close

Вход

Забыли?

вход по аккаунту

?

497

код для вставкиСкачать
American Journal of Medical Genetics (Neuropsychiatric Genetics) 88:4–10 (1999)
Genetic Epidemiological Study of Schizophrenia in
Palau, Micronesia: Prevalence and Familiality
Marina Myles-Worsley,1* Hilary Coon,1 Josepha Tiobech,2 Jay Collier,2 Paul Dale,3 Paul Wender,1
Fred Reimherr,1 Anthony Polloi,2 and William Byerley1
1
Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah
Belau National Hospital, Koror, Palau, Micronesia
3
University of Hawaii at Manoa, Honolulu, Hawaii
2
We are studying the genetic etiology of
schizophrenia in the Republic of Palau, a remote island nation in Micronesia that has
been geographically and ethnically isolated
for approximately 2,000 years. The first epidemiological phase sought to estimate the
lifetime prevalence of schizophrenia and
evaluate the familiality of the illness based
on complete ascertainment of cases and
families segregating schizophrenia. A total
of 160 strictly defined cases of schizophrenia were ascertained in a population of
13,750 adults who were 15 years of age and
older. The lifetime prevalence of strictly defined schizophrenia in Palau was 1.99%
overall and 2.77% in males vs. 1.24% in females. This greater than 2:1 male-to-female
risk ratio for schizophrenia was accompanied by an earlier mean age of onset for
males (23.3 years) than for females (27.5
years). These 160 cases of strict schizophrenia represent 59 separate families each
identified by a single common founder.
Eleven of these families have 5 to 14 cases
and represent nearly half of the strict
schizophrenia cases in Palau. Although
schizophrenia is clearly aggregating in
these 11 families, cases are distributed
sparsely throughout the large sibships. In
the entire sample of 160 cases of strict
schizophrenia, there were only 11 sib-pairs
and 2 sib-trios. When a family was defined to
include third-degree relatives, only 11 cases
(6.9%) were nonfamilial. The majority of the
ascertained cases can be linked together
into extended pedigrees with complex mul-
Contract grant sponsor: National Institute of Mental Health;
Contract grant numbers: MH54186, MH56098, MH10889, and
MH52055.
*Correspondence to: Marina Myles-Worsley, Department of
Psychiatry, University of Utah School of Medicine, 50 North
Medical Drive, Salt Lake City, UT 84132
Received 9 December 1997; Revised 11 March 1998
© 1999 Wiley-Liss, Inc.
tilineal inheritance patterns. These intricately interconnected families may pose
challenges for traditional linkage techniques. However, these Palauan families
represent a valuable resource for studying
the genetic etiology of schizophrenia because there may be fewer susceptibility
genes for schizophrenia in this genetic isolate than in the heterogeneous populations
that are common throughout the world today. Am. J. Med. Genet. (Neuropsychiatr.
Genet.) 88:4–10, 1999. © 1999 Wiley-Liss, Inc.
KEY WORDS: genetic isolate; multilineal
pedigrees; gender differences; age-of-onset
INTRODUCTION
The importance of genetic factors in determining liability to schizophrenia has been firmly established by
family, twin, and adoption studies [Gottesman et al.,
1982, 1987]. Additional evidence for the genetic transmission of schizophrenia is provided by epidemiological
studies that have found a remarkably narrow range of
prevalence rates across populations living in vastly different geographic and socioeconomic environments. Estimates of lifetime risk for schizophrenia based on the
World Health Organization Ten Country Study
[Jablensky et al., 1992] range from 0.5% in Honolulu,
Hawaii to 1.7% in Chandigarh, a rural area in India.
However, pockets of elevated prevalence in the 2% to
3% range have been reported in certain regions of the
world where geographical or cultural influences have
resulted in genetically isolated populations. For example, lifetime morbid risk for schizophrenia is 2.4% in
an isolated region in Northern Sweden [Book et al.,
1978] and 3.2% in an internal isolate in Finland [Hovatta et al., 1997]. Genetically isolated populations like
these represent a potentially valuable resource for
studying the genetic etiology of schizophrenia because
they may have fewer genes predisposing to schizophrenia than the genetically heterogeneous populations
that are common throughout the world today.
Schizophrenia in Palau, Micronesia
Another genetic isolate where the rate of schizophrenia may show signs of elevation is Palau, Micronesia.
Dale [1981] studied the prevalence of schizophrenia
throughout Micronesia and found evidence for a westto-east gradient with the highest rates in Palau and
Yap to the west and the lowest rates in the easternmost
island territories. The Republic of Palau, also known as
Belau, is the westernmost archipelago in Micronesia.
The Palau islands were probably settled by migrants
from the Philippines and Indonesia approximately
2,000 years ago [Parmentier, 1987]. Archaeological
studies report radiocarbon dates of 40 ± 70 AD for pottery fragments found in Palau [Takayama, 1981].
Blood group clustering, linguistic analysis, and ethnographic studies indicate that the Palauan population
has developed in relative isolation, even from other Micronesian populations, since its original settlement
[Simmons et al., 1965]. Over the past century, Palau
has been ruled by Spain (1885–1898), Germany (1899–
1914), Japan (1914–1945), and finally the United
States, which administered Palau as a United Nations
Trusteeship from the time World War II ended in 1945
until 1994 when Palau became an independent nation.
The Palauan population was reduced to 3,500 during
World War II. Today, there are 20,470 native Palauans, 13,750 of whom are 15 years of age or older.
Palau consists of more than 200 islands that stretch
125 miles along a northeast-to-southwest axis, but only
five islands are inhabited. Over half the population resides on the island of Koror where the Belau National
Hospital is situated, and the remaining Palauans live
either on the adjoining island of Babeldaop, accessible
by bridge, or on neighboring islands within a 1 h boat
ride or 20 min plane trip from Koror.
The basic unit of social organization in Palau is the
clan, a blood-based, landholding group of families that
share a common female founder. Ownership of land is
inherited matrilineally, and every clan birth is on file
at the Ministry of Justice. Clan members are expected
to participate actively and financially in the traditional
ceremonies that mark major life events such as births,
marriages, and deaths. These communal events serve
to teach younger members of the clan about their genealogy and clarify the blood relationships that bind
the clan. Matings between clan members, even third or
fourth degree relatives, have traditionally been forbidden. Consequently, inbreeding is rare in the Palauan
population despite its isolation. Furthermore, outbreeding via marriage to outsiders has been rare because of the financial rights that accrue to native Palauans. Some Palauans have Asian or European ancestors, but such cases are the exception: the majority can
trace their lineage back through five or more generations of full-blooded Palauans.
There are none of the technical, linguistic, or practical barriers to conducting research that are usually
found in remote, isolated locations. Since the country
became a U.S. Trust Territory after World War II, Palau has evolved into a modern society. Both English
and Palauan are official languages in Palau. The literacy rate is currently over 90%, and all Palauans who
have been educated in Palau since the late 1940s have
5
received their elementary school through high school
education in English. As a former U.S. Trust Territory,
Palau’s medical services and research have been under
the jurisdiction of the U.S. Public Health Service. All
inpatient and outpatient services are administered by
Belau National Hospital, and complete medical records
written in English have been kept since the early
1950s.
The first phase of our study examined the epidemiology of schizophrenia in Palau. Given the size of the
population, the quality of the medical records at Belau
National Hospital, and the spirit of co-operation of the
Palauan people, complete ascertainment was considered feasible. Our aim was to diagnostically assess all
cases of schizophrenia in Palau and construct a pedigree for each confirmed case by identifying all first,
second, and third degree relatives. Based on these
data, our objectives were to a) estimate lifetime morbid
risk for schizophrenia in Palau including gender and
age-of-onset characteristics and b) evaluate the familiality of the illness in this genetic isolate.
MATERIALS AND METHODS
Ascertainment of Cases and Families
We used medical records on file at Belau National
Hospital where all mental illness is treated to identify
every Palauan who has ever been treated for a psychotic illness. For patients meeting our diagnostic criteria, we ascertained the individual’s first, second, and
third degree relatives to identify other potentially affected family members and to reveal any relationships
to previously ascertained families. Families were extended by identifying all offspring of the Generation I
‘‘founder’’ parents and ascertaining all subsequent descendants 15 years of age or older. The initial framework for family ascertainment was provided by pedigree diagrams drawn by Dr. Anthony Polloi, who returned from medical training in Fiji in 1968 to become
Director of Mental Health at Belau National Hospital.
Noting that many of the schizophrenic patients seeking
regular treatment were members of several large clans,
Dr. Polloi began constructing pedigrees and inserting
them in medical records as part of the patient’s history.
Psychiatric Assessment
All living and consenting subjects were interviewed
by Dr. William Byerley by using a modified version of
the Schedule for Affective Disorders and Schizophrenia—Lifetime Version [SADS-L, Endicott and Spitzer,
1978]. Questions were added pertaining to childhood
development and educational, occupational, adult
medical, and female reproductive history. Age of onset
was defined as the earliest age at which the presence of
a clear psychotic symptom could be identified. All interviews were conducted in the presence of a Belau
National Hospital Behavioral Health professional, primarily Josepha Tiobech, the Psychiatric Nurse Practitioner who has supervised psychiatric care in Palau for
the past 10 years. When subjects preferred to be interviewed in their native language, each of Dr. Byerley’s
questions was immediately repeated in Palauan, and
the subject’s response was then translated into English
6
Myles-Worsley et al.
and recorded by Dr. Byerley. For subjects who were
deceased, we interviewed relatives with knowledge of
the patient’s illness. The SADS-L interviews were
supplemented by a review of psychiatric medical records. These records, which date back to the early
1960s and are written in English, document every inpatient and outpatient contact, which typically included presenting symptoms or complaints, summary
of patient interview, diagnosis, and treatment plan. In
addition, a psychosocial history was prepared by a Palauan social worker for every psychiatric patient receiving regular treatment.
All available information on each subject was compiled with names deleted and identifying information
such as race, religion, or unique cultural references
generalized or disguised. The information was forwarded to two board certified psychiatrists (F.R. and
P.H.W.) who have been conducting blind reviews of
psychiatric patient data for ongoing genetic studies of
schizophrenia and bipolar affective disorder at the University of Utah since 1986. After reviewing this information individually, Dr. Reimherr and Dr. Wender met
and established consensual diagnoses according to
RDC criteria [Spitzer et al., 1978]. If diagnostic disagreement occurred, an attempt was made to collect
additional information for review. If agreement could
not be reached, the subject was coded unknown. The
RDC diagnoses included in the strict diagnostic category versus other psychotic illnesses are presented in
Table I.
RESULTS
Complete Ascertainment
A total of 262 individuals were evaluated for the
presence of a psychotic illness based on their medical
records or referral by a family member. Using RDC
criteria, we identified 160 cases of strictly defined
schizophrenia and 55 cases of other psychotic illnesses
(see Table II). Included in the broad diagnostic category were five cases of acute/subacute schizophrenia,
31 cases of affective psychoses (22 bipolar affective disorder with psychosis, six schizoaffective disorder with
mainly affective course, three psychotic depression),
and 19 cases of unspecified functional psychosis. Of the
remaining 47 individuals, eight were diagnosed as bipolar I without psychosis, bipolar II, or cyclothymic, 1
patient was diagnosed with delusional disorder, five
TABLE II. Number of Subjects in Each Diagnostic Category
by Gender
Strict diagnostic category
Chronic schizophrenia
Schizoaffective, mainly schiz.
Total strict schizophrenia
Other psychotic illnesses
Acute/subacute schizophrenia
Affective Psychoses
Bipolar I with psychosis
Schizoaffective, mainly aff.
Psychotic depression
Unspecified functional psychosis
Total other psychotic illnesses
Broad diagnostic category
Total all cases
Male
Female
Total
%
Male
104
5
109
36
15
51
140
20
160
74.3
25.0
68.1
2
3
5
40.0
12
1
1
10
26
10
5
2
9
29
22
6
3
19
55
54.5
16.7
33.3
52.6
47.3
135
80
215
62.8
patients met criteria for psychosis but had a prominent
organic component (e.g., chronic seizures), and 33 individuals (15 of whom were deceased) were considered
unknown because of insufficient information.
Among Palauans with strictly defined schizophrenia,
there was a 2:1 male-to-female ratio with males representing 68.1% of total cases (chi-square ⳱ 12.54, df ⳱
1, P < .01). This gender imbalance did not extend to
patients with other psychotic illnesses, only 47.3% of
whom are male.
Prevalence
We calculated the lifetime morbid risk (LMR) of
schizophrenia based on complete ascertainment of
cases and 1997 Palau population estimates by age
group (Office of Planning and Statistics, Republic of
Palau). The LMR [Gottesman and Shields, 1982] represents the probability that an individual who survives
through the period of risk (15 to 54 years of age) will
develop schizophrenia and is corrected for age using
the following approximation to life table analysis:
LMR =
冋 冉
a
1
N − n0 − nw
2
冊册
a = number of observed schizophrenics
N = total sample size
n0 = number of subjects under 15 years
TABLE I. Diagnostic Categories Based on RDC Criteria
Strictly defined schizophrenia
Chronic schizophrenia (symptoms > 2 years duration)
Subchronic schizophrenia (symptoms > 1 year but < 2 years
duration)
Schizoaffective disorder, mainly schizophrenic course
Other psychotic illnesses
Acute schizophrenia (symptoms < 6 months duration)
Subacute schizophrenia (symptoms > 6 months but < 1 year
duration)
Schizoaffective disorder, mainly affective course
Bipolar I disorder with psychotic symptoms
Psychotic depression
Unspecified functional psychosis
nw = number of nonschizophrenics 15 to 54
years of age
For strictly defined schizophrenia, the LMR in the
Palauan population was 1.99%. When a broad diagnostic category including other psychotic illnesses was
used, LMR for Palauans increased to 2.67%. For males,
the risk of developing strictly defined schizophrenia
was 2.77% and the risk of developing a broadly defined
psychotic illness was 3.42%. The corresponding LMR
estimates for females were substantially lower: 1.24%
for strict schizophrenia and 1.95% for an illness in the
broad diagnostic category.
Schizophrenia in Palau, Micronesia
7
Age of Onset
Table III presents mean age of onset by gender for
each diagnostic category. The onset of strict schizophrenia typically occurred at an earlier age (24.7 ± 6.8
years) than the onset of other psychotic illnesses (28.8
± 8.9 years), t ⳱ 3.02, df ⳱ 211, P < .01, two-tailed.
Onset of strict schizophrenia in Palau occurred predominantly between ages 15 and 42 years (mean age of
onset ⳱ 24.7 ± 6.8) with three males showing an earlier
onset and one female showing a later onset. The average age of onset was 4 years younger for male (23.3 ±
6.2 years) than for female strict schizophrenia patients
(27.5 ± 7.1 years), t ⳱ 3.79, df ⳱ 156, P < .001, twotailed. Age of onset distributions also showed strikingly
different patterns by gender (see Fig. 1). There was a
clear peak for Palauan men at 21–23 years of age. However, onset age for Palauan women showed a more complex pattern first peaking at 18 to 20 years, dropping
back markedly at 20–23 years, then rising to a second
peak that extends from 24 to 32 years of age. It is
noteworthy that 61% of men with strict schizophrenia
had onset before 24 years of age vs. only 29% of women,
whereas 39% of women had onset in their thirties or
later compared to only 18% of men. There was no gender difference in age of onset for patients with other
psychotic illnesses.
Familiality
The 160 cases of strict schizophrenia represent a total of 59 families identified by a common founder.
Eleven of these families each have 5 to 14 cases and
represent nearly half (48.1%) of the strict schizophrenia patients in Palau, 20 families have 2 to 4 cases, 17
families have one patient who is distantly related to
another previously counted case through a different
common founder, and the remaining 11 strict schizophrenia patients are nonfamilial cases.
Therefore, 93.1% of strict schizophrenia cases in Palau are familial (see Table IV). Of particular interest in
this genetic isolate is the distribution of the illness
within families. Although the 11 largest families each
have 5 to 14 cases, these families cannot be described
as high-density. Rather, the distribution of schizophrenia cases even within these multiply affected families
would be more accurately described as sparse. To illustrate this point, Figure 2 presents a truncated pedigree
drawing for Kindred 1583, which has the greatest number of cases descending from a single founder. The female founder had two children by two different males.
The son had four children and the daughter had nine
children, a total of 13 offspring in Generation III. These
13 individuals had a total of 94 offspring who comprise
Generation IV. Among these 94 Generation IV family
TABLE III. Mean Age of Onset in Years by Gender and
Diagnostic Category
Male
Female
Total
Strict
schizophrenia
Other psychotic
illnesses
All cases
combined
23.3 ± 6.2
27.5 ± 7.1
24.7 ± 6.8
28.7 ± 10.2
28.9 ± 7.6
28.8 ± 8.9
24.4 ± 7.4
28.0 ± 7.2
25.8 ± 7.6
Fig. 1.
Frequency distribution of age of onset by gender.
members, the youngest of whom are currently in their
early 30s, there are only four affected cases to date. In
Generation V, which currently ranges in age from 2 to
55 years and older, 10 cases of strict schizophrenia (one
of which is counted in another family via the affected
father) and three cases of Bipolar I with psychosis have
been ascertained to date. In Generation VI, which will
eventually span an even broader age range than Generation V, there is only one schizophrenia case so far.
Another approach to describing the sparse distribution of cases within families is to examine number of
cases by sibship size. Table V presents number of sibships with one, two, or three cases of strict schizophrenia by sibship size, including only full sibs. The average
size of affected Palauan sibships is 5.7 individuals, and
in these sibships, the risk for schizophrenia is 19.4%.
Among the 160 cases ascertained, there are only 11
sib-pairs and two sib-trios. There are four additional
half-sib-pairs in the sample.
An important feature of the Palauan families segregating schizophrenia is the complex interconnections
among the families via marriage that occur at every
generational level studied. Based on these interconnections, the 48 multiply affected families we identified
can be linked together into extended pedigrees with as
many as 25 cases of schizophrenia. Figure 3, which
presents a family identified by a single female founder
TABLE IV. Cases of Strict Schizophrenia per Family
5–14 Strict cases per family
2–4 Strict cases per family
Single-case families
Familiala
Nonfamilial
Total
a
No. of
families
No. of
cases
Percent of
total cases
11
20
77
55
48.1
34.4
17
11
59
17
11
160
10.6
6.9
100.0
Families with one strict schizophrenia patient who is related (third degree
or more distant) to a previously counted case through a different common
founder.
8
Myles-Worsley et al.
Fig. 2.
Pedigree for Kindred 1583 showing number of affected cases to date for each Generation III branch.
with seven affected direct descendants, illustrates how
marriages between clans can result in complex patterns of multilineal transmission. Of the eight marryin spouses that are circled, three are members of Kindred 1583 (presented in Fig. 2) and the other five are
members of five other multiply affected families. Consequently, all seven affected descendants are either bilineal or multilineal.
DISCUSSION
The objectives of our epidemiological study were to
estimate the prevalence of schizophrenia in Palau and
TABLE V. Number of Sibships With 1, 2, or 3 Cases of
Strict Schizophrenia
Total no.
of full sibs
in sibship
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unknown
Total no.
of cases
No. of sibships with
1 Affected
2 Affecteds
3 Affecteds
24
13
7
8
13
11
11
7
5
5
8
5
—
2
1
12
—
—
1
1
—
—
2
1
2
2
1
—
—
1
—
—
—
—
—
—
—
—
1
—
—
—
1
—
—
—
—
—
132
22
6
evaluate the influence of familial factors on the illness.
Complete ascertainment of cases was possible because
the relatively small population of Palauan adults lives
in close geographical proximity in a communal society
organized on the basis of large extended families or
clans with excellent geneological documentation. The
identification of potential cases was simplified by the
centralization of all psychiatric care and medical records at Belau National Hospital and the assistance of
the Palauan Behavioral Health staff who have extensive knowledge of patients and their families.
We identified a total of 160 cases of strictly defined
schizophrenia and estimated the lifetime morbid risk
in Palau at 1.99%. Considering that Palau is a genetic
isolate, this prevalence rate fits well within the range
of estimates that have been reported in the literature
over the past half century [Torrey, 1987; Jablensky et
al., 1992].
It has been hypothesized that elevated prevalence
rates in genetic isolates are due to the enrichment of
genes predisposing to schizophrenia. However, enrichment would likely result in high-density pedigree
branches, and these are rare in Palau. In Palau, expression of cases of schizophrenia resulting from susceptibility genes of low penetrance is more likely because of the large sibships and half-sibships produced
by Palauan marriages. Another possible explanation
for the elevated prevalence rate stems from the numerous marriages between members of different clans segregating schizophrenia. As a result of these interclan
marriages at every generational level, a number of minor susceptibility genes may be aggregating in certain
pedigree branches via a series of bilineal transmissions
across multiple generations.
Although the lifetime prevalence rate for schizophre-
Schizophrenia in Palau, Micronesia
9
Fig. 3. Truncated pedigree for Kindred 2239B showing eight marry-in spouses (circled) and their family affiliation.
nia may be somewhat elevated in Palau, this rate is not
as high as prevalence rates found in other genetic isolates. For example, Hovatta et al. [1997] recently reported an age-adjusted prevalence rate for schizophrenia in a Finnish isolate of 3.2%. The higher rate found
in the Finnish isolate may be due to the broader diagnostic definition for schizophrenia which included
schizophreniform disorder, all schizoaffective disorders, plus ‘‘simple’’ and ‘‘latent’’ schizophrenia. Also,
cases were identified based on hospital registers which
may have overdiagnosed schizophrenia: A test of their
diagnostic validity showed that 13% of patients with a
diagnosis of schizophrenia did not fulfill DSM-III-R criteria for the illness. It is also possible that we have
understated the number of cases of schizophrenia in
Palau. Our ‘‘unknown’’ category, which includes 36 individuals with some signs of psychiatric illness, likely
includes some cases with premorbid symptomatology
that could develop into schizophrenia over time as well
as cases with atypical course that do not qualify as
schizophrenia according to RDC criteria. A final possibility is that there are actual differences in the degree
of elevation in prevalence rates across genetic isolates
that result from the unique genetic characteristics of
each isolated population.
In Palau, the male-to-female risk ratio for schizophrenia is greater than 2:1. A similar finding was reported in the Finnish isolate where the age-adjusted
lifetime prevalence rate was 3.9% for males and 2.4%
for females [Hovatta et al., 1997]. These results are
consistent with the majority of more recent epidemiological studies reporting an excess of male cases, including several studies in Ireland [NiNullain et al.,
1987; Kendler et al., 1993], England [Cooper et al.,
1987], Denmark [Munk-Jorgensen, 1986], Canada
[Bland, 1984; Iacono and Beiser, 1992], and Korea [Lee
et al., 1990]. We found that the mean age of onset for
Palauans was 4.2 years earlier in men than in women.
Kraepelin [1909] first reported that men with a diagnosis of dementia praecox had been hospitalized an average of 5–10 years earlier than women. This observation of a gender difference in age at first admission has
since been replicated in more than 50 studies [see An-
germeyer and Kuhn, 1988 for a review]. However, no
gender effects on age of onset were found in the Finnish
isolate [Hovatta et al., 1997] nor in multiply affected
families in County Roscommon, Ireland [Kendler and
Walsh, 1995]. Furthermore, a recent reanalysis of data
from the WHO 10-Country study of schizophrenia suggests that this gender difference in age of onset may be
due, in large part, to differences in marital status
[Jablensky and Cole, 1997]. It is important to note that
these gender differences in age of onset apply to patients with strictly defined schizophrenia. For patients
with other psychotic illnesses, which include affective
psychoses, age of onset is no earlier in males than in
females. The impact of family history factors on age of
onset could not be evaluated because of the small number of nonfamilial cases in Palau.
Schizophrenia in Palau clearly aggregates in families. However, the delineation of distinct families
transmitting a heightened risk for schizophrenia is
complicated by the multiple interconnections between
pedigrees via marriage. We were able to assign the 160
cases of strictly defined schizophrenia to 59 families
identified on the basis of a common founder. However,
as interconnections between families were defined, it
became apparent that the grouping of cases within
families was often determined by which parent was
ascertained first, particularly if that parent descended
from one of the largest families. We found, for example,
that it was possible to group eight cases from three
different families under a different common founder. It
has been difficult to find Palauan families that are exempt from psychotic illness. Most Palauans have at
least a fourth degree relative who is affected.
The well-documented genealogy of Palauan families
that made complete ascertainment possible may account for the low proportion of nonfamilial cases (less
than 7%) that we found in this isolated population.
Family studies in large, outbred populations have reported a substantially higher proportion of sporadic
cases [Gottesman, 1991]. However, if these families
were as large and the genealogies as well known as
they are in Palau, many of these ‘‘sporadic’’ cases might
actually be redefined as distantly familial.
10
Myles-Worsley et al.
With complete ascertainment of schizophrenia in Palau accomplished, our study is now proceeding with the
search for susceptibility genes in this geographic and
ethnic isolate. As in the Finnish isolate, the majority of
the ascertained cases can be linked together into extended pedigrees with complex multilineal patterns of
transmission of the clinical phenotype. Although traditional analytical techniques may not be capable of generating strong linkage signals in the more complex
multilineal pedigrees, these Palauan families represent a potentially valuable data resource for the application of new analytical techniques based on neural
network models [Kaufman, 1997] that can accommodate complex mechanisms of inheritance such as gene
interactions and epistasis.
ACKNOWLEDGMENTS
This research was supported by grants MH54186
(M.M.W.), MH56098(W.B.), MH10889(W.B.), and
MH52055 (H.C.) from the National Institute of Mental
Health, a NARSAD Independent Investigator Award
(M.M.W.), and a NARSAD Senior Investigator Award
(W.B.). We greatly appreciate the support and cooperation of the families in Palau. We thank Leatha
Allred, Patrick Aribuk, Adeline Franz, Annabel Lyman, Humi Masayos, Felix Mereb, Hilda Ngiralmau,
Druscilla Patris, Jennifer Williams, and the support
staff at Belau National Hospital for their important
contributions.
REFERENCES
Angermeyer MC, Kuhn L. 1988. Gender differences in age at onset of
schizophrenia: An overview. Eur Arch Psychiatr Neurol Sci 237:351–
364.
Bland RC. 1984. Long-term mental illness in Canada: An epidemiological
perspective on schizophrenia and affective disorders. Can J Psychiatry
29:242–246.
Book JA, Wetterberg L, Modrzewska K. 1978. Schizophrenia in a north
Swedish geographical isolate, 1900–1977. Epidemiology, genetics and
biochemistry. Clin Genet 14:373–394.
Cooper JE, Goodhead D, Craig T, Harris M, Howat J, Korer J. 1987. The
incidence of schizophrenia in Nottingham. Br J Psychiatry 151:619–
626.
Dale PW. 1981. Prevalence of schizophrenia in the Pacific Island populations of Micronesia. J Psychiatr Res 16:103–111.
Endicott J, Spitzer RL. 1978. A diagnostic interview: The schedule for
affective disorders and schizophrenia. Arch Gen Psychiatry 35:837–
844.
Gottesman II. 1991. Schizophrenia Genesis. New York: WH Freeman.
Gottesman II, Shields J. 1982. Schizophrenia: The epigenetic puzzle. New
York: Cambridge University Press.
Gottesman II, McGuffin P, Farmer AE. 1987. Clinical genetics as clues to
the ‘‘real’’ genetics of schizophrenia: (A decade of modest gains while
playing for time). Schizophr Bull 13:23–47.
Hovatta L, Terwilliger J, Lichtermann D, Makikyro T, Suvisaari J, Peltonen L, Lonnqvist J. 1997. Schizophrenia in the genetic isolate of
Finland. Am J Med Genet 74:353–360.
Iacono WG, Beiser M. 1992. Are males more likely than females to develop
schizophrenia? Am J Psychiatry 149:1070–1074.
Jablensky A, Sarorius N, Ernberg G, Anker M, Korten A, Cooper JE Day
R, Berrtelsen A. 1992. Schizophrenia: Manifestations, incidence and
course in different cultures. Psychol Med 22[Monograph Suppl 20].
Jablensky A, Cole S. 1997. Is the earlier age at onset of schizophrenia in
males a confounded finding? Results from a cross-cultural investigation. Br J Psychiatry 170:234–240.
Kaufman CA. 1997. Neural network analysis of schizophrenia susceptibility loci. Presented at the World Congress on Psychiatric Genetics,
Santa Fe, NM, October 1997.
Kendler KS, McGuire M, Gruenberg AM, O’Hare A, Spellman M, Walsh D.
1993. The Roscommon family study. I. Methods, diagnosis of probands
and risk of schizophrenia in relatives. Arch Gen Psychiatry 50:527–
540.
Kendler KS, Walsh D. 1995. Gender and schizophrenia: Results of an epidemiologically-based family study. Br J Psychiatry 167:184–192.
Kraepelin E. 1909. Psychiatrie. Leipzig: Barth.
Lee CK, Kwak YS, Yamamoto J, Rhee H, Kim YS, Han JH, Choi JO, Lee
YH. 1990. Psychiatric epidemiology in Korea. Part I: Gender and age
differences in Seoul. J Nerv Ment Dis 178:242–246.
Munk-Jorgensen P. 1986. Schizophrenia in Denmark: Incidence and utilization of psychiatric institutions. Acta Psychiatr Scand 73:172–180.
NiNullain M, O’Hare A, Walsh D. 1987. Incidence of schizophrenia in Ireland. Psychol Med 17:943–948.
Parmentier RJ. 1987. The sacred remains: Myth, history, and polity in
Belau. Chicago: University of Chicago Press.
Simmons RT, Graydon JJ, Gajdusek DC, Brown P, Riesenberg SH. 1965.
Blood group genetic variations in natives of the Caroline Islands and in
other parts of Micronesia. Oceania 36:132–170.
Spitzer RL, Endicott J, Robins E. 1978. Research diagnostic criteria. Arch
Gen Psychiatry 35:773–782.
Takayama J. 1981. Early pottery and population movements in Micronesian prehistory. Asian Perspectives 24:1–10.
Torrey EF. 1987. Prevalence studies in schizophrenia. Br J Psychiatry
150:598–608.
Документ
Категория
Без категории
Просмотров
2
Размер файла
128 Кб
Теги
497
1/--страниц
Пожаловаться на содержимое документа