Genetics of Schizophrenia Principles Problems Dr Hisham Ramy

Genetics of Schizophrenia: Principles & Problems Dr. Hisham Ramy Ass. Prof of Psychiatry (ASUH) Consultant Psychiatrist (UK)

Introduction n n Nature & Nurture (Gene & Environment). Gene Expression. Proband. Mendelian & Non-Mendelian. Genetic Epidemiology & Biology.

Family Studies n n n n Relatives > Non-relatives. The More-related > the Less-related. Evidence not Proof. Risk estimation. Concept of spectrum. Anticipation. Major difficulty: Relatives assessment.

Twin Studies n n n MZ > DZ. < 100%. Evidence not proof. Finding twins. Assessing zygocity.

Adoption Studies n n n Adoptee design. Adoptive design. Cross-fostering design. Evidence not proof. Problem: No adoption.

Linkage & Association n n Linkage: markers with known sites. Association: candidate genes. Linkage: controls are family members. Association: general population. Problems: Caseness, Large families, genetic variation.

Family-based Association n n Overcome difficulties. Sib-pair analysis. Haplotype Relative Risk Design. Multiple small family linkage.

Molecular Techniques n n n n Obtaining blood. Isolating DNA. Replicating DNA (PCR). Splicing DNA. RFLP, VNTR, SNP. Identifying gene or site. Analysing (sequencing).

Candidate" Genes n The following are some of the candidate genes thought to increase risk for schizophrenia and explains what they do.

COMT (catechol-O-methyl transferase) n n 22 q 11 Enzyme that breaks down dopamine. People who have the val version have low dopamine levels in their prefrontal cortex and do not perform as well on cognitive tasks as people with the met version

Dysbindin (DTNBP 1) n n 6 p 22 Decreases the amount of glutamate in the brain, which interferes with the action of the receptor NMDA (N-methyl. D-aspartame). NMDA is necessary for memory, learning, and being able to adapt to changing circumstances in the environment.

Neuregulin 1 (NRG 1) n n 8 p 12 -21. Regulates many brain cell functions. It affects how well brain wiring develops in the womb, how well neurotransmitters work, and how well the brain can grasp and adapt to new situations.

GRM 3 n n 7 q 21 -22 Alters glutamate levels in the prefrontal cortex and the hippocampus, and thereby affects higher cognitive functions

G 72 and DAAO n n n 12 q 32 -34 and 12 q 24 Activates DAAO (D-amino acid oxidase), which promotes the action of NMDA G 72 may promote schizophrenia by disrupting the functioning of the prefrontal cortex and hippocampus.

CHRNA 7 (Alpha-7 Nicotinic Receptor Gene) n n 15 q 13 -14. Regulates how sensitive the system is to nicotine, which slows down attention and sensory processing. CHRNA 7 also helps promote good dopamine and glutamate signaling between neurons. This gene is seen less often in the cells of people with schizophrenia, especially in brain regions often implicated in this disorder, such as the hippocampus, thalamus, frontal cortex and the cingulate cortex.

PRODH 2 n n 22 q 11 Helps regulate the levels of the enzyme proline. When proline levels are too high, glutamate levels in the brain drop too low.

RGS 4 (regulator of G-protein signaling 4) n Helps neurons mature and is part of the way neurotransmitters work inside neurons.

PPP 3 CC n n 8 p 21. A subunit of the calcineurin gene, PPP 3 CC helps dopamine and glutamate transmit messages from neuron to neuron.

Future Implications n n n Diagnosis ? ? Gene expression. Pharmacogenomics, Pharmacogenetics. Gene therapy? ? Ethical Issues.