Supplementary Material for “Expanding the range of ZNF804A variants conferring risk of
psychosis”
Supplementary Methods
Samples
China. The Chinese sample included 470 schizophrenia cases and 470 controls from Sichuan Province,
Southwest China. Cases were ascertained from West China Hospital, and diagnosis of schizophrenia was
assigned on the basis of a psychiatrist’s interview using the Structured Clinical Interview for Axis I DSM-IV
Disorders (SCID)1 and medical records according to Diagnostic and Statistical Manual of Mental Disorders,
4th edition (DSM-IV) criteria. Patients were excluded if they had a history of neurological disorders or head
injury, or reported intellectual disability. The unrelated controls were volunteers from the local population
and were free of major mental illness.
Denmark/Aarhus. The Danish Aarhus sample included 236 schizophrenia cases (193 incident cases and 43
cases ascertained from twin pairs) and 500 controls. Cases were diagnosed with schizophrenia according to
the International Classification of Disease, 10th revision, Diagnostic Criteria for Research (ICD-10-DCR)
and DSM-IV through the use of the Schedule for Clinical Assessment in Neuropsychiatry (SCAN)2
interview and a best estimate procedure. The controls were medical students from the University of Aarhus.
Both cases and controls were of Danish parentage three generations back.
Denmark/Copenhagen. The Danish sample from the Copenhagen region included 514 patients and 1,340
controls typed as part of the follow-up set and used in the SNP association analysis and 580 patients and 567
controls typed later on Illumina BeadChips and used for CNV association analysis. Of the subjects, 482
patients and 433 controls were included in both sets. Patients were recruited to the Danish Psychiatric
Biobank from the psychiatric departments of the six hospitals in the Copenhagen region and were clinically
diagnosed with schizophrenia according to ICD-10 (F20) without ever having received a diagnosis of mania
or bipolar illness (F30 or F31). An experienced research-and-consultant psychiatrist verified the high
reliability of the clinical diagnoses using the Operational Criteria Checklist for Psychotic and Affective
Illness (OPCRIT)3. Of the controls, 889 were recruited through the Danish Blood Donor Corps in the
Copenhagen area; for these samples, apparent behavioral abnormality was an exclusion criterion. An
additional 451 controls from the Copenhagen area were recruited by the Danish Headache Center.
England. The English sample included 118 schizophrenia patients drawn from the Maudsley Family Study
of psychosis4, the psychosis twin study5, and the genetics and psychosis (GAP) study6 and 98 unrelated
controls with no history of major mental illness. Patients were interviewed with the Schedule for Affective
Disorders and Schizophrenia Lifetime Version (SADS-L)7 or the Item Group Checklist (IGC) of the
Schedule for Clinical Assessment in Neuropsychiatry (SCAN)2 and diagnosed according to ICD-10-DCR.
Finland. The Finnish sample was made up of 200 schizophrenia patients drawn from a nationwide collection
of families with schizophrenia spectrum disorders and 200 controls. Patients were diagnosed by two
independent psychiatrists, blind to family structures, who made a consensus diagnosis to give best-estimate
lifetime diagnoses according to DSM-IV criteria. Controls were derived from the Health 2000 survey8, 9. Of
the patients, 137 were from Kuusamo, an internal isolate of Finland having a 3.0% age corrected lifetime
risk for schizophrenia compared to 1.1% in the general population10, and 63 came from outside of Kuusamo.
Of the controls, 50 were from Kuusamo and 150 were from outside of Kuusamo.
Germany/Bonn. The Bonn sample was comprised of 285 patients and 522 controls used in the SNP
association portion of the study and 491 patients and 881 controls used in the CNV part of the study.
Patients were recruited from consecutive hospital admissions. At least two experienced
psychiatrists/psychologists made lifetime, best-estimate diagnoses according to DSM-IV criteria using
multiple sources of information including structured interviews with the SCID1 or the SADS-L11, OPCRIT3
data, medical records, and family history. Controls were derived from two German population-based studies,
Heinz Nixdorf Recall and a study in the Mannheim region.
Germany/Munich. The Munich sample consisted of 185 cases and 322 controls used in the SNP association
part of the study and 620 cases and 622 controls used in the CNV part of the study. Cases diagnosed with
DSM-IV schizophrenia were ascertained from the Munich area. Detailed medical and psychiatric histories
were collected, including a clinical interview using the SCID1. Exclusion criteria included a history of head
injury or neurological diseases. The controls were unrelated volunteers randomly selected from the general
population of Munich. To exclude subjects with central neurological diseases and psychotic disorders or
subjects who had first-degree relatives with psychotic disorders, several screenings were conducted before
the volunteers were enrolled in the study.
Hungary. The Hungarian sample included 280 schizophrenia patients and 230 controls. Inpatients and
outpatients with a DSM-IV diagnosis of schizophrenia were enrolled in the study from two major psychiatric
units in Budapest — the Department of Psychiatry and Psychotherapy at Semmelweis University and the
Psychiatry Unit at Szent János Hospital. Exclusion criteria were severely disorganized behavior that
prevented patient cooperation and hindered testing, and severe comorbidity, such as neurological disorders,
head trauma, mental retardation, or substance-abuse. The DSM-IV diagnosis for schizophrenia excluding
schizoaffective disorder was validated using the Mini International Neuropsychiatric Interview (MINI) 5.012.
Healthy controls were recruited from the employees of Semmelweis University and outpatients of the
Department of Internal Medicine after screening for psychiatric disorders.
Iceland. The Icelandic sample consisted of 620 cases with schizophrenia, 424 cases with bipolar disorder,
1,201 cases with depression and anxiety and 37,154 controls. Patients and controls were recruited from all
over Iceland. For the schizophrenia patients and 316 of the bipolar patients, diagnoses were assigned
according to Research Diagnostic Criteria (RDC)11 through the use of the SADS-L7. The remaining 108
bipolar patients and the depression and anxiety patients were recruited through a genetic study of anxiety
and depression13 and had been characterized using the Composite International Diagnostic Interview
(CIDI)14, 15. The 37,154 controls were recruited as a part of various genetic programs at deCODE and were
not screened for psychiatric disorders.
Italy. The Italian sample consisted of 90 patients and 93 controls from Verona. Patients were interviewed
using the IGC2 and diagnosed with schizophrenia according to ICD-10-DCR. Controls were unrelated
volunteers randomly selected from the general population of South Verona.
The Netherlands. The Dutch sample consisted of 715 patients and 3,977 controls. In-patients and outpatients were recruited from different psychiatric hospitals and institutions throughout the Netherlands,
coordinated via academic hospitals in Amsterdam, Groningen, Maastricht and Utrecht. Detailed medical and
psychiatric histories were collected, including the Comprehensive Assessment of Symptoms and History
(CASH), an instrument for assessing diagnosis and psychopathology16. Only patients with a DSM-IV
diagnosis of schizophrenia were included as cases. Controls came from two sources: 643 were volunteers,
free of any psychiatric history collected by the University of Utrecht and 3,334 were cancer and control
samples collected by the Radboud University Nijmegen Medical Centre for genetic studies.
Norway. The Norwegian sample included 283 schizophrenia patients, 266 bipolar patients and 468 controls.
The patients were recruited to the TOP (Tematisk område psykoser) study from all the psychiatric hospitals
in the Oslo area and diagnosed according to SCID1 as having schizophrenia or bipolar disorder. The healthy
control subjects were randomly selected from statistical records of persons from the same catchment area as
the patient groups. Only subjects born in Norway, of Caucasian origin, were contacted by letter and invited
to participate.
Russia. The sample from Moscow included 498 cases and 500 controls, all ethnic Russians. Patients were
recruited from Moscow psychiatric clinics and met the diagnosis of DSM-IV schizophrenia based on their
MINI, version 5.012 responses and medical records. Exclusion criteria were organic or neurological
disorders. The controls were unrelated volunteers randomly selected from the general population of
Moscow.
Scotland. The Scottish sample was comprised of 671 schizophrenia cases and 671 controls. All
participants self-identified as born in the British Isles (95% in Scotland). Cases met DSM-IV and ICD-10
criteria for schizophrenia with diagnosis made by OPCRIT3. Controls were volunteers recruited through
general practices in Scotland. Practice lists were screened for potentially suitable volunteers by age and sex,
and subjects with major mental illness or use of antipsychotic medication were excluded.
Sweden. The Swedish sample included 257 Caucasian patients recruited from psychiatric clinics in
northwestern Stockholm County and 293 Caucasian controls. Patients were clinically diagnosed according to
DSM-III-R/DSM-IV diagnostic criteria based on interviews and record reviews. Controls were recruited
either among subjects previously participating in biological psychiatric research at the Karolinska Institute
or drawn from a representative register of the population in Stockholm County. Controls were interviewed
and did not suffer from schizophrenia.
Supplementary Table 1. Association of rs1344706[T] with schizophrenia by study group
Study group (N cases / N controls)
Illumina genome-wide typeda
England (89/88)
Finland, excl. Kuusamo (58/145)
Finland, Kuusamo (122/49)
Iceland (586/11,395)
Italy (84/89)
Netherlands (689/3,677)
Scotland (652/656)
Follow-up
China (439/446)
Denmark, Aarhus (236/487)
Denmark, Copenhagen (507/1324)
Germany, Bonn (271/507)
Germany, Munich (177/313)
Hungary (251/220)
Norway (188/344)a
Russia (474/477)
Sweden (254/289)
Control
frequency
OR (95% CI)
P value
0.598
0.556
0.556
0.583
0.599
0.587
0.612
0.87 (0.55,1.36)
1.48 (0.91,2.41)
1.01 (0.60,1.71)
1.06 (0.93,1.21)
1.20 (0.75,1.90)
1.08 (0.95,1.22)
1.14 (0.96,1.36)
0.54
0.12
0.96
0.41
0.45
0.26
0.14
0.546
0.589
0.565
0.592
0.634
0.616
0.583
0.606
0.583
0.95 (0.79,1.15)
1.09 (0.87,1.37)
1.22 (1.05,1.42)
1.00 (0.81,1.24)
0.94 (0.71,1.23)
1.09 (0.83,1.42)
1.07 (0.83,1.38)
1.22 (1.02,1.47)
0.94 (0.74,1.19)
0.62
0.45
0.0077
0.98
0.63
0.54
0.62
0.033
0.59
a
analysis for each genome-wide typed group was adjusted using genomic control (see Materials
and Methods)
Supplementary Table 2. Association of rs1344706[T] with bipolar disorder
Study group (N cases / N controls)
Iceland (403/11,395) a
Norway (194/344) a
All (597/11,739)
Control
Frequency
0.583
0.582
0.583
OR (95% CI)
1.13 (0.97,1.31)
1.19 (0.92,1.53)
1.14 (1.00,1.30)
P value
0.13
0.19
0.047
a
analysis was adjusted using genomic control (see Materials and Methods). Note that the results for
bipolar disorder are not independent of the results for schizophrenia as the same control samples were
used. In the combined analysis, the control samples were used only once.
Supplementary Table 3. Phenotypic features of ZNF804A CNV carriers
Patient
1
2
3
a
Origin
Scotland
Iceland
Iceland
Diagnosis
schizophrenia
bipolar disorder
anxiety
Sex
M
F
F
Age at onset
27
20
NA
Family historya
yes
yes
NA
Family history of a psychiatric disorder in a first or second degree relative. NA, not available
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