Cognitive Genetics Flashcards
What is a complex trait?
A quantifiable property of an organism influenced by multiple genetic and environmental factors as well as the interactions between them
What is a phenotype?
Physical appearance of an organism with respect to a trait
What is an endophenotype?
Measurable components that lies along the causal pathway between disease and distal genotype
If a gene is a length of DNA that specifies a particular protein product, what is an allele?
One of two or more forms of a gene, located on a specific position on a chromosome
Genetic variability is the occurrence of different types of the same gene. What are these known as, and how can we measure them?
Genotypes; Through twin studies, candidate genes, and genome wide association
How can we measure the way genetic variability influences cognitive ability?
By measuring complex traits, disorder phenotypes, and endophenotypes
What’s the difference between Homozygous and Heterozygous?
Homozygous - having the same alleles at a particular gene locus on homologous chromosomes (2 copies of the same) Heterozygous - having two different alleles at a particular gene locus on homologous chromosomes (different versions)
What are polymorphisms, and which are the most common?
The presence of two or more variants (alleles) in a gene or DNA sequence in a population; Most common are SNPs
What is a SNP?
Single Nucleotide Polymorphism - reflect a change in a single base in the DNA that differs from the usual base at the position
Another common type of genetic variation is VNTR. What is it?
Variable Number of Tandem Repeats - polymorphism in the length of tandemly repeated short sequences of DNA
Individuals in the population can be classified based on what?
How many copies of the repeat length of interest (e.g 12 repeat) they have (0, 1, or 2)
List the requirements for diagnosing ADHD according to DSM-5
6 or more symptoms of inattention persisting for at least 6 months (impairing & developmentally inappropriate); 6 or more symptoms of hyperactivity impulsivity for at least 6 months; age of onset before 7 yrs; impairment in multiple settings; not better accounted for by another disorder (e.g mood/anxiety)
If ADHD is a phenotype, what is the endophenotype, and how is it assessed?
Sustained attention - ability to maintain goal-directed focus in the absence of exogenous or external cues; Assessed behaviourally using tasks such as sustained attention to reaction time task (SART)
What can heritability/twin studies tell us?
About the relationship between genes and environment, and how much they contribute to our phenotype
If we gave monozygotic twins (who share 100% of genes & grew up in the same environment) an attentional task, any difference in attention ability must be due to what?
Non-shared environmental effects
If attention ability is highly correlated within both MZ and DZ pairs, then what must the effect be due to?
Shared environment
If attention ability is highly correlated in MZ but not DZ pairs, then what must the effect be due to?
Genetics
What are heritability estimates for ADHD?
Between 60-90%
How do unaffected siblings perform on sustained attention tasks?
Better than ADHD affected siblings but worse than healthy controls
What’s the heritability estimate for sustained attention in children, and how does this change with age?
Between 46-72%; environment becomes more important with age
In Davis et al.’s study investigating 45 phenotypes (e.g IQ, school achievement and ADHD) in the UK, what was found?
A greater amount of variance was explained by non-shared environments (more important at predicting classroom behaviour in London; more diversity); genes contribute more to ADHD if living in London (busier and more stress may trigger this)
Define heritability
It’s the proportion of variance explained by genetic factors in a certain phenotype, estimated by comparing concordance rates of MZ and DZ twins
When does gene x environment interaction occur?
When the relationship between an environmental experience (e.g stress, trauma, toxin exposure) and the emergence of altered physiological or behavioural responses is contingent on individual differences in genetic makeup (i.e genetic polymorphisms)
What do Candidate Gene Studies investigate?
How a specific candidate gene influences individual differences in a specific cognitive process
If, in a population, a high frequency of C/C genotypes show average attention performance, with a lower frequency of C/T genotypes showing good attention, and low frequency of T/T showing poor attention, what might we conclude?
That the C in the gene leads to increased attention ability
In order to understand how attention works from a candidate gene perspective, it’s important to draw on our knowledge of which four research areas?
Pharmacology; Brain imaging; Behavioural studies; Animal research
What has experimental depletion of dopamine been shown to lead to?
Sustained attention deficits
What is Methylphenidate (MPH), and what clinical and behavioural benefits does it have?
A stimulate medication commonly used to treat ADHD (effective in 60% of cases); often attributed to blocking the dopamine transporter (DAT); Significantly improves sustained attention deficits in children and adults with ADHD
What’s the function of DAT?
It’s a protein transporter that breaks dopamine down at the synapse and pushes it back into the cell
The most commonly studied variant in the DAT1 gene is the VNTR in the 3’UTR, with the most frequent allele having 10 or 9 repeats. What do participants with one copy of the 10-repeat allele have?
Higher dopamine transport density compared to 10/10 carriers (if they have two versions of the gene, dopamine is present in the synapse for longer)
MPH acts by inhibiting the reuptake of dopamine via the DAT transporter. How do children with ADHD that are homozygous for the 10-repeat allele perform on sustained attention tasks?
More poorly than children with other genotypes; when the transporter is inhibited, the dopamine doesn’t stick around long enough so they make more errors
Too much dopamine blocks the transporter, and too little leads to inattention, thus the optimal level is at the middle of the bell curve. What happens when a person with ADHD takes a stimulant compared to someone without it?
With ADHD: it will help them to focus more; without ADHD: it will lead to mistakes in attention
Which is the most commonly studied variant in the Dopamine D4 Receptor gene (DRD4), and where is it predominantly expressed?
A VNTR in exon 3; predominantly expressed in the prefrontal cortex
What does the most frequent allele in the DRD4 have, and what has it been shown to affect?
7-repeats or 4-repeats; affects receptor function
Explain how there have been mixed findings for the DRD4 gene
Two studies found children with ADHD with the 7-repeat allele to make fewer errors on a sustained attention task than those without it; another study reported the opposite
What does Swanson et al. suggest in regards to children with ADHD and the 7-repeat allele?
Children who have it display extreme/impulsive behaviour but no cognitive symptoms, and those without it are at risk for poorer cognition
What did Durston et al. find the DRD4 genotype to influence?
Prefrontal grey matter brain volumes in children with ADHD; carriers of the 7-repeat allele had larger prefrontal volumes than those homozygous for the 4-repeat allele
What is an Exon?
The protein coding portion of a gene
What is an Intron?
A nucleotide sequence in a gene that does not code for the gene product (might be involved with gene regulation)
What do Genome-wide association studies investigate?
Variation in genes across the entire genome, and how these genes influence individual differences in a specific cognitive process
What are the pros and cons with genome-wide association studies?
Pros: no selection bias; looks at all possible genes in the genome; Cons: very expensive; have to run many statistical tests so more chance of false positives; collect large samples of data so quick measures or questionnaires lead to a lot of noise
What kinds of genetic variants are very hard to identify in genome-wide association studies?
Rare variants of small effect
Which studies have confirmed an association with ADHD that has reached genome-wide significance?
None to date; all associations are suggestive and must be replicated
What is a Genome?
The entirety of an organism’s hereditary information
Define Genome-wide significance, and explain how statistical significance is generally claimed
Statistical term indicating that a genetic association is real (rather than false positive); a stringent genome-wide significance threshold level of 5x10^-8 (due to the large number of SNPs tested simultaneously in GWAS
Genome-wide significance is based on the testing of what?
One million SNPs, and uses the simple Bonferroni correction for multiple testing (.05 divided by the number of tests
What are the strengths and weaknesses of twin studies?
Strength: allows estimation of genetic and environmental contribution; Weakness: doesn’t tell you which genes are responsible
Describe the strengths and weaknesses of candidate gene studies
Strengths: allows specific hypothesis to be tested; provides greater power than GWAS as less statistical tests are conducted; inexpensive; Weaknesses: not all possible genes are investigated; if the theory is incorrect then important genetic effects can be missed
What are the strengths and weaknesses of genome-wide association studies?
Strengths: no prior information about the gene is required; allows examination of genetic variation across the entire genome; Weaknesses: expensive; very large sample sizes are needed in order for effects to survive correction for multiple comparisons
In what ways can genetic information help?
Improved diagnosis; improved pharmacological and behavioural treatments; development of environmental interventions
