Cognitive Genetics

Question 1

What is a complex trait?

Answer 1

A quantifiable property of an organism influenced by multiple genetic and environmental factors as well as the interactions between them

Question 2

What is a phenotype?

Answer 2

Physical appearance of an organism with respect to a trait

Question 3

What is an endophenotype?

Answer 3

Measurable components that lies along the causal pathway between disease and distal genotype

Question 4

If a gene is a length of DNA that specifies a particular protein product, what is an allele?

Answer 4

One of two or more forms of a gene, located on a specific position on a chromosome

Question 5

Genetic variability is the occurrence of different types of the same gene. What are these known as, and how can we measure them?

Answer 5

Genotypes; Through twin studies, candidate genes, and genome wide association

Question 6

How can we measure the way genetic variability influences cognitive ability?

Answer 6

By measuring complex traits, disorder phenotypes, and endophenotypes

Question 7

What’s the difference between Homozygous and Heterozygous?

Answer 7

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)

Question 8

What are polymorphisms, and which are the most common?

Answer 8

The presence of two or more variants (alleles) in a gene or DNA sequence in a population; Most common are SNPs

Question 9

What is a SNP?

Answer 9

Single Nucleotide Polymorphism - reflect a change in a single base in the DNA that differs from the usual base at the position

Question 10

Another common type of genetic variation is VNTR. What is it?

Answer 10

Variable Number of Tandem Repeats - polymorphism in the length of tandemly repeated short sequences of DNA

Question 11

Individuals in the population can be classified based on what?

Answer 11

How many copies of the repeat length of interest (e.g 12 repeat) they have (0, 1, or 2)

Question 12

List the requirements for diagnosing ADHD according to DSM-5

Answer 12

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)

Question 13

If ADHD is a phenotype, what is the endophenotype, and how is it assessed?

Answer 13

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)

Question 14

What can heritability/twin studies tell us?

Answer 14

About the relationship between genes and environment, and how much they contribute to our phenotype

Question 15

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?

Answer 15

Non-shared environmental effects

Question 16

If attention ability is highly correlated within both MZ and DZ pairs, then what must the effect be due to?

Answer 16

Shared environment

Question 17

If attention ability is highly correlated in MZ but not DZ pairs, then what must the effect be due to?

Answer 17

Genetics

Question 18

What are heritability estimates for ADHD?

Answer 18

Between 60-90%

Question 19

How do unaffected siblings perform on sustained attention tasks?

Answer 19

Better than ADHD affected siblings but worse than healthy controls

Question 20

What’s the heritability estimate for sustained attention in children, and how does this change with age?

Answer 20

Between 46-72%; environment becomes more important with age

Question 21

In Davis et al.’s study investigating 45 phenotypes (e.g IQ, school achievement and ADHD) in the UK, what was found?

Answer 21

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)

Question 22

Define heritability

Answer 22

It’s the proportion of variance explained by genetic factors in a certain phenotype, estimated by comparing concordance rates of MZ and DZ twins

Question 23

When does gene x environment interaction occur?

Answer 23

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)

Question 24

What do Candidate Gene Studies investigate?

Answer 24

How a specific candidate gene influences individual differences in a specific cognitive process

Question 25

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?

Answer 25

That the C in the gene leads to increased attention ability

Question 26

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?

Answer 26

Pharmacology; Brain imaging; Behavioural studies; Animal research

Question 27

What has experimental depletion of dopamine been shown to lead to?

Answer 27

Sustained attention deficits

Question 28

What is Methylphenidate (MPH), and what clinical and behavioural benefits does it have?

Answer 28

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

Question 29

What’s the function of DAT?

Answer 29

It’s a protein transporter that breaks dopamine down at the synapse and pushes it back into the cell

Question 30

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?

Answer 30

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)

Question 31

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?

Answer 31

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

Question 32

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?

Answer 32

With ADHD: it will help them to focus more; without ADHD: it will lead to mistakes in attention

Question 33

Which is the most commonly studied variant in the Dopamine D4 Receptor gene (DRD4), and where is it predominantly expressed?

Answer 33

A VNTR in exon 3; predominantly expressed in the prefrontal cortex

Question 34

What does the most frequent allele in the DRD4 have, and what has it been shown to affect?

Answer 34

7-repeats or 4-repeats; affects receptor function

Question 35

Explain how there have been mixed findings for the DRD4 gene

Answer 35

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

Question 36

What does Swanson et al. suggest in regards to children with ADHD and the 7-repeat allele?

Answer 36

Children who have it display extreme/impulsive behaviour but no cognitive symptoms, and those without it are at risk for poorer cognition

Question 37

What did Durston et al. find the DRD4 genotype to influence?

Answer 37

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

Question 38

What is an Exon?

Answer 38

The protein coding portion of a gene

Question 39

What is an Intron?

Answer 39

A nucleotide sequence in a gene that does not code for the gene product (might be involved with gene regulation)

Question 40

What do Genome-wide association studies investigate?

Answer 40

Variation in genes across the entire genome, and how these genes influence individual differences in a specific cognitive process

Question 41

What are the pros and cons with genome-wide association studies?

Answer 41

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

Question 42

What kinds of genetic variants are very hard to identify in genome-wide association studies?

Answer 42

Rare variants of small effect

Question 43

Which studies have confirmed an association with ADHD that has reached genome-wide significance?

Answer 43

None to date; all associations are suggestive and must be replicated

Question 44

What is a Genome?

Answer 44

The entirety of an organism’s hereditary information

Question 45

Define Genome-wide significance, and explain how statistical significance is generally claimed

Answer 45

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

Question 46

Genome-wide significance is based on the testing of what?

Answer 46

One million SNPs, and uses the simple Bonferroni correction for multiple testing (.05 divided by the number of tests

Question 47

What are the strengths and weaknesses of twin studies?

Answer 47

Strength: allows estimation of genetic and environmental contribution; Weakness: doesn’t tell you which genes are responsible

Question 48

Describe the strengths and weaknesses of candidate gene studies

Answer 48

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

Question 49

What are the strengths and weaknesses of genome-wide association studies?

Answer 49

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

Question 50

In what ways can genetic information help?

Answer 50

Improved diagnosis; improved pharmacological and behavioural treatments; development of environmental interventions