Schizophrenia Genetics Quest for the Holy Grail Nancy Buccola MSN, - - PDF document

APNA 29th Annual Conference Session 2016: October 29, 2015 Buccola 1

Schizophrenia Genetics

Quest for the Holy Grail

Nancy Buccola MSN, APRN, PMHCNS, CNE

Louisiana State University Health Sciences Center‐New Orleans

Leaders Defining the Art & Science of Nursing

The speaker has received research support from NIMH R01 MH61675 R01 MH067257 Objectives

Upon completion of this presentation, participants will be able to describe

• Current findings in genetic research related to

schizophrenia susceptibility

• How current findings in schizophrenia

genetics aid in understanding the etiology of this disease

• The implications of genetic research for the

care of people with schizophrenia

APNA 29th Annual Conference Session 2016: October 29, 2015 Buccola 2

• Poor outcomes (Desbonnett et al., 2012; Robinson et al., 2004)

– > 50% of affected people have poor outcomes; 80% relapse rate

• Diagnosis (Bromet et al., 2011; Wray et al., 2012)

– Based on observation and self‐report

• Limited treatments (Conley & Kelly, 2001; Tansey et al., 2015)

– There had not been a mechanistically novel class of drugs since 1960s

• Resource intensive

– Among top 10 disorders causing disability (Bosia et al. 2015)

• SCZ is the end state of processes that started years

before onset

The Problem with Schizophrenia Schizophrenia

• Kraepelin, Bleuler, Schneider, DSM

– Diagnosis based on symptoms – Mostly self‐reported

• Nature, 2009

– Three studies implicate the MHC region on chromosome 6 in European ancestry subjects

• International Schizophrenia Consortium
• Shi et al.
• Stefansson et al.
• Nature, 2014

– Schizophrenia Working Group of the PGC identifies 128 independent associations over 108 loci

• Nature, 2015

– The Network and Pathway Analysis Subgroup of the PGC identifies common pathways across SCZ, MDD, and BP

• Its complicated

– Complex disease – Polygenic traits – Rare and common variants

• Size matters

– We need even larger samples

• Not just the usual suspects

– Look beyond traditional candidate genes

• DNA has not read the DSM

– Cannot rely on current diagnostic classification

• Different strokes for different folks

– Unlikely that any single treatment target of strategy will be effective

What We Know

APNA 29th Annual Conference Session 2016: October 29, 2015 Buccola 3

Its Complicated

• Large number of genetic loci contribute to risk

– Common and rare variants – Common variants account for ⅓ to ½ of heritability – No single risk variant explains more than a small fraction of the genetic risk (~0.1%)

Kendler & O’Donovan, 2014; Schizophrenia Working Group of the Psychiatric Genetics Consortium, 2014

Its Complicated

• Over 100 genetic loci have been identified

– Encompassing 341 protein‐coding genes – Most are in non‐coding genes – There are many more yet to be identified

• Risk genes increase susceptibility/predisposition

– When the genes are present, development of SCZ symptoms is more likely but not certain

• Not randomly distributed
• Not specific to SCZ

Schizophrenia Working Group of the Psychiatric Genetics Consortium, 2014; The Network and Pathway Analysis Subgroup of the Psychiatric Genetics Consortium, 2015

Size Matters

• By 2013

– About 30 loci with genome wide significance

• Current successes

– Detailed information about variation in the genome – Availability of very large samples

• Largest single study prior to 2014 ‐ 21,000 cases and

38,000 controls (Ripke et al., 2013)

• In the 2014 study ‐ 36,989 cases and 113,075 controls

(Schizophrenia Working Group of the Psychiatric Genetics Consortium, 2014)

Increase sample size Increase significant findings

APNA 29th Annual Conference Session 2016: October 29, 2015 Buccola 4

Not Just the Usual Suspects

• The large scale GWAS implicate genes and

pathways beyond the old candidate genes

– DRD2 – Histone methylation (gene expression) – Synaptic function/plasticity

• Post‐synaptic density
• Glutamatergic neurotransmission

– Neuronal signaling

• Calcium channel subunits

– Immunity

• MHC region as well as genes associated with acquired

autoimmunity outside of the MHC region

Kendler & O’Donovan, 2014; Schizophrenia Working Group of the Psychiatric Genetics Consortium, 2014; The Network and Pathway Analysis Subgroup of the Psychiatric Genetics Consortium, 2015

DNA Has Not Read the DSM

• Wide variety of presentations
• In terms of risk genes

– High overlap between SCZ and BP – Moderate overlap with MDD – Small but significant overlap with ASD

Cross Disorder Group of the Psychiatric Genetics Consortium, 2013a; Cross Disorder Group of the Psychiatric Genetics Consortium, 2013b

DNA Has Not Read the DSM

• Graphic_Genotypic – Phenotypic Architecture

– Arnedo, J., Svrakic, D. M., Del Val, C., Romero‐Zaliz, R., Hernandez‐Cuervo, H., Fanous, A. H., . . . Zwir,

• I. (2015). Uncovering the hidden risk architecture
• f the schizophrenias: Confirmation in three

independent genome‐wide association studies. American Journal of Psychiatry, 172, 139‐153. http://dx.doi.org/10.1176/appi.ajp.2014.1404043 5

APNA 29th Annual Conference Session 2016: October 29, 2015 Buccola 5

DNA Has Not Read the DSM

• Graphic_Genotypic Network

– Arnedo, J., Svrakic, D. M., Del Val, C., Romero‐Zaliz, R., Hernandez‐Cuervo, H., Fanous, A. H., . . . Zwir,

• I. (2015). Uncovering the hidden risk architecture
• f the schizophrenias: Confirmation in three

independent genome‐wide association studies. American Journal of Psychiatry, 172, 139‐153. http://dx.doi.org/10.1176/appi.ajp.2014.1404043 5

DNA Has Not Read the DSM

• From data (genotype, phenotype, severity)

identified 8 classes of SCZ

‒ Severe process, with positive and negative symptoms ‒ Positive and negative SCZ ‒ Negative SCZ ‒ Positive SCZ ‒ Severe process, positive SCZ ‒ Moderate process, disorganized negative SCZ ‒ Moderate process, positive and negative SCZ ‒ Moderate process, continuous positive SCZ

Arnedo et al., 2015

Different Strokes for Different Folks

• Right medication/dosing is challenging
• Unlikely that any single treatment

target/strategy will be effective across all/or even a majority of patients

• Pharmcogenetics not widely used in psych

practice (Harrison, 2015a)

APNA 29th Annual Conference Session 2016: October 29, 2015 Buccola 6 Different Strokes for Different Folks

• Precision medicine

– More targeted approach

• Beyond symptoms

– The ability to identify disease subtypes will improve the accuracy of diagnosis and treatment

• Therapy based on fine tuning “circuits”

– Using the brain’s plasticity to alter neural circuits

• DBS
• TMS
• Cognitive/behavior therapy

Insel & Cuthbert, 2015

In Search of the Holy Grail

• In mental health, we are still waiting for

research to bear fruit

– Prevention/attenuation – Early identification – Effective treatment – Minimize disability

• What are the modifiable risk factors

– Gene expression depends to some extent on the context

• Gene x environment studies/gene expression

studies

– Genes influence risk of SCZ only in the presence of a particular environmental factor and vice versa – Epigenetic modifications can reduce or exacerbate gene expression – We need to know which stressors affect which genes

The Holy Grail ‐ Prevention/attenuation

Clarke et al., 2009; Clarke et al., 2012; Harrison, 2015b; Shorter & Miller, 2015; Stilo & Murray, 2010

APNA 29th Annual Conference Session 2016: October 29, 2015 Buccola 7 The Holy Grail ‐ Early Identification

• Genetic Testing

– Familial risk in a child of a mother with SCZ is 10% – Attributable risk for BP/SCZ/ASD is 98% for an individual with 22q11 deletion ‒ We are beginning to see markers which are significant in increasing risk

• Differential diagnosis
• Prediction of treatment outcomes
• Identification of high risk individuals
• Caution

Belsky & Israel , 2014; Delisi, 2014

The Holy Grail ‐ Early Identification

• Medical Test May Predict Risk of Schizophrenia

http://www.medicalnewstoday.com/articles/245591.php

– “Once the new test is refined, it could help physicians and caregivers identify which young people in families with a history of the disease are more likely to develop schizophrenia, prompting early intervention and treatment”

• Researchers Identify Genes Linked With the

Mental Illness, Create Risk Test

http://www.webmd.com/schizophrenia/news/20120515/new‐clues‐to‐schizophrenia

– “Scientists have developed a test that may be able to predict who is at risk for schizophrenia”

Ayalew et al., 2015

The Holy Grail ‐ Early Identification

• Because risk is often associated with many

genes of small effect

– Polygenic risk score (International Schizophrenia Consortium, 2009)

• Combining genetic markers into a single score
• May be helpful in stratifying samples
• Not ready to predict individual risk (Dudbridge (2015)

APNA 29th Annual Conference Session 2016: October 29, 2015 Buccola 8 The Holy Grail ‐ Early Identification

• Infinium PsychArray BeadChip

– Research tool – DNA microchip helps identify alterations – ≈ 50,000 markers associated with common psych disorders – PGC expects a psych chip paper in 2015

Courtesy of Illumina_http://www.illumina.com/content/dam/illumina‐ marketing/documents/products/datasheets/datasheet‐infinium‐psych‐array.pdf

• Right treatment/right person/right dose

– CATIE Study – SNPs related to drug response (Liu et al.,

2012)

– ADR/metabolic syndrome/TD (Crowley et al., 2012; De Leon, 2009;

Ellingrod et al., 2008)

– Identify SCZ that is “treatment resistant” (Frank et al., 2015)

• Treatment must focus on underlying pathology

– Genotypes have the potential to provide a profile which will serve as a guide to specific pharmacologic targets (O’Connell et al., 2010)

• Biomarkers that will predict response/side effects
• Cost of bringing new drugs to market is high

– Without biomarkers it is difficult to stratify populations for clinical trials

The Holy Grail ‐ Effective Treatment

• New (molecular) drug targets (Duan, 2015; Dunlop & Brandon, 2015)

– Glutamate transmission

• Metabotropic glutamate receptor 2/3 antagonist

– Dopamine signaling in the striatum

• PDE 10 inhibitor

– NMDA receptor

• GlyT1 inhibitor

– Cognitive benefit

• α 7 Nicotinic agonist
• Treatment response

– Novel Candidate Genes for Treatment Response to Antipsychotics in Schizophrenia (GEXANT) ClinicalTrials.gov Identifier: NCT02205437

The Holy Grail ‐ Effective Treatment

APNA 29th Annual Conference Session 2016: October 29, 2015 Buccola 9

• Re‐purpose existing drugs known to target

pathways (Lence & Malhotra, 2015)

– Several anti‐inflammatories have been tried as potential add‐on treatments

– Celecoxib (Akhondzadeh et al., 2007; Müller et al., 2010) – ASA (Laan et al., 2010) – Pregnenolone (Marx et al., 2009, Ritsner et al., 2010) – Minocycline (Levkovitz et al., 2010)

The Holy Grail ‐ Effective Treatment

The Holy Grail ‐ Effective Treatment

• Graphic_Induced Pluripotent Stem Cells

(iPSCs)

– Cincinnati Children’s Hospital, Pluripotent Stem Cell Facility website. (2011‐2014). https://research.cchmc.org/stemcell/ipsc

Fibroblasts from 4 people with SCZ reprogrammed to hiPSCs Differentiated into neurons 5 antipsychotics (Clozapine, Loxapine, Olanzapine, Risperidone, Thioridazine) administered for the final 3 weeks of neuronal differentiation Loxapine significantly increased the neuronal connectivity in hiPSC neurons in all patients

Brennand et al., 2011

The Holy Grail ‐ Effective Treatment

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• Personalized care
• Treatment based on underlying physiology

‒ Medication ‒ DBS ‒ TMS ‒ Cognitive behavioral therapy

The Holy Grail ‐ Minimize Disability

Arsian, 2015; Cox et al., 2015; Kida et al., 2015

• Target identification
• Rational drug design
• Genetic stratification in clinical trials
• Genetic prediction of efficacy/toxicity

The Holy Grail

Harrison, 2015b

Full reference citations are on the references handout nbucco@lsuhsc.edu