Schizophrenia

Question 1

Schizophrenia - genetic concordance rate with twin and relative and lifetime risk

Answer 1

monogenetic twins: 50%
first degree relative: 10%
lifetime risk: 1%

Question 2

Genetic Contributions to SZ

Answer 2

Common variation
Rare copy number variants
Rare sequence variants

Question 3

What are copy number variants?

Answer 3

Copy number variation (CNV) is a general term used to describe a molecular phenomenon in which SEQUENCES OF THE GENOME ARE REPEATED, and the number of repeats varies between individuals of the same species.

Question 4

Copy number variants in SZ

Answer 4

• can be deletions
• can be duplications

There are regions more susceptible to these but they are overall rare.

NRXN1 deletion seems to be the only related CNV.

Question 5

Types of DNA change that alter amino acids

Answer 5

1. nonsense (stop) variant
2. frame shift mutation
3. splice-site mutation

Question 6

what is a synonymous variant

Answer 6

change to DNA that gives the same amino acid.

Question 7

nonsense (stop) variant

Answer 7

change to DNA that introduces a STOP codon

Question 8

frame shift mutation

Answer 8

change to DNA that add/removes

Question 9

splice-site mutation

Answer 9

change to DNA that will not introduce intron or not include exon.

Question 10

High impact coding variants in SZ

Answer 10

• Loss of function (LoF) variants / protein truncating variants (PTV): stop-gained, frameshift, splice site.
• Damaging missense: nonsynonymous variants with high score using missense badness, polyphen-2 and constraint (MPC) pathogenicity classifier.

Question 11

SZ and SETD1A

Answer 11

SETD1A loss of function are very rare variants, that are implicated in SZ.

There are 10 different LoF variants in SETD1A in SZ.

SETD1A codes for a methyl trasnferase for HISTONE H3.

Question 12

what did the SCHEMA study for SZ find:

Answer 12

FOUND: SZ risk higher in carriers of protein truncating (LOF) or missense (MPC>3) variants in LOF-intolerant genes.

• Identified ten genes, incl. GRIN2A, SP4, and SETD1A, in which rare coding variants increase risk.

These were extremely rare.

Question 13

SETD1A mouse model

Answer 13

SETD1A LoF variant - methylates H3K4 lysine.

These mice have abnormal architecture and subtle cognitive deficits

Treatment with Tranylcypromine (TCP) restores SETD1A deficient mice to normal functioning.

Question 14

GRIN2A and SP4 and SZ risk

Answer 14

GRIN2A codes for subunit of NMDAR receptor

SP4 required for expression of GRIN1, which codes for another subunit of NMDAR.

SO - NMDAR as a drug target

Question 15

NMDAR as a drug target

Answer 15

can be enhanced by SARCOSINE.

small molecules can also target NMDAR to enhance function.

• Small molecules which are LSD1 inhibitors (balancing SETD1A hypofunction)
• Lipid nanoparticles to deliver mRNA for GRIN2A or GRIA3 (glutamate receptor genes