Evidence of genetic role in psychopathology

Question 1

Lifetime risk. Relatedness studies. DZ and MZ concordance.

Answer 1

• c.1%.
• SZ increases as a function of number of genes shared with individual. Obvious environmental confound, so –> DZ (c.17%) and MZ (c.48%) suggest contribution of genes.

Question 2

Heston (1966): c.11% vs. 0%. What did subsequent studies do to expand on this?

Answer 2

• Incidence of SCZ in adopted-away offspring of SCZ mothers was 11% (547) compared to 0% controls. Similar risk found for children by their SCZ parents.
• Subsequent studies: larger sample sizes, more sophisticated designs (parent-offspring and sibling-sibling comparisons, & paternal genetic information),

Question 3

Tienari et al. (2004): Finland, 10%.

Answer 3

10% of adoptees who had SCZ parent also showed some form of psychosis, compared to 1% of control. Also suggestion of G*E interaction, adoptees whose biological parents were SCZ were more likely to have SCZform disorders if their adoptee family functioned poorly.

Question 4

What is the utility of cohorts?

Answer 4

Allow long-term, longitudinal assessment of health/disease across the life-course (ideally from conception to grave). W/ sufficiently large samples, allows mapping of life events (inc. in conjunction w/ genetic makeups onto health outcomes, inc. psychiatric health).

Question 5

Life course effects: In-Utero, Dutch Winter Famine, foetal CNS (1st/2nd trimester)

Answer 5

(1944-45): Key determinant of inc. risk of SCZ/CNS anomalies as an adult was being conceived during famine, not being born during it. Suggests effects of famine conditions mainly on early development of foetal CNS esp. during 1st/beginning of 2nd trimester, due to severe calorie restriction & micronutrient deficits (folate [B9] deficiency).

Question 6

Three life course effects occurring at birth.

Answer 6

Obstetric complications, birth season, social deprivation.

Question 7

Three life course effects occurring during childhood.

Answer 7

Bullying, life stresses, urbanicity.

Question 8

Cannabis: RTCs of THC

Answer 8

Tetrahydrocannibol, the main active compound in cannabis, has long been thought to induce transient psychotic-like experiences. What about likelihood of schizophrenia?

Question 9

Cannabis: Two hypotheses of genetic role.

Answer 9

Cannabis-causing-psychosis hypothesis, or shared-vulnerability hypothesis.

Question 10

Bewildering variety: 8000 potential SNPs. Biological pathway incredibly difficult BUT (Bossong & Kniesking, 2010).

Answer 10

Endocannaboid system particularly vulnerable to the effects of cannabis during adolescent brain maturation.

Question 11

What does the exposure to THC (neurotoxic) do to the brain during maturation?

Answer 11

THC (neurotoxin) disturbs adolescent neural circuits in PFC by primarily targeting CNR1 receptor.

Question 12

What does CNR1 do? How is it affected by THC?

Answer 12

Under normal circumstances, CNR1’s interaction with endocannabinoids is important in controlling the release of glutamate (important, amongst other things, for strengthening and pruning of synapses during postnatal development, so is crucial during adolescence). THC’s interaction with CNR1 may cause insufficient regulation of glutamate, which may have functional consequences in transmission abnormalities of dopamine and GABA, particularly PFC. Dopamine and PFC.

Question 13

Cannabis genes: Leroy et al. (2001)

Answer 13

CNR1 receptor gene polymorphism assoc. w/ cannabis abuse in SCZ.

Question 14

Ho et al. (2011): heavy cannabis use, CNR1 polymorphisms, cerebral volume, cognitive function.

Answer 14

Interaction. SCZ patients w/ heavy cannabis use = smaller fronto-temporal white matter volumes than SCZ w/o. SCZ patients w/ specific CNR1 polymorphisms +vulnerable to impact of heavy cannabis use, w/ greater white matter volume decrease and cognitive impairments than those who abused cannabis but didn’t have these SNP variants. Suggests G*E interaction for phenotypical abnormalities and severity in SCZ.

Question 15

Ado cannabis use, COMT, catabolism of catecholamines (e.g. synaptic DA) Caspi et al. (2005)

Answer 15

Relationship adolescent cannabis use & psychotic symptoms may also be attributed to polymorphism in COMT gene, which encodes an enzyme which degrades catecholamines, e.g. dopamine. Two allelic variants of COMT that code for either valine or methionine. COMT w/ valine catabolises synaptic DA faster than methionine. Caspi et al. (2005) found that COMT carriers who used cannabis more likely to exhibit psychosis and develop a SCZform disorder. In contrast, cannabis consumption had no effect in those with homozygous met variant.

Question 16

Has Caspi et al. (2005; cannabis SCZ) been replicated (Zammit et al., 2007 , 1438; Zammit et al., 2011, 2yr 2630)?

Answer 16

A case-only analysis of 1438 individuals found no interaction between COMT polymorphism and cannabis use w/ regard to scz (Zammit et al., 2007). Neither did a 2yr longitudinal study of 2630 genotyped patients showing no interaction COMT and psychosis development.

Question 17

Support for Caspi et al. (2005) G*E (abuse) interactions (Vinkers et al., 2013, 918 X-sectional analysis 3-way interaction; Alemany et al. 2013 replication)

Answer 17

Cross-sectional analysis of 918 individuals in Europe found significant 3-way interaction between Val, cannabis, and childhood abuse in moderating psychosis. Those homozygous for Val more likely to experience psychosis assoc. w/ cannabis use, if they had experienced childhood abuse, than those cannabis-using indiviuals homozygous/heterozygous for Met, even if they had also experienced childhood abuse. These findings were replicated by Alemany et al. (2013).

Question 18

Cannabis use and psychosis, bidirectionality (Ksir & Hart, 2016)

Answer 18

Argue and present evidence that cannabis does not in itself cause psychosis, but rather early use and heavy use are more likely in individuals with vulnerability to psychosis, and even suggest that cannabis usage (presented in conjunction w/ other problem behaviours) is a prodromal sign of psychosis that merits further investigation.

Question 19

Childhood maltreatment and adult antisocial behaviours (Caspi et al., 2002)

Answer 19

Dunedin cohort (Male: MAOA is X-linked- most studies concentrate on males due to complexities in studying females hetero/homozygous for implicated MAOA alleles). Maltreatment as child = antisociality and adverse outcomes later life (cycle of violence). Positive relationship between extent of maltreatment as child (3-11yr) and anti-social behaviour at age 26.

Question 20

low activity MAOA polymorphism. 12% of cohort, 44% violent convictions. Byrd & Manuck (2014) MA of 27 studies using 20 male cohorts. Fergusson et al. (2011) 30yr longitudinal 398 NZ males, stable G*E interaction. Small effect sizes. Tenuous link MAOA variant and levels in brain (Balciuiene et al., 2002)

Answer 20

Low activity variant of MAOA gene found in 12% of cohort, but accounted for 44% violent convictions. Confirmed by MA by Byrd & Manuck, 2014). Fergusson et al. G*E interaction, in that those with low activity and high abuse significantly more likely to report later offending, hostility, and conduct problems. HOWEVER, small effect sizes that are difficult when studying single genes so contributions limited in scope. Also, tenuous link between MAOA genes and levels of MAOA in brain.