How genetically informative study designs can inform interventions.pdf

How genetically informative study designs can inform interventions 12 November 2023 Main Ideas 21:03 Notes Notes Notes What is an intervention? ○ The act of intervening, interfering or interceding with the intent of modifying the outcome. ○ In medicine, an intervention is usually undertaken to help...

How genetically informative study designs can inform interventions 12 November 2023 Main Ideas 21:03 Notes Notes Notes What is an intervention? ○ The act of intervening, interfering or interceding with the intent of modifying the outcome. ○ In medicine, an intervention is usually undertaken to help treat or cure a condition Possibility to change heritable behaviours ○ Genetic risk is not deterministic ▪ DNA is just code ▪ So from DNA to phenotype there are numerous developmental steps that can be interfered with ○ Genetic (and environmental) risk may mean it is difficult for some people to remain healthy ○ In theory, should be able to attenuate genetic risk using interventions Example: Phenylketonuria (PKU) □ Treating depression ® 40% fail to respond to first antidepressant they are prescribed ◊ Though, these individuals are not treatment-resistant as 70% will eventually respond to a different medication ◊ Finding the most effective and tolerable drug is a trial and error process that has a negative impact on treatment □ Family studies of antidepressant response ® Response to antidepressants (TCAs, MAOIs and SSRIs) among relative pairs seem to run in families ® Could be due to shared environment or shared genes ▪ Twin studies □ By comparing identical and non-identical twins, able to see how much of the variation in drug response is due to genes □ Studies of metabolism of antidepressants which suggest a significant genetic component □ However, there are no twin studies of clinical response to antidepressants ▪ Genome-wide Complex Trait Analysis (GCTA) Genetics and intervention ○ Can identify genes that influence behaviour ○ May be possible to use this info to modify people's behaviour ○ Genome editing ▪ Repair or replacement of genes ○ Medical Interventions ▪ Using medication to change behaviour ○ Environmental interventions ▪ e.g., change in diet or education Genome editing ○ This is the ability to add, remove or change DNA sequence ○ A more recent technique includes CRISPR (clustered regularly interspersed short palindromic repeats): ▪ Seen as a "molecular scalpel" which is actually programmable RNA molecule ▪ Precise, easy to use ▪ Can be used in vivo ○ 2020 Nobel Prize in Chemistry (Doudna & Charpentier) ○ Fundamental science ▪ Used to remove/add genes to understand how they work and interact ○ Applications ▪ Used to modify crops ▪ Application in humans for the treatment Sickle Cell disease and β-Thalassemia ▪ Clinical trials currently ongoing for many diseases including: □ Inherited blindness □ HIV □ Cancer ○ Ethical questions ▪ Modified germline (the cells that form the egg, sperm and the fertilised egg) ▪ Possible unintended consequences Pharmacogenetics ○ The study of heritable differences in the metabolism and activity of exogenous agents such as drugs or environmental toxins (Vogel, 1959) ▪ Antidepressants □ Antidepressants are often the first choice for treating depression ® Examples: TCA, SSRI, SNRI, NARI, SARI □ Efficacy of antidepressants ® Past meta-analyses have reported only modest benefits over placebo treatment ® Unpublished trial data has found even lower benefits for the accepted criteria for clinical significance ® However, a meta-analysis which took into account baseline depression scores (as efficacy may depend on this) found a statistically significant effect of antidepressants compared to placebo (Kirsch et al.,) ◊ Though, these findings weren't clinically meaningful according to NICE guidelines Summary Therapygenetics: ○ Differential response to cognitive behavioural therapy based on genotype? ○ Future studies: ▪ Whole genome approaches ▪ Large homogeneous samples Genetics can be as a tool for understanding interventions Pharmacogenetics ○ use genetic information to help personalise treatment Therapygenetics ○ Genes associated with environmental responsivity may influence response to psychological therapy ○ Differential susceptibility hypothesis also suggests that those at greatest need might be most likely to benefit from interve ntions Future research ○ Studies to predict which individuals would be more suited to pharmacological or psychological therapy ○ How do interventions get under the skin? ▪ Biological mechanisms (e.g. epigenetics) PSYC0036 Genes and Behaviour Page 1 □ Uses genome-wide data (more than 1 million variants across the genome) 5-HTTLPR and antidepressant response ○ 5-HTTLPR is a gene that is the main regulator of serotonin ○ Escitalopram medicine vs nortriptyline medicine ▪ On average depression severity (MADRS) scores decreased over 1 Pharmacogenetics: summary ○ Genetic factors are likely to affect treatment response ▪ E.g. evidence from GCTA ○ A number of variants in genes implicated in the pharmacodynamics of a response ○ Replication of these findings: ▪ heterogeneity of study designs ▪ the complexity of the antidepressant response phenotype Therapygenetics This is a parallel field to pharmacogenetics Research looking at the relationship between specific genetic variants and diff (Eley et al., 2011) Caspi et al (2003) - interaction between the 5HTTLPR genotype and stressful □ Work out the relatedness of individuals based on the sharing of variants □ Find out how much of the variance in treatment response is explained by this relatedness ▪ Difference between twin design and GCTA □ ▪ GCTA studies □ A study by Tansey et al. investigated the contribution of common genetic variation to antidepressant response with GTCA □ Researchers found that the heritability estimate = 42%. ® In other words, 42% of the variance in treatment response is explained by common genetic variation ▪ Which genes and where to look □ Treatment response to antidepressants shown to be heritable but uncertain about which genes are important ○ The level of depression symptoms increases with the number of stressf steeper for the s/s genotype. ○ People with the s/s genotype of the 5HTTLPR gene have higher levels o genotype, even when they have experienced no stressful life events ○ There are two alleles of the 5HTTLPR gene: ▪ a short allele (s) and a long allele (l). ▪ People who have two copies of the short allele (s/s) have the low ▪ People who have two copies of the long allele (l/l) have the highe ▪ People who have one copy of each allele (s/l) have intermediate Diathesis Stress Model (Bakermans-Kranenburg & van Ijzendoorn, 2007) ○ The resilient individuals are less likely to develop mental disorders, even ○ The vulnerable individuals are more likely to develop mental disorders, ® Pharmacokinetics ◊ About what the body does to the drug ◊ Involves: drug metabolism, drug distribution ® Pharmacodynamics ◊ About what the drug does to the body ◊ Involves: effects of the drug at the target organ ® Hypothesis free approaches ◊ identifies co-enriched genes without prior knowledge ▪ Pharmacodynamic genes □ Tricyclic antidepressants ® Clomipramine, amitriptyline, nortriptyline ® Target the noradrenaline and serotonin transporters □ Selective serotonin reuptake inhibitors ® Citalopram, escitalopram, fluoxetine ® Target and inhibit the serotonin transporter Differential susceptibility hypothesis (Belsky et al., 2009) ○ The DSH proposes that some individuals are more sensitive to the effec ○ This means that they are more likely to be influenced by both positive a ○ Plastic/malleable individuals are more susceptible to the effects of the e Differential susceptibility (Bruce & Boyce, 2008) ○ Some individuals will be generally less affected by environmental influences: ▪ More resilient to adverse experiences ▪ Less responsive to positive experiences ○ Some individuals will be generally more affected by environmental influences: ▪ More vulnerable to adverse experiences ▪ More responsive to positive experiences ○ Belsky et al. - 5HTTLPR as a marker of environmental plasticity ▪ Individuals with certain genetic variants (alleles) are more vulnerable to the effects of environmental stress on mental health ▪ Researchers propose that the concept of "vulnerability genes" should be replaced with the concept of "plasticity genes." □ This is because these genes do not simply make individuals more vulnerable to mental disorders; they make them more responsive to the environment, both positive and negative Cognitive behavioural therapy ○ CBT can be seen as a positive environmental influence ○ Based on differential susceptibility model might expect response to vary according to genotype Therapygenetics: CBT and Anxiety ○ CBT is the most common treatment for child anxiety ○ It is effective in approximately 60% of cases (Cartwright-Hatton, 2004) ○ Lack of response to treatment is associated with (Hudson, 2005): ▪ Older age ▪ Severity of symptoms including comorbidity ▪ Parental psychopathology □ Genetic influence on treatment response? ○ Predicting change in Clinical Severity Ratings following CBT from 5HTTLPR genotype (Eley et al., 2011) 12 weeks antidepressants have been shown to be predictive of fferences in the level of success of psychological therapy l life events on adult depression ful life events for both genotypes, but the increase is of depression symptoms than people with the s/l est levels of serotonin transporter expression st levels of serotonin transporter expression evels of serotonin transporter expression en when exposed to high levels of stress. , especially when exposed to high levels of stress cts of the environment than others. and negative experiences environment, while fixed individuals are less susceptible ▪ found that people with the short (s) allele of the 5HTTLPR gene had a greater reduction in clinical severity ratings following CBT than people with the long (l) allele of the gene ▪ suggests that people with the s/s genotype of the 5HTTLPR gene may be more responsive to CBT than people with the l/l genotype ○ Non-replication of the association between 5HTTLPR and response to psychological therapy for child anxiety disorder (Lester et al.) ▪ Results of the study showed that there was no significant association between the 5HTTLPR genotype and response to CBT. ▪ Children with the short (s) allele of the gene did not show any greater improvement in their anxiety symptoms than children with the long (l) allele of the gene ▪ findings are inconsistent with some previous studies, which have found an association between the 5HTTLPR genotype and response to CBT for anxiety disorders ▪ Authors of the current study suggest that the mixed findings in the literature may be due to differences in study samples, methodology, and treatment protocols Genome-wide approaches Genome Wide Analysis of MZ twin differences (Keers et al., 2016): ○ Identifying markers of environmental plasticity ○ MZ twin differences capture non-shared environmental influences ○ In twin pairs who are more susceptible to environmental influences, that difference should be larger ○ Genetic variants associated with larger differences may index genes that govern plasticity PSYC0036 Genes and Behaviour 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