New Advances in Psychiatric Genetics Joseph Shen, M.D., Ph.D. Aisha Furqan, LCGC Clinical Genetics UCSF-Fresno Community Regional Medical Center Background Genetic testing Treatment options: Pharmacogenetics Gene therapies General Outline Background ~3.2 billion base pairs ~21000 genes, vast majority come in pairs Many parts to a gene exon, intron, 5 UTR, 3 UTR, regulatory sequences Patterns of inheritance Autosomal dominant Autosomal recessive X-linked Others (mitochondrial, imprinting, mosaic, anticipation, multifactorial) 1
Background What is the diagnosis? Other affected organ systems? Natural history Anticipatory guidance Recurrence risks Other relatives affected? Treatment Background Clinical Case 1 Genetics called to evaluate newborn infant in the NICU who was prenatally recognized with congenital heart defect. Background Clinical Case 1 Genetics called to evaluate newborn infant in the NICU who was prenatally recognized with congenital heart defect. Family medical history notable for psychiatric disorders in the father, and several paternal first degree and second degree relatives. 2
Background Clinical Case 1 What is the diagnosis? Velocardiofacial syndrome (VCFS, 22q11.2 deletion, DiGeorge syndrome) Natural history nothing of note Background Clinical Case 1 (cont.) Other affected organ systems? clefting, vertebral anomalies, intellectual disability, renal abnormalities Anticipatory guidance possible immunodeficiency Recurrence risks autosomal dominant and de novo deletions Other relatives affected? psychiatric disorders Treatment - none Background Clinical Case 2 15 year old male with new onset diabetes mellitus. Known to have progressively deteriorating vision due to optic atrophy when evaluated by Ophthalmology. Also has mild sensorineural hearing loss. First child to his parents. Negative overall family medical history. 3
Background Clinical Case 2 What is the diagnosis? Wolfram syndrome, also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) Other affected organ systems? growth retardation, neurogenic bladder, delayed puberty/hypogonadism, hypothyroidism Natural history mildly neurodegenerative, dementia, movement disorders Background Clinical Case 2 (cont.) Anticipatory guidance monitor for above issues, also increased risk of suicidal ideation and psychiatric illnesses Recurrence risks autosomal recessive Other relatives affected? none Treatment - none Background What is the diagnosis? Other affected organ systems? Natural history Anticipatory guidance Recurrence risks Other relatives affected? Treatment 4
Molecular Genetics Testing Different types of gene disruption Chromosomes, FISH, Sanger sequencing Microarrays High throughput assays Whole exome sequencing Molecular Genetics Testing Different types of gene disruption Chromosomes, FISH, Sanger sequencing Microarrays High throughput assays Whole exome sequencing Disruption of genetic information AGTTCTGAGGCATTACC TCAAGACTCCGTAATGG Chromosome Genomic region DNA Chromosome band Gene Exon Karyotype FISH Sequencing 5
Karyotype Fluorescence in situ hybridization Green TUPLE1 (22q11.2) Red ARSA (22q13.3) Fluorescence in situ hybridization Green TUPLE1 (22q11.2) Red ARSA (22q13.3) Velo-cardio-facial syndrome 6
Molecular Genetics Testing Different types of gene disruption Chromosomes, FISH, Sanger sequencing Microarrays High throughput assays Whole exome sequencing Microarray 7
Comparative Genome Hybridization Source www.genome.gov CGH Source Implen website Molecular Genetics Testing Different types of gene disruption Chromosomes, FISH, Sanger sequencing Microarrays High throughput assays Whole exome sequencing 8
Next Generation Sequencing Several different genes cause the same disease/syndrome Symptom-based gene panels No clear distinguishing features between genes Too many genes to try and only aim at one Giegling et al (2017) World J Biol Psychiatry (epub ahead of print) 9
Molecular Genetics Testing Different types of gene disruption Chromosomes, FISH, Sanger sequencing Microarrays High throughput assays Whole exome sequencing Exome = Exon + Genome ~ 5000 of the ~21000 genes Background What is the diagnosis? Other affected organ systems? Natural history Anticipatory guidance Recurrence risks Other relatives affected? Treatment Aisha Furqan, MS, LCGC Joseph Shen, MD, PhD 10
Pharmacogenomics is a study of how genes affect a person s response to drugs. It combines pharmacology and genomics to develop effective, safe medications and doses that will be tailored to a person s genetic makeup. Goal is personalized medicine: the right patient with the right drug at the right dose at the right time. 11
Drug metabolism enzymes In 1977: Cytochrome P4502D6 is identified as the cause for some patients to experience an overdose and intensity of the effects of hypertension drug debrisoquine. Clozapine atypical antipsychotic drug used in treatment of schizophrenia substrate for many CYP450 isozymes 1A2 2D6 3A4 12
Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted. A subset (3% 10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. Concomitant use of CLOZARIL with other drugs metabolized by CYP2D6 can increase levels of these CYPD26 substrates. Use caution when coadministeringclozaril with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide). Demographics Age -32 y o Sex -female Complaint Pre-conception genetic counseling Plan Order Expanded carrier screen panel Carrier screening is the practice of testing unaffected individuals to identify those at increased risks of having children with genetic disorders. Various size of panels are now commercially available with up to ~250+ disorders. 13
A condition in which a person's body is abnormally slowat breaking down a certain class of drugs used for surgical anesthesia. Most common drug: Succinylcholine (suxamethonium). After receiving a normal dose of succinylcholine, people with pseudocholinesterasedeficiency will experience a longer than normal period of breathing paralysis. Carriers/Heterozygotes one working and one not working copy of the gene Affected/Homozygotes both copies of the gene are not working 14
Homozygotes show 1 to 3 hours of breathing paralysis after receiving normal dose. Heterozygotes show 5 minutes to an hour of breathing paralysis after receiving normal dose. Demographics Age 69 years old Sex male Ethnicity White/Caucasian Complaint need to take much higher doses of omeprazole, Ambien (zolpidem), and hydrocodone for efficacy PCP worries about respiratory side effects prescribed Narcan( treat narcotic overdose) in the interim referred to genetics to find variants in cytochrome P450 to providing a molecular basis for his high physiologic tolerance family history unremarkable for high metabolizers 15
Hydrocodone opioid pain medication CYP2D6 - into more bioactive hydromorphone CYP3A4 - into less bioactive norhydrocodone Zolpidem to treat insomnia CYP3A4 -into less/non-bioactive metabolites. Omeprazole to treat GERD CYP3A4 and CYP2C19 -into less/non-bioactive metabolites CYP2D6 More bioactive metabolite, hydromorphone hydrocodone Less bioactive metabolite, norhydrocodone omeprazole CYP3A4 zolpidem CYP2C19 Less bioactive metabolites Less bioactive metabolites 16
CYP2D6 Hydrocodone One normal metabolizer allele One intermediate metabolizer allele CYP3A4 Zolpidem and Omeprazole homozygous for normal metabolizer allele CYP2D6 More bioactive metabolite, hydromorphone hydrocodone Less bioactive metabolite, norhydrocodone omeprazole CYP3A4 zolpidem CYP2C19 Less bioactive metabolites Less bioactive metabolites CYP2D6 More bioactive metabolite, hydromorphone hydrocodone Less bioactive metabolite, norhydrocodone CYP3A4 zolpidem Less bioactive metabolites omeprazole CYP2C19 Less bioactive metabolites 17
CYP2D6 More bioactive metabolite, hydromorphone hydrocodone Less bioactive metabolite, norhydrocodone CYP3A4 zolpidem Less bioactive metabolites omeprazole CYP2C19 Less bioactive metabolites CYP2D6 More bioactive metabolite, hydromorphone hydrocodone CYP3A4 Less bioactive metabolite, norhydrocodone omeprazole Less bioactive zolpidem metabolites CYP2C19 Less bioactive metabolites pharmacogenetic studies in the field of anxiety disorders, OCD, and PTSD point to a potential role of the SLC6A4, HTR1A, HTR2A, MAOA, COMT, and CRHR1 gene variants in mediating interindividual differences in response to pharmacotherapy or cognitive-behavioral therapy in panic disorder with or without agoraphobia, social anxiety disorder and/or generalized anxiety disorder.. 18
Polymorphisms in genes involved in anti-depressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signaling (FKBP5), serotonin neurotransmission (SLC6A4 and HTR2A), and others (HTR1A, BDNF, CRAB1, GDNF, CRP, IL-1β, IL-6, TNF-α) polymorphisms within the genes encoding for the brain-derived neurotrophic factor (BDNF), the dopamine 2 receptor gene (DRD2), the dopamine receptor 3 gene (DRD3), the cathechol-o-methyltransferase (COMT), the serotonin-transporter (5-HTT), the 5-hydroxytryptamine 2 A receptor (5-HT2A), and the norepinephrine transporter (NET), appear to predict a good response to ECT. 19
intriguing data supporting the role of two noncoding RNAs (lncrnas), AL157359.3 and AL157359.4, in the lithium response 20
Conclusions Reason for referral to genetics, and to perform genetic testing, is to provide comprehensive information for the patient and the family Genetics in psychiatry is advancing, although not to the point of widespread clinical applicability Future breakthroughs in psychiatric genetics will be in the form of pharmacogenomics and permanent treatment options 21