Lecture 10 Schizophrenia PDF

PS403 Biological Psychology Schizophrenia Lecture 10 Anne Marie Keane BA MLitt School of Psychology University of Galway [email protected]  Core Textbook Current Key Chapter Reading Basic Reading: Ø Kalat, J.W. (2019). Bi...

PS403 Biological Psychology Schizophrenia Lecture 10 Anne Marie Keane BA MLitt School of Psychology University of Galway [email protected]  Core Textbook Current Key Chapter Reading Basic Reading: Ø Kalat, J.W. (2019). Biological Psychology, 13th edition. Boston, Massachusetts: Cengage Learning. ! Chapter 14: Module 14.3 Schizophrenia  Aetiology of Schizophrenia  Aetiology of Schizophrenia ! Both genetic and environmental factors appear to play a role in aetiology / cause of schizophrenia ! Studies demonstrate that a predisposition for schizophrenia may be transmitted genetically  Aetiology of Schizophrenia ! Research evidence for genetic transmission of a predisposition for schizophrenia comes also from: " Family studies " Twin studies " Adoption studies  Twin Studies ! Concordance rates in MZ twins make two important points: " Proves that a predisposition for schizophrenia may be inherited " Data also prove genetics is not whole story – if it were, concordance rate would be 100%  Twin Studies ! We can therefore expect that some people may carry ‘gene(s)’ for schizophrenia, but do not express it  Twin Studies ! To explore this – researchers going through medical records of Norway and Denmark conducted clever analysis ! Analysis supports a genetic interpretation of high concordance rates found in MZ twins (e.g., Gottesman & Bertelson, 1989; Kringlen & Kramer, 1989)  Twin Studies Gottesman & Bertelson (1989) posed following question: ! Suppose a person with schizophrenia has a twin who does not develop schizophrenia (identical MZ, or fraternal DZ – discordant twins) and that both twins eventually become parents What risk of schizophrenia do their children have?  Twin Studies Data from records indicated: ! In MZ twins – children of twin without schizophrenia had almost same risk as children of twin with schizophrenia {17.4% vs.16.8%} ! In DZ twins – risk was 17.4% for children of twin with schizophrenia and 2.1% for children of twin without schizophrenia Genes and Schizophrenia Susceptibility Gottesman & Bertelson (1989)  Twin Studies ! Gottesman & Bertelson (1989): ! Data suggest some individuals possess a genetic vulnerability for schizophrenia that they pass on to their offspring – despite fact they were never diagnosed with illness themselves  Twin Studies Twin studies have been criticised on several grounds: ! Twins are not representative of general population – have more birth injuries, higher mortality rate, lower birth weights (Eagles, 1994) ! As Reveley & Reveley (1987) stated: ‘Twins could be concordant equally on basis of birth injury, as on genetic predisposition.’  Twin Studies ! Twin method assumes that MZ & DZ twins ‘share common social environments’ ! However – MZ twins spend more time together & have more similar social networks than DZ twins (Horwitz et al., 2003) ! In addition – parental treatment of MZ (identical) twins differs considerably from their interaction with DZ (fraternal) twins  Twin Studies ! All these factors generate confounding environmental variables (Torrey et al., 2019; Breedlove & Watson, 2013; Mirsky, 2000)  Large-scale Twin Study ! Recall large-scale Danish twin study we reviewed last week (Hilker et al., 2018) ! The concordance rates of schizophrenia reported were: " 33% in MZ (identical) twins " 7% in DZ (non-identical) twins ! However, the genetic heritability of schizophrenia was estimated to be 79%  Large-scale Twin Study ! Hilker et al.’s (2018) study used the proband wise method for counting concordant twins (Torrey et al., 2019) ! Method has been criticised because it involves the double counting of concordant twin pairs, if both members of pair have been ascertained independently (Torrey, 1992)  Large-scale Twin Study ! Proband wise method increases concordance rate on which the calculation of heritability is based ! Torrey highlights that in Hilker et al.’s (2018) study – only 12 out of 81 pairs of MZ twins (15%) became concordant ! However, because proband wise method was partially used, concordance rate reported was 33%  Twin Studies ! Modelling process used to calculate genetic heritability in twin studies has been criticised (e.g., Torrey et al., 2019) ! The model’s assumptions are: ! Twins are comparable to general population ! MZ & DZ pairs share common environmental effects to same extent ! Gene-environmental interactions are minimal  Twin Studies ! Such assumptions are known to be incorrect ! So, the derivation of 79% genetic heritability estimate from a study in which only 15% (as opposed to 33%) of MZ twins became concordant – suggests that something is fundamentally wrong with modelling  Twin Studies ! Most critical problem of interpretation remains ! Since twins are reared together – common deviant environment (rather than common genetic factors) could account for concordance rates ! Hence why researchers have conducted adoption studies  Aetiology of Schizophrenia ! Research evidence for genetic transmission of a predisposition for schizophrenia comes also from: " Family studies " Twin studies " Adoption studies  Adoption Studies ! Third line of evidence – examines adopted children who develop schizophrenia – studies support a genetic basis for schizophrenia ! In adoption studies – genetic and rearing factors can be disentangled to an extent  Adoption Studies ! What is hypothesis? Adults with schizophrenia, adopted as children, are more likely to have biological relatives with schizophrenia compared with adults, adopted as children, who do not have schizophrenia  Adoption Studies ! Adoption studies try to eliminate possible effects of deviant environment ! But, of course, the prenatal environment of biological mother cannot be discounted  Adoption Studies ! Kety (1994) compared the relatives of adoptees with and without schizophrenia using records from entire country of Denmark ! In adoptees with schizophrenia – Kety found schizophrenia in 12.5% of first- degree biological relatives  Adoption Studies ! Kety found no schizophrenia in biological relatives of adoptees without schizophrenia ! Similar findings reported by Heston (1966) and Kety (1988)  Adoption Studies ! Tienari et al. (2004) carried out a long- term follow-up study of adoptees in Finland ! Empirically explored the genotype- environment interaction in the development of schizophrenia- spectrum disorder  Adoption Studies ! Study designs up to then had not incorporated observations of family- rearing environment ! In this study – the outcome was presence or absence of schizophrenia-spectrum disorder in adoptee  Adoption Studies ! Tienari blindly compared family-rearing environment of two groups of adopted away offspring from Finnish nationwide sample of 303 adoptees ! 145 adoptees had biological mothers with diagnosis of schizophrenia- spectrum disorder high-genetic risk  Adoption Studies ! 158 adoptees had biological mothers with non-schizophrenia-spectrum psychiatric diagnosis or no psychiatric diagnosis low-genetic risk  Adoption Studies Family Rearing Environment ! Groups were matched on demographic variables ! Adoptive parents of those at high versus low genetic risk – blindly observed, interviewed, and tested to evaluate independently the families’ environments  Adoption Studies ! Clinical procedures included: " Jointinterviews with whole family and with parental couples " Semi-structured personal interviews with family members  Adoption Studies ! Clinical observation and interview information – used to rate ‘family functioning’ on Oulu Family Rating Scale (OPAS)  Adoption Studies What did the researchers find? ! Tienari reported a higher probability of schizophrenia or related conditions among children who had a biological mother with schizophrenia ! Association was not seen in low-genetic- risk group  Adoption Studies What did the researchers find? ! The probability was higher for children who had a mother with schizophrenia and growing up in a dysfunctional family magnified that risk (see next slide) Probability of Schizophrenia or Similar Conditions in Adopted Children Source: Based on data from Wynne et al. (2006)  Adoption Studies ! Example of genotype–environment interaction i.e. adoptees at genetic risk were more sensitive to problems in the adoptive family ! Alternative way to view findings – seemed to be a protective effect of being reared in ‘healthy’ adoptive family Diathesis-Stress Model  Heritability of Schizophrenia ! Many questions remain unanswered: " How is the disorder transmitted? " What is being inherited? " What gene(s) are related to this disorder, and what processes do they control?  Efforts to Locate a Gene ! What is clear is that no single gene causes schizophrenia ! More probably are multiple susceptibility genes – each with a small effect and acting in concert with epigenetic and environmental factors " (Cannon, 2015; Van Os & Kapur, 2009; Mueser & McGurk, 2004)  Efforts to Locate a Gene ! These include the genes encoding: " COMT (catechol-O-methyltransferase) involved in metabolising dopamine " G72 – thought to contribute to glutamatergic activity " Neuregulin 1 – participates in NMDA, GABA and ACh receptor regulation  Efforts to Locate a Gene " Dysbindin – presynaptic glutamate function " DISC1 (disrupted in schizophrenia 1) Two portions of different chromosomes swapping positions with each other (Gejman, Sanders & Kendler, 2010; Di Forti et al., 2007; Kennedy et al., 2003)  Efforts to Locate a Gene ! DISC1 gene controls differentiation & migration of neurons in brain development (Steinecke et al., 2012) ! DISC1 gene controls production of dendritic spines and generation of new neurons in hippocampus (Duan et al., 2007)  Genetic Factors ! So, genetic factors can affect production & levels of neurotransmitters & their receptor sites ! Genetic factors can also affect the size of brain structures & their level of connectivity  GWAS Study ! Ambitious genome-wide association (GWAS) study was published by Schizophrenia Working Group of Psychiatric Genomics Consortium in 2014 (Schizophrenia Working Group of PGC, 2014) ! Analysed genetic data from >35,000 individuals with schizophrenia and >110,000 controls  GWAS Study ! GWAS analysis identified 108 distinct loci – 83 of which had not been previously implicated in schizophrenia ! Noteworthy gene locations included: " Dopamine receptor D2 gene – highlighting known importance of dopamine neurotransmission in pathology of schizophrenia  GWAS Study ! Noteworthy gene locations included: " Several genes encoding proteins involved in glutamatergic neurotransmission " Genes expressed in tissues with important roles in immunity – supporting hypothesised link between schizophrenia & immune system  GWAS Study ! Ma and colleagues analysed data from several different GWAS studies ! Identified 6 crucial genes linked to increased risk of developing schizophrenia – five of which are related to neurodevelopment (Ma, Gu, Huo et al., 2018)  In Summary ! Many genes are known to be involved in schizophrenia, each with small effect & unknown transmission and expression (Coelewij & Curtis, 2018) ! The summation of these effect sizes into a polygenic risk score can explain at least 7% of variability in liability for schizophrenia (Kendler, 2016)  In Summary ! Around 5% of schizophrenia cases are understood to be partially attributable to rare copy number variants (CNVs – small duplications or deletions, or inversions) ! Some CNVs can increase risk of developing schizophrenia by as much as 20-fold (Lowther, Costain, Baribeau, & Bassett, 2017) To Be Continued