Imaging Genetics PDF

Imaging Genetics 20 November 2023 14:53 Notes Main Ideas Notes Why large-scale psychiatric genetics studies have failed (until recently) ○ Polygenic, heterogenous disorders ○ Generally tiny risk effects, requiring enormous samples (hundreds of thousands per group) ○ Epistasis and gene-environment in...

Imaging Genetics 20 November 2023 14:53 Notes Main Ideas Notes Why large-scale psychiatric genetics studies have failed (until recently) ○ Polygenic, heterogenous disorders ○ Generally tiny risk effects, requiring enormous samples (hundreds of thousands per group) ○ Epistasis and gene-environment interactions ○ Rare, highly influential alleles not captured by GWAS Multifactorial liability-threshold polygenic model ○ In 99% of cases, individual genes are probably neither necessary nor sufficient to cause the phenotype - instead they increase risk ○ Polygenic (individually tiny) effects accumulate with environmental effects to increase liability to mental illness in a give n individual About the brain… ○ 70% of all genes expressed in the brain - many of these genes are polymorphic ○ These functional polymorphisms can account for individual differences in how the brain processes information ○ Brain links genes and behaviour Imaging genetics: candidate gene association approach ○ 'candidate gene association' approach - relationship between a phenotype and specific allele of a gene ○ ‘Imaging genetics’ is just another type of genetic association analysis ○ Phenotype is the structure or physiological response of the brain Why should imaging genetics be more successful than other approaches? ○ Traditionally, the impact of genetic polymorphisms on mental well -being has been examined using questionnaires and diagnoses ▪ Results often weak and inconsistent ▪ Enormous samples required ○ People can manifest the same symptoms for different underlying reasons (like a cough ○ Brain regions subserving specific cognitive and emotional processes are - in theory - more objectively measurable than the subjective consequences of these processes (like self -report) ○ Genetic effects may be more easily apparent at the level of brain – more ‘signal to noise' ○ Imaging studies: ▪ Require fewer participants – this is good as imaging is expensive! ▪ Can examine specificity of gene effects to functional circuits (e.g. prefrontal, striatal, limbic) ▪ ‘in vivo’ study of functional genetic variation Protocol for imaging genetics 1. Selection of candidate genes ○ Well-defined functional polymorphisms, associated with specific physiological effects at the cellular level ○ Genes containing allele variants with likely functional implications involving neuroanatomical systems 2. Control for non-genetic factors ○ Any gene affecting brain response will not explain all of the variability in the outcome measure ▪ Systematic differences between genotype groups could either obscure a true gene effect or masquerade as one: □ Age, gender, IQ, population stratification (ethnicity) □ Environmental factors such as illness, injury, or substance abuse ® Task performance ◊ Linked with BOLD response ◊ Match or consider variability 3. Task selection ○ Imaging tasks must maximise sensitivity, reliability and inferential value, as the interpretation of potential gene effects d epends on the validity of the information processing paradigm ▪ Engage specific brain circuits ▪ Produce robust and reliable signals ▪ Show variance across subjects ○ Imaging genetics not an appropriate venue to test novel cognitive activation paradigms Brain structure integration ○ Replication of any finding that has extreme importance Serotonin transporters (5-HTTLRPR) - transcription Notes ○ Generic effects are not static over development ○ ○ Recycles serotonin ○ Long and short alleles (l or s) ○ Long allele is more efficient at producing serotonin Serotonin transporter gene and depression ○ s allele carriers appear at greater risk for anxiety and depression (gene x environment interaction ) ○ This finding - controversial - some studies have failed to replicate Serotonin transporter gene and the amygdala ○ s allele carriers have increased 'resting state' amygdala activation ○ s allele carriers have increased amygdala response to fearful faces ○ Greater amygdala activation observed in s allele carriers - hyper-responsiveness of amygdala to emotional environmental stimuli Links beyond the amygdala complex What neural mechanisms should we focus on? ○ Those that are theoretically plausible in explaining symptoms ▪ Question: do they look the same across different developmental stages ○ Those that might influence the canalization of particular outcomes? ▪ Need to move away from simple explanations and univariate problem space ▪ Canalisation is a measure of the ability of a population to produce the same phenotype regardless of variability of its environment or genotype Measurement ○ Functional neuroimaging and experimental psychology measures ▪ Question: how do we measure comparable constructs over development ▪ Question: where should we anticipate developmental change + what will it look like? Reliability ○ Different foci in experimental and correlational research: ▪ Paradigms that can robustly reveal an average response may not be optimised for detecting individual differences □ reliable within subject effects at group level can arise from unreliable between-subjects measurements Challenge ○ If we want to link genetic and imaging data over development we need to develop: ▪ new paradigms ▪ new analytic approaches ○ These should maximise the ability to reliably and sensitively distinguish between participants and also isolate meaningful neurocognitive constructs ○ Need new approaches beyond cross-sectional neurocognitive research or non-mechanistic longitudinal studies ○ ○ Lower coupling between amygdala and subgenual anterior cingulate in s allele carriers ○ Amygdala-anterior cingulate coupling linked to harm avoidance ○ Interpretation: 5-HTTLPR genotype affects prefrontal control over amygdala reactivity, leading to altered emotional experience and temperament Next steps and challenges ○ Large multi-sites GWAS studies Polygenic Risk Score ○ Polygenic risk scores in imaging genetic studies of psychiatric outcomes ○ ○ Polygenic risk for bipolar disorder is associated with activation to emotional faces in a sample of healthy volunteers ○ Longitudinal studies needed: ▪ Developing neural circuitry of particular interest ▪ Taking into account variability in environmental stressors as well as developmental genetic effects Majority of imaging genetic research has been cross -sectional ○ Focus often on just one mechanisms at this times ○ Sample not always comparable between studies Challenges ○ Multifinality ▪ “The principle of multifinality suggests that any one component may function differently depending on the organization of the system in which it operates” (Cicchetti & Rogosch, 1996) ○ Development ▪ “The complex dynamics of both normal and atypical development indicate, in my view, that the neuroconstructivist approach is the most viable theoretical framework… The dynamics of development itself are the key to understanding developmental disorders.” ▪ Neuroconstructivist approach: a theoretical framework focusing on the construction of representations in the developing brain Summary Neuroimaging methods allow us to analyse brain structure and function Some of these measures are highly heritable Genes known to affect neuronal function are associated with psychiatric illness Neuroimaging genetic studies suggest plausible neurobiological mechanisms underlying some of these associations Psychiatric disorders are developmental in nature - we need to develop new methods and form research consortia to study imaging genetics in a developmental context PSYC0036 Genes and Behaviour Page 1 PSYC0036 Genes and Behaviour Page 2