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Descriptions of the Samples Listed in Table 1
German participants (ie, all 4 grandparents being German) were randomly selected from the general population of Munich, Germany, and contacted by mail. 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. First, subjects who responded were initially screened by telephone for the absence of neuropsychiatric disorders. Second, detailed medical and psychiatric histories were assessed for both themselves and their first-degree relatives by using a semistructured interview. Third, if no exclusion criteria were fulfilled, the subjects were invited to a comprehensive interview including the Structured Clinical Interview for DSM-IV Axis I Disorders–Patient Edition1 and the Structured Clinical Interview for DSM-IV Axis II Personality Disorders2 to validate the absence of any lifetime psychotic disorder. Additionally, the Family History Assessment Module3 was conducted to exclude psychotic disorders among first-degree relatives. A neurological examination was also conducted to exclude subjects with current central nervous system impairment. In volunteers older than 60 years, the Mini-Mental Status Test4 was performed to exclude subjects with possible cognitive impairment. All participants completed the full Wechsler Adult Intelligence Scale–Revised assessment5.
The LOGOS project recruited 1540 randomly selected young male conscripts from the Greek Army (mean age 22.13; range 18–29) between June 2008 and July 2011 at the Military Training Camp of Candidate, Supply Army officers (SEAP) in Heraklion, Crete. Following public presentation of the study’s methods and goals in each consecutive series of new conscripts, all participants willing to volunteer received a detailed information sheet and gave written informed consent before screening. All subjects were thoroughly screened for past or current physical and mental health status by the army medical authorities, the study nurse and a trained research psychologist. They underwent a Mini-International Neuropsychiatric Interview6 and were tested on a single occasion at some point during their 2 months military training in this establishment. Inclusion criteria were recent (last two months) conscript status in the camp and written informed consent. Exclusion criteria were left-handedness (n=150), personal history of head trauma, medical and neurological conditions (n=68), personal history of DSM-IV Axis I disorders (n=95), current use of prescribed drugs or a positive recreational drug screen (n=0) and a hearing test (n=53). On the basis of these criteria, and after 47 subjects who dropped out, cognitive data were available for 1127 subjects. The study was approved by the Ethics Committee of the University of Crete, the Executive Army Bureau, and the Bureau for the Protection of Personal and Sensitive Data of the Greek State.
As described in detail previously7, subjects were administered three subtests of the Cambridge Neuropsychological Test Automated Battery8 namely, spatial working memory, Stockings of Cambridge (a planning and problem solving test), and Rapid Visual Information Processing (a sustained attention test). These are nonverbal tests which were administered with the aid of a high-resolution touch-sensitive screen (Advantech) and/or a response key to all subjects in the same order. Visual working memory was assessed with the N-Back Sequential Letter Task9. Cognitive flexibility and problem solving were assessed using a computerized version of the Wisconsin Card Sorting Test10. The Stroop Interference Test11 was used to measure the selection of appropriate response and interference. Subjects were administered the Iowa Gambling Task12 to assess planning based on emotional processing and integration of incentive information for decision-making. Finally, we used the Word Lists subtest of the Wechsler Memory Scale13 to assess verbal learning and memory.
IBG (Institute for Behavioral Genetics):
The samples were collected as part of two population based twin registries: the Colorado Longitudinal Twin Sample (LTS) and the Colorado Twin Sample (CTS)14. Inclusion criteria were that individuals be twins who lived in the area; there were no exclusion criteria with respect to IQ or psychiatric illness. After providing written, informed consent (or assent from minors with consent from parent/guardian), all subjects were administered the vocabulary and block design subtests of the Wechsler Adult Intelligence Scale (WAIS-III)15 if aged 16 or older; the same subtests from the Wechsler Intelligence Scale for Children (WISC-III)16 were administered to subjects younger than 16.
LBC1936 (Lothian Birth Cohort 1936):
The LBC1936 consists of 1,091 relatively healthy individuals assessed on cognitive and medical traits at 70 years of age. They were born in 1936, most took part in the Scottish Mental Survey of 1947, and almost all lived independently in the Lothian region of Scotland. A full description of participant recruitment and testing can be found elsewhere17. A battery of cognitive tests consisting of 6 tests from the Wechsler Adult Intelligence Scale-III UK (WAIS-III,UK)18: Digit Symbol Coding, Block Design, Matrix Reasoning, Digit Span Backwards, Symbol Search, and Letter-number Sequencing. Following informed consent, venesected whole blood was collected for DNA extraction. Ethical approval for all projects was obtained from Scotland’s Multicentre Research Ethics Committee and the Lothian Research Ethics Committee.
TOP (Thematic Organized Psychosis Research Study):
The participants were recruited as part of a large ongoing study on schizophrenia and bipolar disorder, the Thematic Organized Psychosis Research (TOP) Study, which is run from the University Hospitals in Oslo, Norway. The healthy participants were randomly selected from national statistical records from the same catchment area and contacted by letter inviting them to participate. The healthy sample was screened with interview and with the Primary Care Evaluation of Mental Disorders (PRIME-MD)19, and subjects were excluded if they or any close relatives had a history of a severe psychiatric disorder (schizophrenia, bipolar disorder and major depression), or substance abuse or dependency in the last three months. Exclusion criteria for all groups were: IQ score below 70, hospitalized head injury, neurological disorder, unstable or uncontrolled medical condition that interferes with brain function (including hypothyroidism, uncontrolled hypertension and diabetes), outside the age range 17-65 years. To assure valid neurocognitive test performance all participants had to have Norwegian as their first language or have received their compulsory schooling in Norway, and had to score ≥15 on the forced recognition trial in the California Verbal Learning Test (CVLT-II)20. All participants gave written informed consent, and the study was approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate, and the Biobank was approved by the Health Department.
Neurocognitive assessment was carried out by psychologists trained in standardized neuropsychological testing. A 3 hour test battery (including measures of estimated premorbid IQ and adequate test effort) was administered in a fixed order with two breaks with refreshments.
Attention was tested with the Digit Span Backward, Digit Span Forward and Letter Number components of the Wechsler Adult Intelligence Scale Third Edition (WAIS-III)21 and the simple RT and d-prime components of the Bergen n-back test22. Executive functioning was tested with the Letter Fluency, Category Fluency and Category Switching components of the Delis-Kaplan Executive Function System (D-KEFS23) Word Fluency Test and Condition 3:Inhibition (CW-3) and Condition 4:Inhibition/Switching components (CW-4) of the D-KEFS Color-Word Interference Test. Psychomotor speed was tested with Condition 1:Color Naming (CW-1) and Condition 2:Word Reading components (CW-2) of the DKEFS Color-Word Interference Test, the Digit Symbol Coding component of the WAIS-III21 and with the left and right hand average for the Grooved Pegboard Test24. Learning and Memory was tested with the Long Delay Free Recall component of the California Verbal Learning Test Second Edition (CVLT-II)20, the Logical Memory I Recall Total Score and Logical Memory I Thematic Total Score components of the Wechsler Memory Scale Third Edition (WMS-III)25 and the Long Term Memory (RCFT LTM) component of the Rey Complex Figure Test (RCFT)26. Intelligence was tested with the Block Design, Matrix Reasoning, Similarities and Vocabulary components of the Wechsler Abbreviated Scale of Intelligence (WASI)27 and the National Adult Reading Test (NART)28. The 4-subtest estimated IQ from the WASI was strongly correlated (r=.67, p<10-46) with the computed g utilized in the present study.
NCNG (Norwegian Cognitive NeuroGenetics):
Participants were recruited through newspaper advertisements in the Oslo and Bergen urban areas. All participants were interviewed and probed for past or present neurological or psychiatric diseases known to affect the central nervous system, and for history of substance abuse. Any person with a history of treatment for any of these conditions was excluded from the sample. Participants should have completed basic education with no history of learning deficits; persons who, after initial inclusion, on subsequent testing scored more than one standard deviation below their age norm on intelligence or memory were excluded. Furthermore, persons with a score on a depression inventory indicating a previously undiagnosed depressive illness were excluded. The participants were native speakers of Norwegian. All participants gave their informed consent for participation, which included donation of a blood sample, DNA extraction and genotyping, and storage of the remaining blood sample in a biobank. The project plan was approved by the regional ethical committee for medical research. Permission to obtain and store blood samples for genotyping in a biobank and to establish a registry with relevant information was granted by the Norwegian Department of Health. The participants completed a battery of psychometric tests, assessing general cognition, memory, attention and speed of processing faculties. The recruitment procedure resulted in a cognitively normal sample, skewed towards the high functioning intelligence range.
General cognitive ability was generated using a hierarchy of PCA analyses as previously described29. The unrotated first component for three subtests of the California Verbal Learning Test-II20 defined a memory factor. The first component from the four conditions of D-KEFS23 Color Word interference defined a speed factor. These factor scores, together with the raw score of the Matrix Reasoning subscale of the Wechsler Abbreviated Scale of Intelligence27 and the overall mean of median reaction times from a multiple choice reaction time task, were used as input for a further PCA, of which the un-rotated first component defined the general cognitive ability factor.
The data and samples from Manchester, UK come from a longitudinal research programme called the Age and Cognitive Performance Research study30. Volunteers were recruited by advertisements in local community centres, newspapers, radio, and television. These began in Manchester 1984 to 1986, with refreshment samples recruited in 1989/90 and 1991/92. The only exclusion criteria were that volunteers were at least age 45 years and were able to attend a regional test centre independently. Over the period 1983 to 2003, two alternating batteries of cognitive tasks applied biennially were designed to measure fluid and crystallized aspects of intelligence, as described previously30. These included: the Alice Heim 4 (AH4) parts 1 and 2 tests of general intelligence; Mill Hill Vocabulary A and B vocabulary tests; the Cattell and Cattell Culture Fair intelligence tests; and the Wechsler Adult Intelligence Scale Vocabulary test. In 1999-2002 those volunteers still actively participating in the research were invited to consent to collection of blood sample to extract DNA from. All the research studies described were approved by the University of Manchester Research Ethics Committee.
The Helsinki Birth Cohort Study (HBCS) is composed of 8,760 individuals born between the years 1934-44 in one of the two main maternity hospitals in Helsinki, Finland. Between 2001 and 2003, a randomly selected sample of 928 males and 1075 females participated in a clinical follow-up study with a focus on cardiovascular, metabolic and reproductive health, cognitive function and depressive symptoms. Of this sample, 1728 participants were successfully genotyped on the Illumina Infinum 610K Quad chip by the Wellcome Trust Sanger Institute, Cambridge, UK. Of those with genotype data, 320 men participated in assessment of cognitive functions in 2009 at the mean age of 67.7 years (SD: 2.3). The cognitive functions test scores were obtained from the Finnish Defense Forces Basic Ability Test, developed by the Finnish Defense Forces Education Development Center. The test battery and its psychometric properties are described in detail elsewhere31. In brief, the ability test battery, which is designed to measure general ability and logical thinking, is composed of verbal, arithmetic, and visuospatial reasoning subtests. Each subtest is timed and consists of 40 multiple-choice questions that are ordered by difficulty. Correct answers are summed to obtain a test score. The verbal and arithmetic subtests comprise 4 types of questions. In the verbal reasoning test, the subject has to choose synonyms or antonyms of a given word, select a word belonging to the same category as a given word pair, identify which word of a word list does not belong in the group, and discern similar relations between 2 word pairs. In the arithmetic reasoning test, the subject has to complete a series of numbers that have been arranged to follow a certain rule, to solve verbally expressed short problems, to complete simple arithmetic operations, and to choose similar relations between 2 pairs of numbers. The visuospatial reasoning subtest comprises a set of matrices containing a pattern problem with 1 part removed; it is analogous to Raven’s Progressive Matrices. The subject is asked to decide which of the given single figures completes the matrix, and the test requires the subject to conceptualize spatial relations ranging from the very obvious to the very abstract. Detailed information on the selection of the HBCS participants and on the study design can be found elsewhere32-34. The research plan of the HBCS was approved by the Institutional Review Board of the National Public Health Institute and all participants have signed an informed consent.
ZHH (Zucker Hillside Hospital):
Participants from the New York metropolitan area were recruited through advertisements, word of mouth, referrals, and study registries. Participants had no history of a current or past DSM-IV axis I major mood or psychotic disorder as assessed by structured diagnostic interview35 . Other exclusion criteria included: (1) intellectual or learning disability; (2) significant medical illness that could affect brain structure. Written informed consent was obtained from all participants prior to neurocognitive testing and collection of blood (via venipuncture) for DNA extraction. Since participants were recruited to serve as healthy comparison subjects for studies of patients with schizophrenia and other psychiatric disorders, cognitive testing was performed using the MATRICS Consensus Cognitive Battery (MCCB36,37). The MCCB evaluates seven domains of cognitive function including: 1) speed of processing using the Brief Assessment of Cognition in Schizophrenia (BACS) and Trail Making Test part A; 2) attention using the Continuous Performance Test—Identical Pairs (CPT-IP); 3) working memory using the Wechsler Memory Scale (spatial and letter-number span); 4) verbal learning using the Hopkins Verbal Learning Test—Revised (HVLT-R); 5) visual learning using the Brief Visuopatial Memory Test—Revised (BVMT-R); 6) reasoning and problem solving using the Neuropsychological Assessment Battery (NAB) Mazes subtest; and 7) social cognition using the Mayer–Salovey–Caruso Emotional Intelligence Test (MSCEIT). This study was approved by the Institutional Review Board of the North Shore – Long Island Jewish Health System.
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