Supplementary Table 1. Parameterisation of ...

  Supplementary Table 1. Parameterisation of Exposure and Outcome Variables in Molecular Genetic Candidate GxE Studies.

Author

Environmental Risk Factor

Outcome Variable

Cannabis use (Cannabis Experience Questionnaire, modified version (Di Forti et al., 2009)): 1) Lifetime history of cannabis use (had the subject ever used cannabis at any point in Non-organic psychosis diagnosis (SCAN Di Forti et al., 2012 the lifetime; No=0, Yes=1); interview (World Health Organization, 1992)). 2) Lifetime frequency of cannabis use (the frequency that characterized the subject’s most consistent pattern of use; ‘No’ = 0, ‘At weekends or less frequently’ = 1, ‘Everyday’ = 2). Bhattacharyya et al., Experimentally administered single 10-mg D-9-THC induced psychotic symptoms 2012 dose of D-9-THC. (PANSS interview (Kay et al., 1986)). Cumulative use of cannabis reported at age 14 (none, 60 Zammit et al., 2011 occasions), obtained from self-report postal questionnaires.

Psychotic experiences at age 16 (PLIKS-Q questionnaire (Horwood et al., 2008)).

Cannabis use measured as:

- The SIS-R (Kendler et al., 1989; Vollema and Ormel, 2000) was administered to controls and siblings, and positive van Winkel and the 2) Lifetime (CIDI interview (Robins et al., schizotypy was the outcome variable in the Genetic Risk at-risk paradigm (siblings). Outcome Psychosis 1988) assessing pattern of use during the lifetime period of heaviest use, restricted to - In the case-only, case-sibling and caseGroup (2011) individuals in whom the age at most heavy control paradigms, onset of psychosis was use preceded onset of psychosis). the outcome variable (first mental health contact for psychosis). 1) Recent (urinalysis), for the at-risk paradigm (siblings)

 

Kantrowitz et al., 2009

Cannabis use defined as used at least five times in their lives, and when first use of cannabis preceded the first admission for psychotic disorder.

Genotype associations with cannabis use in White and African-American patients with schizophrenia (SCID interview(First, 1996))

Cannabis use in daily life as measured with the ESM (Myin-Germeys et al., 2001) method: 12 times a day on 6 consecutive Psychotic experiences (hallucinations, days, a watch emitted a beep at random Henquet et al., 2009 delusions) in daily life measured with the moments. After each beep, subjects were ESM (Myin-Germeys et al., 2001) asked to report cannabis use, current mood, thoughts and severity of symptoms (7-point Likert scales). Use of Cannabis and Tobacco data Zammit et al., 2007 obtained from interview and case-note records

Schizophrenia diagnosis (SCAN interview (World Health Organization, 1992))

Transient psychotic symptoms under deltaExperimentally administered single dose of 9-THC (positive dimension of the CAPE Henquet et al., 2006 300 mg delta-9-THC/kg body weight in (Konings et al., 2006) self-report tobacco cigarettes questionnaire)

1  

 

Caspi et al., 2005

Adolescent-onset cannabis use: the subject had used cannabis before age 15, or was at least monthly cannabis user by age 18

DSM-IV diagnosis of Schizophreniform disorder, determined at age 26 using the Diagnostic Interview Schedule (Robins, 1995)

Childhood adversity as assessed with the shortened version of the CTQ (Bernstein, 1998), distinguishing five types of trauma: emotional abuse, physical abuse, sexual abuse, emotional neglect and physical neglect. Answers were recorded to 0 Positive and negative psychotic-like Alemany et al., 2011 (never true) and 1 (rarely true, sometimes experiences assessed with the CAPE true, often true and very often true), and (Konings et al., 2006) then grouped into two main categories: 1) childhood abuse (including emotional, physical and sexual abuse) and 2) childhood neglect (including emotional and physical neglect). Muntjewerff et al., 2011

Seasonality of birth; categorising month of birth into four climatic quarters: December– DSM-IV diagnosis of SZ (CASH interview) February (winter), March–May (spring), (Andreasen et al., 1992) June–August (summer), September– November (autumn).

Chotai et al., 2003

Season of birth variations in TPH allele A, Seasonality of birth (January-March, April- 5-HTTLPR allele S, and DRD4 exon3 7June, July-September, October-December)repeat allele in patients with a DSM-IV diagnosis of UPAD, BPAD, or SZ

Tochigi et al., 2002 Winter birth (December through March)

Frequency of HLA-A specificities (A24, A26) in patients with a DSM-IV diagnosis of SZ, AND Associations between HLA-A and winter birth in SZ

Narita et al., 2000

Winter birth (February and March)

Associations between HLA-DR1 and winter birth in patients with a DSM-IV diagnosis of SZ

Nicodemus et al., 2008

Obstetric Complications: questionnaires completed by parents of affected individuals and of control subjects who permitted contact with their parents

DSM-IV diagnosis of schizophrenia, schizoaffective disorder, simple schizophrenia, psychosis NOS, delusional disorder, schizotypal, schizoid or paranoid personality disorder

Peerbooms et al., 2012

ESM (Myin-Germeys et al., 2001) stress: the subject was asked to report, after each ESM (Myin-Germeys et al., 2001) beep, the most important event that had psychosis: sum score of six items “I feel happened between the current and the suspicious”, ”I cannot get rid of my previous report. This event was thoughts”, ”I am afraid of losing control”, ”I subsequently rated on a bipolar Likert feel unreal”, and ”I hear voices”, ”I see scale (-3=very unpleasant, 0=neutral, phenomena”. All items were rated on 73=very pleasant). The responses were point Likert scales (ranging from ”not at all” recoded to allow high scores to reflect to ”very”) (Cronbachs α = 0.71). stress (-3 = very pleasant, 0 = neutral, 3 = very unpleasant).

2  

 

Collip et al., 2011

ESM (Myin-Germeys et al., 2001) stress: the subject was asked to report, after each ESM (Myin-Germeys et al., 2001) beep, the most important event that had momentary psychosis: sum score of six happened between the current and the items “I feel suspicious”, ”I cannot get rid of previous report. This event was my thoughts”, ”I am afraid of losing subsequently rated on a bipolar Likert control”, ”I feel unreal”, and ”I hear voices”, scale (-3=very unpleasant, 0=neutral, ”I see phenomena”. All items were rated on 3=very pleasant). The responses were 7-point Likert scales (ranging from ”not at recoded to allow high scores to reflect all” to ”very”) (Cronbachs α = 0.72). stress (-3 = very pleasant, 0 = neutral, 3 = very unpleasant).

Kéri et al., 2009

Psychosocial stress: during 10-minute conversations, participants discussed two neutral themes, one patient-generated and the other relative-generated (such as Unusual thinking as measured by the television programs, food, or clothing) and Patient Symptom Profile (Rosenfarb et al., two previously identified family problems 1995). (such as occupation, everyday activity, and self-care). Each speech segment represented a unit of analysis. ESM (Myin-Germeys et al., 2001) Stress:

1) Event stress: subjects had to rate the most important event that had happened between the current and the previous ESM assessment on a 7-point bipolar scale (from -3 = very unpleasant, 0 = neutral to 3 ESM (Myin-Germeys et al., 2001) Feelings = very pleasant). of paranoia: subjective ratings of the item “I Simons et al., 2009 feel suspicious” [‘not at all’ (1), to ‘very’ 2) Social stress: subjects reported whether (7)]. they were alone at the time of the assessment. If not alone, they were asked whether they liked the company they were in at that moment (social stress). This was rated on a 7-point Likert scale (from ‘not at all’ = 1 to ‘very much’ =7).

van Winkel et al., 2008

ESM (Myin-Germeys et al., 2001) Psychosis: formed by the sum of nine items (Cronbach’s α=0.77) including ‘‘auditory hallucinations,’’ ‘‘visual hallucinations,’’ ‘‘preoccupation,’’ ESM (Myin-Germeys et al., 2001) Stress: ‘‘suspicion,’’ ‘‘feeling unreal,’’ ‘‘feeling subjects had to rate the most important controlled,’’ ‘‘difficulty of expressing event that had happened between the thoughts,’’ ‘‘racing thoughts,’’ and ‘‘fear of current and the previous ESM assessment losing control’’. on a 7-point bipolar scale (from -3 = very unpleasant, 0 = neutral to 3 = very Negative affect: nine mood-related items, pleasant). including ‘‘down,’’ ‘‘guilty,’’ ‘‘insecure,’’ ‘‘lonely,’’ and ‘‘anxious’’ formed the NA scale, (Cronbach’s α=0.80). All items rated on 7-point Likert scales (1, ”not at all” to 7,”very”).

3  

  Psychotic symptoms as measured with the SCL-90-R (Henquet et al., 2005) self-report questionnaire. At 2 weeks of military Stress: measured as the level of stress by training, and at conclusion of military period (0 = low stress condition at training, the ‘paranoid ideation’ and Stefanis et al., 2007 conclusion of military training; 1 = high ‘psychoticism’ subscales were used to stress condition at army induction). assess state-related psychotic symptoms. Mean scores of both subscales were combined into a mean total score (“SCL90-R psychosis score”).

5-HTTLPR = serotonine transporter gene; BPAD = Bipolar Affective Disorder; CAPE= Community Assessment of Psychic Experiences; CASH = Comprehensive Assessment of Symptoms and History; CIDI = Composite International Diagnostic Interview; CTQ = Childhood Trauma Questionnaire; D-9– THC = delta-9-tetrahydrocannabinol; DIGS = Diagnostic Interview for Genetic Studies scale; DRD4 = dopamine D4 receptor gene; DSM = Diagnostic and Statistical Manual of Mental Disorders; ESM = Experience Sampling Method; HLA = Human Leukocyte Antigen; PANSS = Positive And Negative Syndrome Scale; PLIKS-Q = Psychosis-Like Symptoms Questionnaire; SCAN = Schedules for Clinical Assessment in Neuropsychiatry; SCID = Structured Clinical Interview for DSM IV Axis I Disorders; SCL-90-R = Symptom Checklist-90 – Revised; SIS-R = Structured Interview for Schizotypy–Revised; SZ = Patients with Schizophrenia; TPH = tryptophan hydroxylase gene; UPAD = Unipolar Affective Disorder.

4  

  References

Alemany, S., Arias, B., Aguilera, M., Villa, H., Moya, J., Ibanez, M.I., Vossen, H., Gasto, C., Ortet, G., Fananas, L., 2011. Childhood abuse, the BDNFVal66Met polymorphism and adult psychotic-like experiences. Br J Psychiatry 199(1), 38-42. Andreasen, N.C., Flaum, M., Arndt, S., 1992. The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. Arch Gen Psychiatry 49(8), 615-623. Bhattacharyya, S., Atakan, Z., Martin-Santos, R., Crippa, J.A., Kambeitz, J., Prata, D., Williams, S., Brammer, M., Collier, D.A., McGuire, P.K., 2012. Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of delta-9tetrahydrocannabinol on midbrain and striatal function. Mol Psychiatr 17(12), 1152-1155. Bernstein, D.P.F.L., 1998. Childhood Trauma Questionnaire: A retrospective selfreport. The Psychological Corporation, San Antonio. Caspi, A., Moffitt, T.E., Cannon, M., McClay, J., Murray, R., Harrington, H., Taylor, A., Arseneault, L., Williams, B., Braithwaite, A., Poulton, R., Craig, I.W., 2005. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry 57(10), 1117-1127. Chotai, J., Serretti, A., Lattuada, E., Lorenzi, C., Lilli, R., 2003. Gene-environment interaction in psychiatric disorders as indicated by season of birth variations in tryptophan hydroxylase (TPH), serotonin transporter (5-HTTLPR) and dopamine receptor (DRD4) gene polymorphisms. Psychiatry Res 119(1-2), 99-111. Collip, D., van Winkel, R., Peerbooms, O., Lataster, T., Thewissen, V., Lardinois, M., Drukker, M., Rutten, B.P., Van Os, J., Myin-Germeys, I., 2011. COMT Val158Met-stress interaction in psychosis: role of background psychosis risk. CNS Neurosci Ther 17(6), 612-619. Di Forti, M., Iyegbe, C., Sallis, H., Kolliakou, A., Falcone, M.A., Paparelli, A., Sirianni, M., La Cascia, C., Stilo, S.A., Marques, T.R., Handley, R., Mondelli, V., Dazzan, P., Pariante, C., David, A.S., Morgan, C., Powell, J., Murray, R.M., 2012. Confirmation that the AKT1 (rs2494732) Genotype Influences the Risk of Psychosis in Cannabis Users. Biol Psychiat 72(10), 811-816. Di Forti, M., Morgan, C., Dazzan, P., Pariante, C., Mondelli, V., Marques, T.R., Handley, R., Luzi, S., Russo, M., Paparelli, A., Butt, A., Stilo, S.A., Wiffen, B., Powell, J., Murray, R.M., 2009. High-potency cannabis and the risk of psychosis. Br J Psychiatry 195(6), 488-491. First, M., Spitzer, R., Gibbon, M., Williams, J.B.W., 1996. Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version (SCID-CV). American Psychiatric Press, Inc., Washington, D.C. Henquet, C., Rosa, A., Delespaul, P., Papiol, S., Fananas, L., van Os, J., MyinGermeys, I., 2009. COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life. Acta Psychiatr Scand 119(2), 156-160. Henquet, C., Rosa, A., Krabbendam, L., Papiol, S., Fananas, L., Drukker, M., Ramaekers, J.G., van Os, J., 2006. An experimental study of catechol-omethyltransferase Val158Met moderation of delta-9-tetrahydrocannabinolinduced effects on psychosis and cognition. Neuropsychopharmacology 31(12), 2748-2757.

  Henquet, C., Krabbendam, L., Spauwen, J., Kaplan, C., Lieb, R., Wittchen, H.U., van Os, J., 2005. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ 330(7481), 11. Horwood, J., Salvi, G., Thomas, K., Duffy, L., Gunnell, D., Hollis, C., Lewis, G., Menezes, P., Thompson, A., Wolke, D., Zammit, S., Harrison, G., 2008. IQ and non-clinical psychotic symptoms in 12-year-olds: results from the ALSPAC birth cohort. Br J Psychiatry 193(3), 185-191. Kay, S.R., Opler, L.A., Fiszbein, A., 1986. Significance of positive and negative syndromes in chronic schizophrenia. Br J Psychiatry 149, 439-448. Kendler, K.S., Lieberman, J.A., Walsh, D., 1989. The Structured Interview for Schizotypy (SIS): a preliminary report. Schizophr Bull 15(4), 559-571. Konings, M., Bak, M., Hanssen, M., van Os, J., Krabbendam, L., 2006. Validity and reliability of the CAPE: a self-report instrument for the measurement of psychotic experiences in the general population. Acta Psychiatr Scand 114(1), 55-61. Kantrowitz, J.T., Nolan, K.A., Sen, S., Simen, A.A., Lachman, H.M., Bowers, M.B., 2009. Adolescent Cannabis Use, Psychosis and Catechol-OMethyltransferase Genotype in African Americans and Caucasians. Psychiat Quart 80(4), 213-218. Keri, S., Kiss, I., Seres, I., Kelemen, O., 2009. A polymorphism of the neuregulin 1 gene (SNP8NRG243177/rs6994992) affects reactivity to expressed emotion in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 150B(3), 418420. Muntjewerff, J.W., Ophoff, R.A., Buizer-Voskamp, J.E., Strengman, E., den Heijer, M., Consortium, G., 2011. Effects of season of birth and a common MTHFR gene variant on the risk of schizophrenia. Eur Neuropsychopharmacol 21(4), 300-305. Myin-Germeys, I., Nicolson, N.A., Delespaul, P.A., 2001. The context of delusional experiences in the daily life of patients with schizophrenia. Psychol Med 31(3), 489-498. Narita, K., Sasaki, T., Akaho, R., Okazaki, Y., Kusumi, I., Kato, T., Hashimoto, O., Fukuda, R., Koyama, T., Matsuo, K., Okabe, Y., Nanko, S., Hohjoh, H., Tokunaga, K., 2000. Human leukocyte antigen and season of birth in Japanese patients with schizophrenia. Am J Psychiat 157(7), 1173-1175. Nicodemus, K.K., Marenco, S., Batten, A.J., Vakkalanka, R., Egan, M.F., Straub, R.E., Weinberger, D.R., 2008. Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. Mol Psychiatry 13(9), 873-877. Peerbooms, O., Rutten, B.P., Collip, D., Lardinois, M., Lataster, T., Thewissen, V., Rad, S.M., Drukker, M., Kenis, G., van Os, J., Myin-Germeys, I., van Winkel, R., 2012. Evidence that interactive effects of COMT and MTHFR moderate psychotic response to environmental stress. Acta Psychiatr Scand 125(3), 247-256. Robins, L.N., Cottler, L., Bucholtz, K., Compton, W., 1995. Diagnostic Interview Schedule for DSM-IV. Washington University, St. Louis, MO. Robins, L.N., Wing, J., Wittchen, H.U., Helzer, J.E., Babor, T.F., Burke, J., Farmer, A., Jablenski, A., Pickens, R., Regier, D.A., et al., 1988. The Composite International Diagnostic Interview. An epidemiologic Instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Arch Gen Psychiatry 45(12), 1069-1077. Rosenfarb, I.S., Goldstein, M.J., Mintz, J., Nuechterlein, K.H., 1995. Expressed emotion and subclinical psychopathology observable within the transactions between schizophrenic patients and their family members. J Abnorm Psychol 104(2), 259-267.

  Simons, C.J., Wichers, M., Derom, C., Thiery, E., Myin-Germeys, I., Krabbendam, L., van Os, J., 2009. Subtle gene-environment interactions driving paranoia in daily life. Genes Brain Behav 8(1), 5-12.Tochigi, M., Ohashi, J., Umekage, T., Kohda, K., Hibino, H., Otowa, T., Marui, T., Masui, K., Sugahara, Y., Kanamori, R., Juji, T., Kato, N., Tokunaga, K., Sasaki, T., 2002. Human leukocyte antigen-A specificities and its relation with season of birth in Japanese patients with schizophrenia. Neurosci Lett 329(2), 201-204. Stefanis, N.C., Henquet, C., Avramopoulos, D., Smyrnis, N., Evdokimidis, I., MyinGermeys, I., Stefanis, C.N., Van Os, J., 2007. COMT Val158Met moderation of stress-induced psychosis. Psychol Med 37(11), 1651-1656. van Winkel, R., Genetic Risk Outcome Psychosis Group, 2011. Family-Based Analysis of Genetic Variation Underlying Psychosis-Inducing Effects of Cannabis Sibling Analysis and Proband Follow-up. Arch Gen Psychiat 68(2), 148-157. van Winkel, R., Henquet, C., Rosa, A., Papiol, S., Fananas, L., De Hert, M., Peuskens, J., van Os, J., Myin-Germeys, I., 2008. Evidence that the COMT(Val158Met) polymorphism moderates sensitivity to stress in psychosis: an experience-sampling study. Am J Med Genet B Neuropsychiatr Genet 147B(1), 10-17. Vollema, M.G., Ormel, J., 2000. The reliability of the structured interview for schizotypy-revised. Schizophr Bull 26(3), 619-629. World Health Organization, 1992. Schedules for Clinical Assessment in Neuropsychiatry (SCAN). World Health Organization, Geneva. Zammit, S., Owen, M.J., Evans, J., Heron, J., Lewis, G., 2011. Cannabis, COMT and psychotic experiences. Br J Psychiatry 199(5), 380-385. Zammit, S., Spurlock, G., Williams, H., Norton, N., Williams, N., O'Donovan, M.C., Owen, M.J., 2007. Genotype effects of CHRNA7, CNRI and COMT in schizophrenia: interactions with tobacco and cannabis use. Brit J Psychiat 191, 402-407.