L13 Schizophrenia (SCZ) Genetics

Schizophrenia (SCZ)

• Severe psychiatric disorder affecting up to 1% of the population.
• Genetic risk follows a polygenic model.
• Disturbances in dopaminergic and serotonin systems suggest a role for polymorphisms in these systems.
• Susceptibility studies involve family and case-control studies.

Large GWAS on SCZ

• Displayed 74776 cases and 1011023 controls.
• ZNF804A and KLF6 are transcription factors.
• Genes relevant to calcium and glutamate signalling are implicated; ATP2A2 encodes a calcium pump.
• Variants in ATP2A2 also associate with bipolar disorder.

ACE and SCZ

• ACE risk variant associates with low angiotensin converting enzyme expression.
• ACE is a dipeptidyl-carboxy oligopeptidase on neuron cell membranes.
• It has several functions in the CNS implicated in other phenotypes.
• Involved in neurosignalling by catalyzing the degradation of neuropeptides.

ACE Inhibitors

• ACE is a target for major anti-hypertensive drugs that relax veins and arteries.
• a-adducin gene (Gly460Trp) study showed Trp460 associated with hypertension and salt sensitivity.
• Subjects homozygous for Gly460Gly had no MI/stroke reduction with diuretic therapy.
• Trp460 allele carriers had a 51% reduction in MI or stroke with diuretic therapy.
• Reduced hypertension decreased cognitive function; ACE inhibitors increase cognitive function.
• This links to schizophrenia as it decreases cognitive function.

CYP2D6 and SCZ

• Cyp2D6 associates with SCZ, but the etiology is unknown.
• Numerous linked SNPs (rs16947, rs133377) associate with exon 3 skipping.
• Involved in the metabolism of numerous xenobiotics.
• Metabolizes 1 in 4 clinically used drugs and 40% of anti-psychotics.
• Neuroleptics like olanzapine have a narrow therapeutic index and are metabolized by CYP1A2.

Alzheimer's Disease (AD)

• Affects 5% of people over 65 and 20% over 80.
• Accounts for 60-80% of dementia cases.
• Has early and late onset forms.
• Early onset is often monogenic, late onset is more common and polygenic.
• Apoliprotein E (APOE) gene locus is a susceptibility locus.

GWAS on AD

• Displayed 90338 cases and 1036225 controls.
• Has 36 loci identified.
• HAVCR2 accumulates in aged microglia and binds to precursor beta-amyloid protein.
• BIN1 variant associates with endosome-size deregulation.
• Genetic risk is polygenic in most people with AD.

APOE Gene

• Transfers cholesterol and phospholipids between cells and is important in injury repair in the brain.
• APOE2 is protective, while E3 and E4 have amino acid substitutions.
• APOE2 distinguished from E3 by Cys to Arg at 158, E3 from E4 Cys to Arg at 112.
• APOE2 associated with lower cholesterol and higher APOE protein compared with APOE4.
• APOE4 carrier status is a risk factor for AD, possibly due to facilitating accumulation of beta-amyloid protein in the brain.

Clinical Relevance of APOE variants and AD

• 25% of individuals carry one copy of the APOE4 allele, and 3% carry two copies.
• APOE4 homozygotes develop AD by the age of 40.
• Overall contribution of APOE locus to AD susceptibility contributed to approx. 50%.

Smoking Behaviour

• Nicotine is responsible for addiction to smoking, cocaine, and heroin.
• Acts on nicotinic acetylcholine receptors, producing stimulatory and inhibitory effects.
• Withdrawal symptoms include nausea, insomnia, depressed concentration, and psychomotor activity.
• Twin studies show genetic influence on smoking initiation, continuation, and cessation.

CYP2A6

• Mainly expressed in the liver, metabolizes nicotine and cotinine
• Metabolizes toxins and procarcinogens.
• Activity is estimated by measuring coumarin oxidation, showing around 300 fold interindividual variation.
• 1% of Caucasians and 20% of Asians are PMs (Poor Metabolisers).
• Responsible for 90% of nicotine metabolism.
• Cocaine treatment reduces the desire to smoke, irritability, and anxiety.

Action of Nicotine

• Nicotine binds to nicotinic receptors in nerve cells of the brain.
• Triggers dopamine release at nerve synapses, causing an emotional reward.
• Brains release dopamine at different times and become dependent on nicotine for dopamine release.

Human Nicotinic Acetylcholine Receptor Genes (NACHRs)

• Includes genes: CHRNA2, CHRNA4, CHRNA7, CHRNA9, CHRNA10, CHRNB2
• Gene cluster CHRA3-A5-B4 is located on chromosome 15 at 15q24 and is associated with smoking behaviour and lung cancer.
• Gene cluster CHRNB3-A6 is located on chromosome 8 at 8q11.2.
• All NACHRs are associated with smoking behaviour and lung cancer.

GWAS on Smoking Behavior

• Significant associations at chromosomes 15, 8, and 19.
• Associations were confirmed in additional cohorts.

Smoking and Lung Cancer Link

• Link between lung cancer and other cancers (adenocarcinoma, squamous cell carcinoma).
• Significant variants: CHR gene cluster and CYP2A6 polymorphisms.
• CHR polymorphism D398N (rs16969968) in CHRNA5 is associated with nicotine dependence and lung cancers.
• Shared genetic susceptibility exists in SCZ and smoking.

SCZ and Nicotine Use

• Chr 15 -- CHRNB4 and CHRNA3.
• Patients with SCZ continue to smoke to relieve anxiety.
• Smoking may drive SCZ symptoms.
• SCZ and smoking have a bidirectional relationship.
• Tobacco smoking is suggested to increase risk of schizophrenia spectrum disorder.

Smoking Cessation

• Nicotine can be used as a substitute (less harmful than other tobacco components).
• Bupropion is an antidepressant prescribed for smoking cessation.
• CYP2B6 genotype affects bupropion metabolism and overall response.
• Outcome depends on the interaction between genes and exposure.

Depression and Drug Metabolism

• TCAs (Tricyclic antidepressants) are better substrates for CYP2D6.
• Polymorphisms in CYP2D6 impact clinical outcomes with TCAs.
• Therapeutic drug monitoring is recommended for TCAs.
• CYP2C19 is involved in antidepressant metabolism but only has influence depending on the genotype effect and contribution it has to antidepression metabolism than other CYPs.
• Clomipramine affected by CYP2C19 genotype; PMs have higher plasma concentrations.

Sertraline and Citalopram Drug metabolism

• Sertraline demethylated into inactive metabolite desmethylsertaline have higher AUC in PM than EM.
• CYP2C219 metabolizes citalopram into demethylated metabolite with lower plasma concentration and potency than citalopram.
• Citalopram gene dose effect is shown for both with a difference in concentration ratio.
• Increased dose 10-20 mg appears to increase response rates in severely depressed patients.

Organ Transplantation

• Calcineurin inhibitors (cyclosporine and tacrolimus) are important immunosuppressants.
• CYP3A4 and CYP3A5 metabolize cyclosporine and tacrolimus.
• Genetic polymorphisms in these genes affect drug elimination rates.
• Dose-adjusted trough concentrations for tacrolimus are 3-fold higher in CYP3A5*3 homozygous patients.
• CYP3A4 genotype affects cyclosporine pharmacokinetics.

Rheumatoid Arthritis Treatment

• Treated with NSAIDs, corticosteroids, DMARDs, and immunosuppressants.
• NSAIDs metabolized by polymorphic CYP2C9; low activity conferred by CYP2C92 & CYP2C93.
• These influence pharmacokinetics of ibuprofen, naproxen, diclofenac, and celecoxib.

Gastrointestinal (GI) Disorders

• CYP2C19 genotype is a strong determinant of acid-related disorder treatment success.
• PPIs used to treat acid-related disorders and H. pylori-positive gastric ulcers.
• Omeprazole has a higher affinity to CYP2C19.
• Low omeprazole doses treat ulcers, cure rates were low in EMs, higher in IMs, and complete in PMs showing higher levels of plasma is needed for effective treatment of GI disorders.
• CYP2C19 genotypes increase pH from 1.2-5.5 in IMs and up to >6 in PMs.
• Japanese patients display 20% of the pop. as PMs and were given standard treatment to eradicate H.pylori bacteria, where 30 mg of Lansoprazole 2x daily with clarithromycin and amoxicillin

Helicobacter pylori Treatment

• Genotype based treatment allowed 96% eradication of H.pylori.
• standard protocol treatment only showed 70% eradication.

Cardiovascular Disease

• Drugs are metabolized by CYP2C9 & CYP2D6.
• Anti-vitamin K anticoagulants acenocoumarin and warfarin are metabolized by CYP2C9.
• CYP2C9*3 patients had major bleeding complications, along with longer hospitalization during warfarin therapy.
• CYP2C19 reduces bioactivation of antithrombotic prodrug clopidogrel.
• CYP2C19*2 allele is not reduced by clopidogrel treatment.

Defective CYP Alleles & Thrombosis

• Subjects expressing defective alleles aren't expected to respond to clopidogrel treatment.
• Increased risk of recurrent thrombosis.

Antiretrovirals for treating HIV

• Efavirenz is metabolized primarily by hepatic CYP2B6 with Polymorphisms 516G>T (Q172H)
• African patients that express less efficient of CYP2B61 enzyme alongside with CYP2D66 allele has much higher plasma levels at standard dosing compared with other subjects carrying other CYP2B6 genotypes
• Nelfinavir is metabolised than CYP2C19 & plasma exposure is associated with defective CYP2C19*2 allele

Diabetes

• CYP2C9 metabolizes oral antidiabetics (sulfonylureas and nateglinide).
• Oral clearance of sulfonylureas CYP2C9*3/3 genotype has 20% of wild type genotype CYP2C91/*1
• Therefore, adverse effects can be reduced by CYP2C9 genotype-based adjustments.

Benzodiazepines

• Diazepam is used to treat preoperative anxiety.
• PMs of CYP2C19 have almost double the time to emerge from general anesthesia.
• 35% lower clearance of diazepam means longer sedation in these patients.
• PKs of Etizolam is affected by CYP2C19 genotype.
• Clobazam is used for treatment of epilepsy mainly converted to N-desmethylclobazam has longer half-life than parent drug, CYP2C19 catalyses further metabolism of N-methylclobazam.
• N-methylclobazam's metabolism to 4-hydroxyesmethylclobazam is drastically impaired causes an increased risk of side-effects such as drowsiness in PM subjects .