APNA 29th Annual Conference Session 2016: October 29, 2015 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 Buccola 1
APNA 29th Annual Conference Session 2016: October 29, 2015 The Problem with Schizophrenia • 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 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 What We Know • 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 Buccola 2
APNA 29th Annual Conference Session 2016: October 29, 2015 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 Increase sample size Increase significant findings • 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) Buccola 3
APNA 29th Annual Conference Session 2016: October 29, 2015 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 of 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 Buccola 4
APNA 29th Annual Conference Session 2016: October 29, 2015 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 of 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) Buccola 5
APNA 29th Annual Conference Session 2016: October 29, 2015 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 The Holy Grail ‐ Prevention/attenuation • 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 Clarke et al., 2009; Clarke et al., 2012; Harrison, 2015b; Shorter & Miller, 2015; Stilo & Murray, 2010 Buccola 6
APNA 29th Annual Conference Session 2016: October 29, 2015 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) Buccola 7
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