Genetics of Mental Disease

Question 1

How is heritability calculated?

Answer 1

Double difference between MZ and DZ twin concordance rates

Question 2

What is the effect of a 22q11.2 deletion?

Answer 2

Large increase in SCZ risk

Question 3

What is the effect of a certain CACNA1C SNP?

Answer 3

Slight risk increase for SCZ and BPD

Question 4

What is the effect of a certain ADH1B SNP and why?

Answer 4

Slight risk increase for alcohol dependence

Enables faster alcohol metabolism - must drink more for unpleasant effects

Question 5

Which type of genes did a large 2014 GWAS link to SCZ?

Answer 5

DRD2 (DAergic transmission)

Multiple genes in glutamatergic transmission

Question 6

Which glutamatergic-related genes have been linked to SCZ?

Answer 6

GRM3 - metabotropic glutamate receptor
GRIN2A - NMDAR subunit
SRR - serine racemase

Question 7

Name a SCZ-associated gene within a recombination hotspot

Answer 7

CACNA1C

Question 8

What is the evidence for a role of complement in SCZ?

Answer 8

MHC gene linked to increased SCZ risk - MHC role in complement
Higher C4 levels in SCZ patients than controls
C4 KO mice have decreased demarcation between ipsi- and contralateral retinal inputs to visual cortex - altered synaptic pruning in SCZ

Question 9

What is a polygenic risk score?

Answer 9

Total burden of risk variation of individual for a disorder

Question 10

What does comparison of BPD subtypes with polygenic risk scores for SCZ and MDD show?

Answer 10

BPD1 patients have increased SCZ risk

BPD2 patients have decreased MDD risk

Question 11

What does comparison of polygenic risk scores for SCZ and cannabis use show?

Answer 11

Increased cannabis use risk correlates with increased SCZ risk
May be underlying cause shared for increased SCZ and cannabis use risk

Question 12

What are the effects of a 15q11.2 deletion?

Answer 12

Maths and reading deficits in individuals without neuropsychiatric disorders
Grey matter alterations in ACC (same as in dyscalculia) and insula, supramarginal gyrus (same as in dyslexia)

Question 13

In which genes have rare loss-of-function variants have been linked to increased SCZ risk and what are their roles?

Answer 13

SETD1A - histone methyltransferase
TRIO - neurite outgrowth, synapse development
HERC1 - membrane transport

Question 14

What is linked to SLC39A8 and a certain lncRNA gene variation?

Answer 14

Increased grey matter volume of putamen

SCZ