Gene-Behaviour Associations in Development Flashcards
Define
ADHD
a chronic condition marked by persistent inattention, hyperactivity, and sometimes impulsivity. It begins in childhood and often lasts into adulthood
Define
Autism Spectrum Disorder (ASD)
a developmental disorder of variable severity that is characterized by difficulties in social interaction and communication and by restricted or repetitive patterns of thought and behaviour.
Define
Candidate gene
Any gene thought likely to cause a disease
Define
Epigenetics
the study of how gene activity is regulated, and how genes are expressed, independent of an individual’s genetic sequence
Define
Fragile X disorder
an inherited condition characterized by an X chromosome that is abnormally susceptible to damage, especially by folic acid deficiency. Affected individuals tend to have limited intellectual functions
Define
Heritability
how much of the variation in a given trait can be attributed to genetic variation
Define
Research Domain Criteria Project (RDoC)
a research framework for new approaches to investigating mental disorders. It integrates many levels of information (from genomics and circuits to behavior and self-reports) in order to explore basic dimensions of functioning that span the full range of human behavior from normal to abnormal
Define
Single-nucleotide polymorphism (SNP)
a difference in a single DNA building block, called a nucleotide
Define
Williams syndrome
a developmental disorder that affects many parts of the body. This condition is characterized by mild to moderate intellectual disability or learning problems, unique personality characteristics, distinctive facial features, and heart and blood vessel (cardiovascular) problems
Definition
a chronic condition marked by persistent inattention, hyperactivity, and sometimes impulsivity. It begins in childhood and often lasts into adulthood
ADHD
Definition
a developmental disorder of variable severity that is characterized by difficulties in social interaction and communication and by restricted or repetitive patterns of thought and behaviour.
Autism Spectrum Disorder (ASD)
Definition
Any gene thought likely to cause a disease
Candidate gene
Definition
the study of how gene activity is regulated, and how genes are expressed, independent of an individual’s genetic sequence
Epigenetics
Definition
an inherited condition characterized by an X chromosome that is abnormally susceptible to damage, especially by folic acid deficiency. Affected individuals tend to have limited intellectual functions
Fragile X disorder
Definition
how much of the variation in a given trait can be attributed to genetic variation
Heritability
Definition
a research framework for new approaches to investigating mental disorders. It integrates many levels of information (from genomics and circuits to behavior and self-reports) in order to explore basic dimensions of functioning that span the full range of human behavior from normal to abnormal
Research Domain Criteria Project (RDoC)
Definition
a difference in a single DNA building block, called a nucleotide
Single-nucleotide polymorphism (SNP)
Definition
a developmental disorder that affects many parts of the body. This condition is characterized by mild to moderate intellectual disability or learning problems, unique personality characteristics, distinctive facial features, and heart and blood vessel (cardiovascular) problems
Williams syndrome
What can we achieve by studying gene-behaviour relationships in neurodevelopmental disorders that have a strong genetic origin?
- Improve diagnostic reliability
- Reduce time to diagnosis
- Tease apart the causes of problem behaviours
- Develop sensitive and appropriate treatment options
What are the causes of neurodevelopmental disorders?
Interuterine environment
Extrauterine environment
Genetics
What factors of a interuterine environment can affect neurodevelopmental disorders?
Hormone imbalance, interuterine infection, consumption of alcohol, tobacco or illicit drugs during pregnancy
What factors of an extrauterine environment can affect neurodevelopmental disorders?
Preterm birth, traumatic birth injury, exposure to heavy metals
What are some examples of single gene disorders?
Fragile X
Williams Syndrome
What are some examples of polygenic disorders?
Autism
ADHD
How are neurodevelopmental disorders currently diagnosed?
- Problem behaviours flagged by caregivers/teachers
- Child sees a GP
- Diagnosis made by specialist based on behaviour
What are genes?
A distinct sequence of DNA forming part of a chromosome, which is the blueprint for a protein
What are alleles?
Alternative forms (variants) of a gene
What are single-nucleotide polymorphisms (SNPs)?
A variation in a single nucleotide that occurs at a specific point in the genome
True or False:
Males are more likely to be affected by Fragile X
True
What causes Fragile X syndrome?
Fragile X syndrome is caused by the expansion of the FMR1 gene on the X chromosome.
When the gene lengthens it swithces off production of a protein, Fragile X Mental Retardation Protein (FMRP), that is onvolved in brain development and other functions
What happens as a result of FMR1 gene mutation?
The FMRP protein is commonly found in the brain, and is essential for normal cognitive development and female reproductive function.
FMRP is highly expressed in neurons and helps with plasticity
Mutation of FMRP can result in Fragile X syndrome:
- Intellectual disability
- Autism
- Parkinson’s disease
- Developmental delay
- Cognitive deficits such as poor attention and working memory
How is Fragile X treated?
Work with clinicians to assist with:
- Language and communication (speech pathology, OT)
- Managing anxiety (behavioural interventions and medication)
- Physiotherapist to improve muscle tone
- Special educator to improve learning settings
- Psychologists to work with whole family
What is heritability?
Heritability is the amount of variation in a phenotypic trait in a population that can be attributed to genetic variation among the members of that population
What is a phenotypic trait?
A phenotypic trait is an obvious and observable trait, such as hair colour and include behavioural traits live attention
True or False:
Disorders like ADHD and ASD are highly heritable
True
How do we estimate heritability?
- Parents to offspring
- Comparing siblings
- Comparing twins
What is the Broad Autism Phenotype?
The Broad Autism Phenotyp is a term used to describe non-autistic relatives (parents, siblings) who display subthreshold autistic symptoms
What is the most heriatble neurodevelopmental disorder?
ADHD
What is ADHD?
A persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequently displayed and more severe than is typically observed in individuals at a comparable level of development
How do you diagnose ADHD?
There is no single test for ADHD. Typically several rating scales are used to track ADHD symptoms in a variety of settings. Symptoms must be exhibited prior to 7 years of age and be present for over 6 months
What is the main treatment for ADHD?
Stimulant medication
(methylphenidate, dexamphetamine)
How does methylphenidate control symptoms of ADHD? What does this tell us about the mechanism of ADHD?
It increases the availability of dopamine at the synapse. There is likely to be something wrong with the genes that code for parts of the dopamine system in ADHD
What are the two candidate genes for ADHD?
Dopamine transporter 1 (DAT1) gene
Dopamine receptor (DRD4) gene
Children with ADHD were grouped according to whether they carried the “high risk” DAT1 allele or the “low risk” DAT1 allele and were required to complete attention tasks. What would likely happen?
The high-risk DAT1 ADHD group displayed greater variability on the attention task than either the low-risk DAT1 group or healthy controls, whereas the latter groups did not differ
About 20% of children with ADHD do not respond to methylphenidate. What does that tell us about the mechanism of ADHD in non-responders?
Although the presentation of ADHD symptoms is the same, they have a different genetic or biological cause for their ADHD
What is the typical brain pathology of people with ASD?
Cortical minicolumns
Reduced connectivity between cortical areas
Children with ASD frequently show abnormalties in the ___________: either too small or too large relative to controls
Children with ASD frequently show abnormalties in the cerebellar vermis: either too small or too large relative to controls
What are homeobox genes?
Genes that orchestrate the formation of many body structures during early embryonic development
What is the candidate homeobox gene for ASD? What is it responsible for?
Engrailed-2 (EN-2)
EN-2 is responsible for regulating the timing of Purkinje cell maturation and perinatal cerebellar patterning
What is epigenetics?
Epigenetics is the study of how gene activity is regulated, and how genes are expressed, independent on an individual’s genetic sequence
Overexpression of EN-2 during fetal development results in what?
Purkinje cell loss, reduced cerebellar volume and delayed maturation and migration of the germinal layer
What is different about the cerebellum of children whi have autism without a history of language delay?
There are little or no cerebellar abnormalities
How do we study behaviour-brain-gene relationships?
- Studies comparing individuals, siblings, parents and families
- Animal models
- Gene and protein expression in human (cadaver) or animal brain tissue
- Cell culture
What are the limitations of the current approach to diagnosis?
- Diagnosis currently relies on aubjective interpretation of behavioural symptoms
- Overlap in current DSM symptom descriptions
- There is substatial heterogeneity within disorders
How does the RDoC propose that we diagnose disorders?
- A diagnositc approach based on biology as well as the symptoms by the current DSM categories
- Each level of analysis needs to be understood across a dimension of function
Who wrote this paper?
Objective: Clinical phenomenology remains the primary means for classifying psychosesdespite considerable evidence that this method incompletely captures biologically meaningful differentiations. Rather than relying on clinical diagnoses as the gold standard, this project drew on neurobiological heterogeneity among psychosis cases to delineate subgroups independent of their phenomenological manifestations.
Method: A large biomarker panel (neuropsychological, stop signal, saccadic control, and auditory stimulation paradigms) characterizing diverse aspects of brain function was collected on individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis (N=711), their first-degree relatives (N=883), and demographically comparable healthy subjects (N=278). Biomarker variance across paradigms was exploited to create nine integrated variables that were used to capture neurobiological variance among the psychosis cases. Data on external validating measures (social functioning, structural magnetic resonance imaging, family biomarkers, and clinical information) were collected.
Results: Multivariate taxometric analyses identified three neurobiologically distinct psychosis biotypes that did not respect clinical diagnosis boundaries. The same analysis procedure using clinical DSM diagnoses as the criteria was best described by a single severity continuum (schizophrenia worse than schizoaffective disorder worse than bipolar psychosis); this was not the case for biotypes. The external validating measures supported the distinctiveness of these subgroups compared with clinical diagnosis, highlighting a possible advantage of neurobiological versus clinical categorization schemes for differentiating psychotic disorders.
Conclusions: These data illustrate how multiple pathways may lead to clinically similar psychosis manifestations, and they provide explanations for the marked heterogeneity observed across laboratories on the same biomarker variables when DSM diagnoses are used as the gold standard
Clementz et al. (2016)
Summarise Clemetez et al. (2016)
Objective: Clinical phenomenology remains the primary means for classifying psychosesdespite considerable evidence that this method incompletely captures biologically meaningful differentiations. Rather than relying on clinical diagnoses as the gold standard, this project drew on neurobiological heterogeneity among psychosis cases to delineate subgroups independent of their phenomenological manifestations.
Method: A large biomarker panel (neuropsychological, stop signal, saccadic control, and auditory stimulation paradigms) characterizing diverse aspects of brain function was collected on individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis (N=711), their first-degree relatives (N=883), and demographically comparable healthy subjects (N=278). Biomarker variance across paradigms was exploited to create nine integrated variables that were used to capture neurobiological variance among the psychosis cases. Data on external validating measures (social functioning, structural magnetic resonance imaging, family biomarkers, and clinical information) were collected.
Results: Multivariate taxometric analyses identified three neurobiologically distinct psychosis biotypes that did not respect clinical diagnosis boundaries. The same analysis procedure using clinical DSM diagnoses as the criteria was best described by a single severity continuum (schizophrenia worse than schizoaffective disorder worse than bipolar psychosis); this was not the case for biotypes. The external validating measures supported the distinctiveness of these subgroups compared with clinical diagnosis, highlighting a possible advantage of neurobiological versus clinical categorization schemes for differentiating psychotic disorders.
Conclusions: These data illustrate how multiple pathways may lead to clinically similar psychosis manifestations, and they provide explanations for the marked heterogeneity observed across laboratories on the same biomarker variables when DSM diagnoses are used as the gold standard
