
In a sample of 73 probands born in the internal iso-
late, the validity of the register diagnosis of schizophre-
nia was studied. Sixty-two of them had a register di-
agnosis (DSM-III-R) of schizophrenia (295.10, 295.20,
295.30, 295.60, and 295.90), and 11 had a schizophre-
nia spectrum diagnosis (295.40, 295.70, 301.20, and
301.22). Original case-notes from psychiatric hospitals
and also from outpatient clinics in problematic cases
were collected. Based on the clinical information, a
DSM-III-R checklist [Tienari et al. 1993] was filled out
by a junior researcher (T. Mäkikyrö) trained for diag-
nostic assessment. In this checklist, the DSM-III-R cri-
teria of schizophrenia and schizophrenia spectrum di-
agnoses were condensed, as were the main criteria for
exclusion. The Operational Criteria Checklist for Psy-
chotic Illness was also completed, and the associated
OPCRIT program [McGuffin et al., 1991] used to yield
diagnosis according to DSM-III-R criteria. Finally, two
senior researchers (M. Isohanni and J. Moring) made a
consensus best-estimate diagnosis based on all avail-
able information.
Fifty-four of the 62 cases having a register diagnosis
of schizophrenia fulfilled DSM-III-R criteria for schizo-
phrenia. Four were rediagnosed as suffering from schi-
zoaffective disorder, 1 from delusional disorder, 1 from
schizoid personality disorder, and 2 from psychotic de-
pression. Two of the 11 cases with schizophrenia spec-
trum diagnoses fulfilled DSM-III-R criteria for schizo-
phrenia, while 3 were diagnosed as having schizoaffec-
tive disorder, 1 as having schizophreniform disorder, 1
as having schizoid personality disorder, 1 as having
schizotypal personality disorder, 1 as having psychotic
depression, 1 as having bipolar I disorder, and 1 as
having brief psychotic disorder.
Lifetime prevalence was determined as the number
of probands who had ever had a diagnosis of schizo-
phrenia living in a particular area divided by the total
population living in the same area. Because of the con-
straints on years of birth and diagnosis imposed by our
ascertainment, and the difference in age structure of
the population between the internal isolate and the
rest of Finland, an age-adjusted lifetime ‘‘risk’’ was
computed as follows: for each year of birth there was a
range of possible ages of onset (defined here as time of
first schizophrenia-related hospitalization). We
counted the number of individuals K(X, Y) born in each
year X (between 1940–1969) who were diagnosed at
age Y (where X + Y was between 1974–1991, i.e., the
range of our diagnostic time frame), and the number of
individuals N(X, Y) born in each year X who could have
had onset at age Y (i.e., if X + Y is not between 1974–
1991, then N(X, Y) 4 0; otherwise it is just the number
of individuals born in year X). From this, we computed
the probability of a first hospitalization at each age
Y as:
min~1969, 1991 − Y!
(
K~X, Y!
X = min~1940, 1974 − Y!
fY = min~1969, 1991 − y!
.
(
N~X, Y!
X = min~1940, 1974 − Y!
Then, the age-corrected ‘‘lifetime risk’’ was computed

as f 4 ∑fY. We tested for any differences in age of
Y
onset as a function of year of birth by maximum like-
lihood methods, and found absolutely no evidence for
any differences, and thus treating each year of birth as
if their age of onset density function is the same seems
justified. It is acknowledged that there may be some
slight underestimation of the overall ‘‘lifetime risk,’’ as
some individuals might become affected at ages out-
side the range of admissible values given our time
frame (i.e., at ages over 51), but this number is likely
to be very small, and will add only a small amount to
these estimated lifetime risks. The resulting esti-
mated age-of-onset functions, fY, are shown graphi-
cally in Figure 3, separately for the internal isolate
and for the remainder of Finland. This ‘‘age-corrected
lifetime risk,’’ f, was calculated based on the data from
Hospital Discharge Register for people born between
1940–1969 who had had their first hospital admission
between 1974–1991. Only years after 1974 were
looked at, since the National Hospital Discharge Reg-
ister was founded in 1968, and after that there was a
6-year period when the number of first hospitaliza-
tions was not stably recorded. The mean age at first
hospitalization and the mean number of hospitaliza-
tions were obtained from the Hospital Discharge Reg-
ister, including the years between 1969–1991.
The data from the Social Insurance Institution of
Finland and the Hospital Discharge Register were
linked with the National Population Register in order
to identify all first-degree relatives to the probands
(Fig. 1). All first-degree relatives were included with-
out age limitations. We were unable to identify 9.9% of
fathers and 3.0% of mothers to the internal isolate, and
16% of fathers and 3.4% of mothers in the entirety of
Finland, mainly due to lack of data and scoring errors
in the personal identification code. In Finland it is not
Fig. 1. Identification strategy of the Finnish schizophrenia families.
Inclusion in the study required disability pension or free medication for
schizophrenia from the National Social Insurance Institution, or at least
one admission with a diagnosis of schizophrenia in the Hospital Discharge
Register.
Schizophrenia in Finland 355
obligatory to identify the father of a child, which might
explain the higher number of missing fathers.
The risk of schizophrenia to siblings given 1, 2, or 3
affected siblings was calculated for Finland and for the
internal isolate separately, based on the information
given in Table I. All families with at least one parent
born in the isolate were considered to originate from
the isolate.
RESULTS
We found a total of 267 schizophrenia patients born
between 1940–1969 in the internal isolate (population
18,281) and 29,124 in Finland (population 4,998,478).
The lifetime prevalence of schizophrenia in all munici-
palities (n 4 455) of Finland could be determined and
is shown in Figure 2. Prevalence was unevenly distrib-
uted, varying from 0.000–0.039. The internal isolate is
located in a region with high prevalence in eastern Fin-
land, as indicated in the map (Fig. 2).
The lifetime prevalence for affected males and fe-
males in the internal isolate was 2.49% and 1.93%,
respectively, and in all Finland 1.28% and 1.14%, re-
spectively. There was a sex difference in prevalence in
both samples, but the difference was statistically sig-
nificant only in the sample from the entire country
(x2 4 81.88, df 4 1, P < 0.000001), and not in the in-
ternal isolate (x2 4 2.58, df 4 1, P 4 0.11). The total
prevalence was 2.21% in the internal isolate and 1.21%
in Finland, thus being 1.8 times higher in the isolate
(x2 4 63.67, df 4 1, P < 0.000001). The age-corrected
lifetime risk for affected males and females in the in-
ternal isolate was 3.9% and 2.4%, respectively, and in
Finland 1.3% and 1.0%, respectively. The total age-
corrected lifetime risk for schizophrenia was 3.2% in
the internal isolate and 1.1% in the rest of Finland
(x2 4 285.64, df 4 33, P < 0.00000001). Here again we
also found significant evidence for sex difference only
in the sample from the entire country (x2 4 285.74,
df 4 33, P < 0.00000001).
The mean age at first hospitalization for schizophre-
nia in the internal isolate was 27.9 years for males (SD,
6.4) and 28.6 years for females (SD, 6.5), and in all
Finland 27.7 years for males (SD, 6.5) and 28.4 years
for females (SD, 7.0). This was considered as the age of
onset (Fig. 3). If the first hospitalization is calculated
only for the cohort born between 1950–1959 in order to
avoid the birth cohort bias of the Hospital Discharge
Register, the respective mean age at first hospitaliza-
tion was 23.5 years for males and 25.0 years for fe-
males in the internal isolate, and 25.2 years for males
and 23.7 years for females in all Finland. The mean
number of hospitalizations for schizophrenia in the in-
ternal isolate was 7.5 for males (SD, 9.1) and 7.1 for
females (SD, 10.5) and in all Finland 6.1 for males (SD,
7.4) and 5.8 for females (SD, 7.1) (Table II).
The mean number of children in nuclear families
with schizophrenia cases was 5.13 (SD, 2.75) in the
internal isolate and 3.39 (SD, 1.95) in all Finland. In
the internal isolate there was a total of 365 families
with 1 or more affected family members, 91 families
(24.9%) with 2 or more affected family members, 25
families (6.8%) with 3 or more affected family mem-
356 Hovatta et al.

TABLE I. Number of Siblings in Schizophrenic Families in the Internal Isolate and in All Finland
Number of schizophrenic sibs
Number
Fin- Iso- Fin- Iso- Fin- Iso- Fin- Iso- Fin- Iso- Fin- Iso- Fin- Iso-
of sibs
land late land late land late land late land late land late land late
in the
family 1 1 2 2 3 3 4 4 5 5 6 6 7 7
1 3,246 22
2 5,345 32 236 1
3 4,728 52 374 7 31 0
4 3,250 41 351 11 42 2 8 0
5 2,013 39 238 8 43 4 7 1 3 0
6 1,381 53 222 7 38 1 11 0 1 0 0 0
7 463 15 89 1 15 1 4 0 0 0 1 0 0 0
8 312 13 56 6 13 2 4 0 2 1 0 0 0 0
9 181 11 52 3 21 3 5 0 1 1 0 0 1 0
10 91 7 24 1 8 1 1 0 0 0 0 0 0 0
11 41 4 18 2 2 1 1 0 0 0 1 0 0 0
12 28 3 4 0 1 0 1 1 0 0 1 0 0 0
13 14 3 2 0 3 0 1 1 1 0 0 0 0 0
14 10 1 2 0 1 1 0 0 0 0 0 0 0 0
15 0 0 1 1 0 0 0 0 0 0 0 0 0 0
Total 21,103 296 1,669 48 218 16 43 3 8 2 3 0 1 0

bers, and 8 families (2.2%) with 4 or more affected fam-
ily members. The corresponding numbers for all Fin-
land were 23,045, 2119 (9.2%), 312 (1.4%), and 90
(0.4%). The calculated risk of schizophrenia to siblings
in the internal isolate was 6.4% (95% confidence inter-
val 0.052, 0.078), 9.1% (95% CI 0.062, 0.130), and 6.8%
(95% CI 0.028, 0.135), given 1, 2, or 3 affected siblings,
respectively. The corresponding numbers for all Fin-
land were 4.2% (95% CI 0.036, 0.043), 6.4% (95% CI
0.058, 0.071), and 8.7% (95% CI 0.068, 0.107), respec-
tively. Only the difference in the risk of schizophrenia
given 1 affected sibling was statistically significant.
This would be consistent with a genetic model with an
elevated gene frequency for the trait-predisposing al-
lele(s) in the isolate, leading to the higher risk given
the first affected individual in a sibship but the same
ultimate mode of inheritance, since the risk to addi-
tional sibs is equivalent in the two samples, once there
are enough affected sibs to be reasonably sure the
gene(s) are segregating in the family.
The proportion of families having at least 2 affected
individuals was clearly higher in the isolate (24.9%)
than in all Finland (9.2%), which is mainly due to
larger family sizes in the isolate. However, no signifi-
cant differences could be recorded in the proportion of
families having affected individuals in two genera-
tions. In the isolate 8.2%, and in all Finland 7.3%, of
the schizophrenia families had schizophrenic patients
in two generations. In the internal isolate, 4.4% of in-
dividuals in the parental generation and 24.7% of in-
dividuals in the offsprings’ generation were affected,
and in Finland, 4.2% and 32.3%, were affected, respec-
tively.
DISCUSSION
Validity of the Registers
Our goal was to compare the genetic epidemiology of
schizophrenia in Finland and in one internal isolate
with a well-established population history to see
whether the prevalence rates are higher in the isolate
within Finland, and to test if the isolated population
can be efficiently used in the search for predisposing
genes for schizophrenia.
We used three nationwide registers, the National
Hospital Discharge Register, the Pension Register, and
the Free Medicine Register, in order to find all treated
cases of schizophrenia. The Pension Register and the
Free Medicine Register are reliable because disability
pensions and free medications are paid according to the
information they contain. The reliability of the Hospi-
tal Discharge Register has been studied and found to
be excellent: about 95% of hospital discharges are re-
ported to the register, and the diagnostic codes are
transferred accurately from medical records to the reg-
ister [Keskimäki and Aro, 1991; Aro et al., 1995].
We studied the validity of the register diagnoses in a
sample of cases from the internal isolate. Fifty-four
(87.1%) out of 62 patients having a schizophrenia di-
agnosis in the registers fulfilled DSM-III-R criteria for
schizophrenia, and 2 (18.2%) out of 11 cases with a
spectrum diagnoses received a schizophrenia diagnosis
according to DSM-III-R. Thus, according to this study
the validity is good.
Two other studies of the reliability of diagnosis in the
National Hospital Discharge Register have been made.
Pakaslahti [1987a,b] compared routine hospital diag-
noses with diagnoses obtained by using the PSE-
CATEGO system in all consecutive first admissions to
the two mental hospitals in Helsinki during one calen-
dar year, 1981 (n 4 297). Schizophrenia accounted for
18.8% of hospital diagnoses but 35.0% of PSE-
CATEGO diagnoses. Pakaslahti [1987a,b] concluded
that there appears to be a tendency in clinical practice
to underdiagnose schizophrenia. Isohanni et al. [1997]
investigated all entries to the Hospital Discharge Reg-
ister for a sample based upon the Northern Finland
1966 Birth Cohort. Their diagnostic validation process
was identical to the one used in our study. Out of 563
subjects having a register diagnosis indicating a psy-
chiatric illness, they did not find any false-positive

Fig. 2. Prevalence of schizophrenia in different municipalities in Finland. Internal Isolate under study is indicated in map.
schizophrenia cases: all 37 cases having a register di-
agnosis of schizophrenia also received a schizophrenia
diagnosis according to DSM-III-R criteria. However,
Isohanni et al. [1997] found 34 additional cases of
schizophrenia, who most frequently had a register di-
agnosis of schizophreniform or other psychoses. These
studies do not, of course, cover the whole of Finland or
all of our study period. Nevertheless, they do not give
us reason to assume that there are many false-positive
schizophrenia cases in the Hospital Discharge Regis-
ter.
When interpreting the results, it must be borne in
mind that we used a broad definition of schizophrenia,
including schizophreniform and schizoaffective psycho-
ses, which are often considered to belong to spectrum
Schizophrenia in Finland 357
disorders, and not to core schizophrenia. On the other
hand, we probably missed some cases who never
sought treatment. We only studied patients born be-
tween 1940–1969, who were 22–51 years old in 1991,
which makes comparisons with other studies difficult.
Some studies used different kinds of age-correction
methods to take into account different population
structures. Since we knew that the population in the
internal isolate is younger than the whole population,
we also calculated an age-corrected lifetime risk for
schizophrenia. The age-corrected lifetime risk was
clearly higher than the lifetime prevalence in the iso-
late, whereas the age-corrected lifetime risk and the
lifetime prevalence were almost identical in the whole
country.
358 Hovatta et al.
Fig. 3. Age of onset of schizophrenia in the internal isolate (dashed line)
and in all Finland (solid line) when the first hospitalization was assumed
as the criterion of onset.
Prevalence of Schizophrenia
We found high prevalence of schizophrenia in north-
ern and eastern Finland, especially in rural areas (Fig.
2), as opposed to some previous studies [reviewed in
Freeman, 1994]. The validation of possible mecha-
nisms such as migration, social drift, or viral infections
remains elusive. Interestingly, an unequal distribution
of etiologically relevant genetic and environmental fac-
tors has also been proposed as an explanation of vastly
differing regional prevalence figures of schizophrenia
in Ireland [Youssef et al., 1991].
The prevalence of schizophrenia in the whole country
was similar to that reported in earlier studies in Fin-
land. In the Mini Finland Health Survey, the preva-
lence of schizophrenia was 1.3% for both men and
women. Regionally, schizophrenia was found to be
most frequent in rural areas and least frequent in
densely populated southwestern and southern Finland
[Lehtinen et al., 1990]. In a previous Finnish study a
prevalence rate of 1.5% was obtained in a study popu-
lation of 1,000 people in 1971. After the 16-year follow-
up of this sample, the age-adjusted prevalence rate in
schizophrenia was 2.3% for men and 0.4% for women
[Väisänen, 1975; Lehtinen et al., 1993].
When compared to the prevalence of schizophrenia
found elsewhere in the world, it seems that in Finland
the prevalence is higher. In a review of over 70 preva-
lence studies from 1948–1987, the lowest reported rate
was 0.3 per 1,000 among the Amish population in the
US, and the highest was 17.0 per 1,000 in a restudy of
an isolate population in northern Sweden. It was also
suggested that there could be a possible north-south
gradient in the distribution of the disease [Torrey,
TABLE II. Number of Hospitalizations for Schizophrenia
Among Patients Born in the Internal Isolate and in All Finland
Internal isolate All Finland
Number of
hospitalizations Males Females Males
1 22 (18%) 20 (24%) 3,255 (26%)
2–5 47 (39%) 36 (43%) 5,012 (40%)
6–9 21 (17%) 14 (17%) 1,917 (15%)
10+ 31 (26%) 13 (16%) 2,502 (20%)
1987]. In the Swedish study [Böök et al. 1978], the
prevalence in the northern isolate was about three
times higher than in the entire country, similar to our
results in the present study. It therefore seems that
there are small areas at least in northern Europe
where the prevalence of schizophrenia is higher than
the national average. These regions have been isolated
for several hundred years and high prevalence might
be due to enrichment of genes predisposing to schizo-
phrenia.
New studies have also yielded lower prevalence rates
than in Finland [Helgason and Magnusson, 1989; Bo-
jholm and Strömgren, 1989; Dilling et al., 1989; Gold-
acre et al., 1994]. In the National Comorbidity study
the lifetime prevalence of schizophrenia was 1.1% by
computer algorithm but only 0.15% based on clinician
diagnoses [Kendler et al., 1996]. The latter was, how-
ever, interpreted only as a plausible lower limit be-
cause in the number of cases the diagnostician was
confident about the presence of nonaffective psychosis,
but information was lacking to enable a more specific
diagnosis. The lifetime prevalence of all nonaffective
psychoses was 0.7% based on clinician diagnoses.
As in many other recent studies reviewed earlier, we
found a higher prevalence for males than for females in
the whole country. Age at first hospitalization did not
differ significantly between males and females either
in the internal isolate or in the whole country, and
neither did the number of hospitalizations. Two recent
Finnish incidence studies did not find significant sex
differences in the incidence of DSM-III schizophrenia
[Salokangas, 1993] or psychotic disorders in general
[Lehtinen et al. 1996], but the sample sizes were small,
with 186 schizophrenia cases in the former and 44 psy-
chotic cases in the latter. The incidence study of schizo-
phrenia did not find significant differences in age at
onset, either [Salokangas, 1993]. It seems that the
course of schizophrenia measured by age at onset and
number of hospitalizations is similar in males and fe-
males in Finland. The findings concerning age at onset
are contradictory to many earlier studies but are simi-
lar to the findings in Ireland [Kendler and Walsh,
1995].
Risk of Schizophrenia to Siblings
The risk of schizophrenia for a sibling of an affected
individual in Finland seems to be in the same range as
in other populations. Kendler and Diehl [1995] reana-
lyzed the 11 most recent family studies and found that
the risk for schizophrenia in first-degree relatives var-
ied from a low of 1.4% to a high of 8.9%. They concluded
that there might be true population differences in the
risk for schizophrenia in relatives of schizophrenic pro-
bands. On average, the first-degree relatives of schizo-
phrenic probands had a risk for schizophrenia 5–10-
fold higher than that found in the relatives of control
probands.
Females For the whole of Finland, the risk to remaining sib-
2,669 (26%) lings increased, the higher the number of siblings with
4,109 (41%) schizophrenia. In the isolate we did not see this, which
1,557 (15%) might be due to the fact that the family size is larger
1,789 (18%)
there, so that the probability of these families having

young healthy siblings still at risk of getting the dis-
ease is higher. Also, the number of families having
more than 3 affected children was small. Increase in
risk with birth order has been associated with external
factors such as respiratory viral infections. They are
frequently brought into the home by young children,
and individuals whose second and third trimesters of
fetal life coincide with an epidemic of influenza have a
greater risk of schizophrenia later in life. Having sib-
lings 3–4 years older has been associated with a sig-
nificantly increased risk of schizophrenia [Sham et al.,
1993].
Applications to Molecular Genetic Analyses
We did not find any differences in severity of disease
between the internal isolate and the whole country
when we looked at age of first hospitalization or num-
ber of hospitalizations. The differences in lifetime
prevalence and age-corrected lifetime risk seem to be
due to genetic or environmental factors, and not due to
the different natures of the disease, and the internal
isolate may well be regarded as a representative study
population when trying to identify genes predisposing
to schizophrenia.
The recent history of the internal isolate shows that
the majority of cases of schizophrenia in the modern
population can be linked together into extended pedi-
grees through the registers extending back to 1680. We
are currently tracing the ancestors of these families to
find out the precise relationships between individual
families. The structure of these extended pedigrees,
however, shows that the disease trait is transmitted in
complex multilineal patterns, making the sample inef-
fective for gene detection through traditional pedigree
analyses. However, if we assume that the majority of
cases have descended from a common ancestor, genes
might be amenable to isolation through the analysis of
linkage disequilibrium in affected individuals. Also, in
case of recessive genes, the consanguinity of families
has probably resulted in enrichment of certain predis-
posing genes. Nikali et al. [1995] earlier demonstrated
the feasibility of this technique in the case of a reces-
sively inherited subtype of hereditary ataxia belonging
to the Finnish disease heritage. The locus was assigned
by random screening using the DNA of only 4 affected
individuals.
On the other hand, the entire country represents a
relatively homogeneous population, with still much
greater homogeneity in the genes predisposing to
schizophrenia than to be expected from present-day
mixed populations elsewhere. However, since the pre-
disposing genes for schizophrenia must be quite com-
mon, even in this isolated population more than a
single ancestral genetic defect should be expected. The
presence of an extensive network of diagnostic and
population registers has led to the detection of a large
number of multiplex nuclear pedigrees with a mixture
of affected and healthy individuals from the entire
country, and hopefully the relative isolation of the
Finnish population will allow for a more simple detec-
tion of at least some major genes contributing to the
etiology of schizophrenia in Finland.
Schizophrenia in Finland 359
ACKNOWLEDGMENTS
This work was supported by the Jalmari and Rauha
Ahokas Foundation, the Research and Science Foun-
dation of Farmos, the Sigrid Juselius Foundation, the
Paulo Foundation, the Academy of Finland, grant
HG00008 from the NIH, and a Hitchings-Elion Fellow-
ship from the Burroughs-Wellcome Fund to (J.D.T.).
The authors thank Dr. Matti Huttunen, Dr. Sarnoff
Mednick, and Dr. Leena Väisänen for their contribu-
tions, and Mr. Aki Suomalainen and Mr. Antti Tans-
kanen for their assistance in data management.
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