Honours: Current Topics in Developmental Psych - S2 ADHD Genetic and environmental factors (up to slide 42 - designing GxE studies)

What is unique about DNA in terms of the causal link (compared to other steps in the biological pathway from genes to behaviour/ADHD symptoms)?

Our DNA cannot change - it is set in stone. There is therefore no direction of effect issue (our behaviour and experiences do not change DNA sequence variation).

Population vs. molecular genetics approaches

Population genetics:

- Bigger picture (/top-down) approach with a focus on variation in populations (how genetic variation is distributed + changes in populations over time and space)

- Studies genetic variation and change in populations

- Looks at the frequencies of alleles and genotypes

- Explains evolution and adaptation

Molecular genetics:

- More zoomed in approach with a focus on genes and molecules (how genes and molecules create traits and biological functions)

- Studies the structure, function, and expression of genes

- Looks at DNA and how it is transcribed and translated, and the interactions at play in this process

- Explains how genes work at the molecular level

Heritability Definition

The fraction of phenotypic variance (total trait variance) that is explained by genetic factors within a population. (Heritability estimates thus vary between 0 and 1)

Types of studies used in population genetics

Family studies (of multiple generations, looking at family trees) and twin studies (including studies of twins reared apart, although these are becoming less common).

Candidate Gene

A gene marker hypothesised to be involved in a trait or disorder, based on previous research on physiological, genetic, or biochemical processes thought to be implicated in the trait or disorder.

Allele

One of two or more versions of a DNA sequence at a given locus (position) on the genome.

Polymorphism

A gene is polymorphic if more than one allele occupies that gene's locus within a population (these different versions of the gene are due to differences in nucleotides at that locus).

Polymorphisms are DNA variations that occur commonly in the population (typically at least 1% frequency; e.g. being able to digest lactose in adulthood is due to a polymorphism in the lactase gene).

Single Nucleotide Polymorphism (SNP)

(A type of allele.) The most common form of genetic variation (/polymorphism) - a change in a single base in the DNA that differs from the usual base at a specific position in the genome.

Variable Number Tandem Repeats (VNTR)

Short sequences of nucleotides (ranging from 14 to 100 nucleotides long) that are organised into clusters of tandem repeats (too many repeats of a particular sequence of DNA in a particular place, which can lead to the development of a phenotype associated with a disorder).

The number of repeats at a VNTR locus can differ between individuals.

Genome Wide Association Studies (GWAS)

Analysis of the entire genome looking at different points for SNP variations that occur more often in people with a particular diagnosis.

Polygenic Risk Scores

Total number of genetic variants an individual has, linked to a particular diagnosis, that helps assess heritable risk of developing a particular disease/disorder.

Pleiotropy

Producing or having multiple phenotypic effects from a single genetic source (see examples later in seminar slides).

Cytogenetics

The study of chromosomes

Approaches to identify genetic variants associated with traits/diseases

- Candidate gene approach: focuses on specific genes that are hypothesised to influence a trait/disease based on prior biological knowledge (hypothesis-driven which is useful, however, limited to known genes and pathways, and much about the genetic aetiology of ADHD is unknown)

- Genome-wide association study (GWAS) approach: scans the entire genome for genetic variants associated with a trait or disease in an unbiased way (hypothesis-free which makes it less biased, however, requires very large sample sizes)

- Cytogenics approach: examines chromosomes under a microscope to detect large-scale genetic changes that may influence traits or cause disease (useful for diagnosing chromosomal disorders - phenotypes where chromosomes are affected in some way, which can be the case in a small subset of people with ADHD; good for detecting chromosomal abnormailities that are not captured by SNP genotyping)

Note: see slide 18 for more depth on each and examples in the context of ADHD

ADHD population genetics evidence

- Twin studies in many different countries show high heritability rates for ADHD (71% - 90%)

- Adoption studies corroborate this finding (high heritability rate), as do family studies of first degree relatives

ADHD molecular genetics evidence

- Candidate genes of the dopamine, serotonin, and noradrenaline systems

•Many risk markers, each with a small effect size

- GWAS studies indicate some SNPs associated with brain structure are associated with ADHD

- Increased number (slightly) of rare chromosomal structural variants in ADHD cases

•Copy number variations (CNVs), segments of chromosome that are duplicated or deleted, are implicated in neurodevelopmental disorders including ADHD (it is suggested that these have a pleiotropic effect - multiple different phenotypic effects can arise from a single genetic source); risk for ADHD may follow a polygenic liability threshold model (people with rare large CNVs may require a lower number of common genetic risk variants to be present to develop ADHD)

- Some usefulness of polygenic risk scores

ADHD as a Polygenic Disorder

- ADHD is associated with many common genetic allele variants that each have a small effect size

- It is helpful to calculate a polygenic liability/risk score

•Sum of all risk alleles weighted for the evidence of risk of each variant

•Higher polygenic risk scores have been found to predict inattention and hyperactivity in the general population, and ADHD clinical diagnoses

- Suggests that the clinical diagnosis of ADHD is the extreme of a trait that varies continuously across the population

Biological mechanisms implicated in ADHD

1. Catecholamine systems & serotonergic system

Catecholamine neurotransmitters modulate arousal, attention, mood, motivation and reward.

- Dopaminergic system (dopamine): reward processing, motivation, executie function, motor control

- Noradrenergic system (noradrenaline): attention and vigilance, stress response, arousal, working memory

- Adrenergic system (adrenaline): arousal, fight or flight, cardiovascular regulation

- Serotonergic system (serotonin - not a catecholamine neurotransmitter): mood regulation, impulse control, sleep, appetite

2. Cell development

Encompasses various processes essential for the formation of neural circuits during development

- Neurite outgrowth: growth and extension of axons and dendrites

- Cell adhesion pathways: molecular interactions that enable cells to recognise and bind to each other

- Cell migration: directed movement of neurons to their appropriate locations

3. Synapse formation

The formation and regulation of synapses are critical for communication between neurons

- Postsynaptic density membrane: protein-rich specialisation that organises receptors and signalling molecules at the synapse

- Synapse modulation of chemical messengers: regulation of neurotransmitter release, uptake, and receptor sensitivity

- Synapse organisation: assembly and structural organisation of synaptic components to establish functional connections

4. Cell signalling pathways

Intracellular (within cell) signalling pathways translate extracellular (outside of cell) signals into cellular responses that influence development, plasticity, and neurotransmission

- Glutamate, calcium channel, and G-protein signaling pathways (don't need to know the details of these cell signalling pathways)

5 types of exposure that constitute environmental risk factors for mental health disorders

1. Biological (e.g. hypoxia, lack of oxygen in blood/tissue, is an important risk factor for ADHD)

2. Physical (e.g. head injuries)

3. Chemical (e.g. pesticides)

4. Diet and drugs (e.g. medications)

5. Psychosocial (e.g. childhood abuse/neglect)

How to identify environmental causes of a disorder

- Need to provide a valid identification of environmental causes of the disease/disorder

•Difficult as practical & ethical concerns prevent direct environmental manipulations

•Non-experimental research is open to many confounding variables

•Not impossible though (e.g. non-experimental research has found a link between smoking and lung cancer)

- Best to use a range of methods

- Building evidence takes time

- Causes of a disorder need to be conceptualised as part of a broader socio-biological nexus

Environmental measures - important considerations

- Need to consider developmental influences (therefore important to look at trajectories of change over time)

- Retrospective self-report measures are open to recall bias and mood congruency effects (e.g. someone suffering from depression may not accurately report childhood maltreatment)

•Prospective assessment of environmental measures is helpful (e.g. experience sampling methods to look at within-person changes in symptoms over time)

- Large samples are needed for GxE and genome-wide approaches (high quality environmental measures are very hard/costly/time-consuming for large samples)

•Could take extreme ends of a polygenic score and sample in-depth

- Many environmental exposures are linked to severe mental illnesses, and these environmental exposures overlap with many different disorders

•E.g. childhood maltreatment, childhood social disadvantage, and stressful life events in adulthood are associated with major depressive disorder

•Need to include multiple environmental factors in research

Environmental correlates of ADHD

1. Prenatal and perinatal risk factors:

-Low birthweight, prematurity

-In-utero exposure to maternal stress, cigarette smoking, alcohol, paracetamol, illicit substances

2. Environmental toxins:

-Lead

-Phthalates (found in vinyl, nail polish, and other cosmetics)

3. Psychosocial risks:

4. Childhood atopic diseases (e.g. eczema and asthma) {atopic disease = overactive immune response to harmless things}

Note: not all examples have been included for each (see slide 34 for more)

Gene-Environment Correlations (rGE) and the three categories they can be broken into

- There are genetic influences (either parents' or child's genes can be at play) that help shape/modify one's environment

- Passive rGE: where genetic influences on individual differences in environmental risk exposure are independent of actions of the individual child. Parental effect on the environment of the child.

•Parents' genes affect the environment they provide their child

•E.g. a parent with a genetic tendency toward anxiety may create a more protective, cautious home environment. The child will experience that environment regardless of their own behaviour

- Active rGE: refers to genetic effects on the child's behaviour that serve to select/shape the environments experienced by the child.

•Genetically influenced traits lead the child to actively seek out, create, or avoid certain environments

•E.g. an outgoing child may join more activities and make more friends, creating a richer social environment

- Evocative rGE: refers to genetic effects on the child's interpersonal behaviours (some children are fun to be around, others irritate, annoy etc.) that evoke particular responses from others in the environment

•Genetically influenced behaviours elicit positive or negative reactions from others, shaping the child's environment

•E.g. a child who is irritable or easily frustrated may evoke more criticism or conflict, while a cheerful child may receive more warmth and support

- Active and evocative rGEs are studied through child-based twin and adoption designs

- So environmental risk factors are partly genetically mediated

Epigenetics

- Numerous developmental processes by which genetic code is transformed into the developing organism

•Molecules attach to DNA to alter gene expression

- These epigenetic markers

•Remain stable over cellular generations (can stay marked in the transcription and translation of genes over time)

•Can be altered by experiences and environmental influences

•Are a mechanism by which experiences "get into the body", thereby changing brain and behaviour

•Target for potential treatments in the future