A genetics-guided approach to the clinical management of schizophrenia

Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in ~1% of populations across cultures. There have been recent major advancements in our understanding of the genetic architecture of schizophrenia. Both rare, highly penetrant genetic variants as well as common, low-penetrant genetic variants can predispose individuals to schizophrenia and can impact the way people metabolize psychoactive medications used to treat schizophrenia. However, the impact of these findings on the clinical management of schizophrenia remains limited. This review highlights the few places where genetics currently informs schizophrenia management strategies, discusses major limitations, and reviews promising areas of genetics research that are most likely to impact future schizophrenia care. Specifically, I focuss on psychiatric genetic counseling, genetic testing strategies, pharmacogenetics, polygenic risk, and genetics-guided treatment. Lastly, I emphasize important ethical considerations in the clinical use of genetics for schizophrenia management, including the exacerbation of healthcare inequalities and unintended consequences of new genetic technologies.


Introduction
Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in ~1 % of populations across cultures (Kahn et al., 2015).Schizophrenia, or perhaps dimensional traits of schizophrenia (Ronald and Pain, 2018;Waszczuk et al., 2023), are highly heritable (Hilker et al., 2018), but until recently the specific genetic architecture was unknown.Due to the joint efforts of major consortia, we are beginning to uncover the genetic foundations of schizophrenia, though they are still not fully understood.
287 distinct genomic loci have been significantly associated with schizophrenia (Trubetskoy et al., 2022) through genome-wide association studies (GWAS).At each of these loci, multiple single nucleotide polymorphisms (SNPs) (i.e., single base pair changes that are common in the general population and typically have a mild individual effect) contribute to the observed signal.However, these genome-wide significant SNPs only account for a small percent of the variance in liability for schizophrenia (~2.4 %) (Trubetskoy et al., 2022).When all measured SNPs are considered, the proportion of variance in liability explained increases to ~24 % (Trubetskoy et al., 2022), suggesting that many SNPs that do not meet the stringent threshold for genome-wide significance still collectively contribute to the genetic liability for schizophrenia.This underscores the polygenic nature of schizophrenia, where numerous variants spread across the genome, each with a subtle effect, combine to confer risk for the disorder.Furthermore, several SNPs within the CYP2D6 gene have been linked to the rate of metabolism of antipsychotic drugs used to treat schizophrenia (Islam et al., 2021), suggesting a complex genetic basis for treatment response, in addition to disease onset.
Rare, highly pathogenic variants have also been associated with an increased risk of developing schizophrenia (Singh et al., 2022).These variants include large genomic deletions and duplications known as copy number variants (CNVs) and rare pathogenic single nucleotide changes known as single nucleotide variants (SNVs) (Kato et al., 2023).Rare variants have been identified through both large schizophrenia case-control studies (Singh et al., 2022) as well as through the analysis of large, multiplex families (Li et al., 2021).Rare variants, such as the 22q11.2deletion, can act in concert with SNP-based genetic liability for schizophrenia to contribute to disease onset (Cleynen et al., 2021).
Historically, genetics and genetic testing has had a very limited role in the clinical management of schizophrenia.This is gradually changing, with a growing number of patients who may benefit from a genomicsguided approach, especially those individuals who possess a highly penetrant rare CNV or SNV.Below, I describe the ways in which genetics may inform schizophrenia management currently and attempt to highlight promising areas of psychiatric genetics research that may soon translate into novel management strategies, which are also briefly summarized in Table 1.

Genetic counseling and testing
Genetic counseling is often initiated in the context of schizophrenia due to a family member's concern or curiosity about the potential development of the condition.In this case, providing empiric data on recurrence risk may suffice without resorting to genetic testing (Mc-Guffin et al., 2004).For clinicians uncomfortable with genetic Abbreviations: AED = antiepileptic drug; CIA = clozapine-induced agranulocytosis; CMA = chromosomal microarray; PGx = pharmacogenetic; NMDA-R = N-methyl-D-aspartate receptor; SCARs = serious cutaneous adverse reactions.

A.D. Besterman
counseling, psychiatric genetic counselors may serve as especially helpful partners.They are trained to use a holistic approach to explain the interplay between genetic and environmental factors contributing to psychiatric disorders and to address the emotional concerns and questions of the patients (Austin, 2020).Topics such as guilt, blame, shame, fear, and stigma associated with mental illness are typically covered.
Studies have shown that such counseling improves the understanding of disease recurrence risk, increases objective and subjective genetics knowledge, and reduces internalized stigma, worry, and self-blame in individuals with schizophrenia and their families (Costain et al., 2014a(Costain et al., , 2014b)).
In schizophrenia, there are a number of known, schizophreniaassociated CNVs such as the 22q11.2deletion, 3q29 deletion, 1q21.1 deletion, and 16p11.2duplication (Marshall et al., 2016) and schizophrenia-associated ultra-rare coding SNVs (Singh et al., 2022) There are some unique properties of these variants and their correlation to schizophrenia such that the benefit of genetic testing may not always outweigh the risk, which is different than other neurodevelopmental disorders, such as intellectual disability (ID) or global developmental delay (GDD) (Morris et al., 2022).For example, unlike in ID or GDD, genetic variants associated with schizophrenia tend not to be causal in nature (i.e.not fully penetrant), have a more modest impact on medical management, rarely inform accurate recurrence risk on their own, and may create false beliefs that the state of active symptoms of the condition is permanent or immutable (Morris et al., 2022).Furthermore, in ID/GDD there is a well-established high (~20-40 %) diagnostic yield of pathogenic or likely pathogenic (P/LP) variants using chromosomal microarray for CNVs, exome sequencing for SNVs, and/or genome sequencing for both CNVs and SNVs (Manickam et al., 2021;Muhle et al., 2017).In contrast, the reported diagnostic yield for schizophrenia ranges from <1 % (Balakrishna and Curtis, 2020) to upwards of 15 % (Mojarad et al., 2021), with significant heterogeneity across study populations.The populations differ on psychosis age-of-onset, from childhood-onset (i.e., pre-pubescent) (Ambalavanan et al., 2019(Ambalavanan et al., , 2016)), to early-onset (i.e., adolescent) (Brownstein et al., 2022;Gregoric Kumperscak et al., 2021), to adult-onset (Balakrishna and Curtis, 2020;Costain et al., 2013).Additionally, the degree of comorbidity with other NDDs varies considerably, which can strongly impact diagnostic yield (Lowther et al., 2017).The uncertain benefit and variable diagnostic yield are two key factors leading to indeterminate recommendations for genetic testing in schizophrenia from professional psychiatric organizations like the American Psychiatric Association, Canadian Psychiatry Association, and International Society of Psychiatric Genetics are (Finucane et al., 2021;International Society of Psychiatric Genetics, 2019).Therefore, it is currently up to the discretion of clinicians in consultation with patients and families to decide whether to pursue genetic counseling and/or genetic testing for an individual with schizophrenia.

Antipsychotics
The effectiveness of antipsychotic medications for schizophrenia varies between individuals, with some patients experiencing significant symptom relief and others experiencing little to none.Similarly, the burden of side effects can differ, with certain individuals tolerating the medications and others experiencing severe or intolerable side effects, necessitating dose adjustments or medication switches.Pharmacogenetics (PGx) seeks to identify genetic factors that contribute to this variability in antipsychotic response and tolerability.Antipsychotics are metabolized by several cytochrome P450 genes that code for a group of liver-expressed detoxifying enzymes, with CYP2D6 playing a central metabolic role for many (Islam et al., 2021).Variants within this gene and different copy numbers of the gene can alter an individual's rate of antipsychotic metabolism and subsequent serum level and drug exposure, resulting in metabolic phenotype classifications: Poor (i.e., very slow), intermediate (i.e., reduced), extensive (i.e, normal or wildtype), or ultrarapid (Islam et al., 2021).
In a meta-analysis of 33 studies, CYP2D6 genetic variations significantly impacted the response to and side effects of antipsychotics (Milosavljević et al., 2021).Poor metabolizers experienced more side effects and required lower doses, while ultra-rapid metabolizers needed higher doses for therapeutic effects.Intermediate and extensive metabolizers showed mixed responses (Milosavljević et al., 2021).Similar finding were observed in a meta-analysis of antipsychotic treatment in youth (Maruf et al., 2021).While these studies highlight a correlation between metabolic phenotype and prescribed antipsychotic dose, it should be noted that without knowing PGx status of patients, clinicians naturally adjust antipsychotic dose or switch to a different medication at higher rates for patients with outlier metabolic phenotypes (i.e., poor and ultrarapid metabolizers) (Jukic et al., 2019).Therefore, it remains unclear if CYP2D6 genotyping truly improves treatment outcomes for patients with schizophrenia on antipsychotics or not.Furthermore, CYP2D6 is structurally complex, highly polymorphic, frequently impacted by CNVs, and prone to forming hybrid genes with the neighboring CYP2D7 pseudogene (Gaedigk, 2013).This complexity has resulted in significant inconsistency in metabolic phenotyping between labs (Bousman and Dunlop, 2018).Recent expert consensus recommendations were published to harmonize genotype-to-metabolic phenotype translation (Caudle et al., 2020) and new bioinformatic approaches have been developed to improve CYP2D6 sequencing (Chen et al., 2021;Lee et al., 2019).Therefore, while CYP2D6 testing may provide some information about the rate of metabolism and exposure to antipsychotics in patients with schizophrenia, it is important to consider the technical challenges of genotyping and the subsequent variability in laboratory reporting in addition to the clinical limitations.

Clozapine
Clozapine is likely underutilized in the management of severe and treatment-refractory schizophrenia in part due the substantial concern about serious side effects (e.g., cardiomyopathy, seizures, metabolic syndrome, agranulocytosis) and the need for close monitoring (Kelly et al., 2018).This had led to significant interest in the use of PGx testing to identify patients at greatest risk for adverse outcomes, such as clozapine-induced agranulocytosis (CIA).In a meta-analyses of CIA, out of 13 variants across nine genes (NQO2, CYBA, MPO, HLA-DRB1, HLA-DQB1, HLA-DRB4, HLA-DRB5, HLA-DR2, and HLA-B), only the association between HLA-DRB1*04:02 and CIA was found to be significant compared to non-carriers, with the risk allele associated with a sixfold higher odds of CIA (Islam et al., 2022;Teng et al., 2023).
Likewise, in a recent large-scale PGx study of clozapine response, two SNPs (rs2472297, rs3732218), in genes known to be associated with clozapine metabolism, CYP1A2 and UGT1A, were found to be associated with peripheral concentrations of clozapine metabolites (Bousman, 2023;Pardiñas et al., 2023).When the effects of a large numbers of variants associated with clozapine metabolism were combined into polygenic scores, up to 7.26 % of the variance in drug metabolism could be explained (Pardiñas et al., 2023).The genetic associations with CIA and clozapine exposure suggest that further genetic studies of clozapine response are warranted and will likely yield fruitful results but are not yet strong enough to warrant clinical use.

Carbamazepine and oxcarbazepine
For individuals with schizoaffective disorder or an otherwise significant mood component to their psychosis, PGx testing can help guide the safe use of the mood stabilizers carbamazepine and oxcarbazepine.The HLA-A*31:01 variant is associated with an increased risk of serious cutaneous adverse reactions (SCARs; e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) for individuals of European-ancestry (Fricke-Galindo et al., 2018;McCormack et al., 2011).Currently, only the European Medicines Agency explicitly recommends regular HLA-A*31:01 for patients of European ancestry, while other regulatory agencies such as the American Food and Drug Administration, the United Kingdom's Medicines and Healthcare products Regulatory Agency, and Japan's Pharmaceuticals and Medical Devices Agency acknowledge the risk but defer to clinical judgement on testing.The HLA-B*15:02 variant is likewise associated with an increased risk of SCARs for individuals of Asian-ancestry (Chen et al., 2011;Fricke-Galindo et al., 2018).Per the Clinical Pharmacogenetics Implementation Consortium, both HLA-A*31:01 and HLA-B*15:02 PGx testing have level 1 A evidence supporting their clinical use (Phillips et al., 2018).Regulatory agencies in many places, including the United States, Europe, the United Kingdom, Australia, Japan, Taiwan, Singapore, and Thailand have explicit recommendations for HLA-B*15:02 testing in patients of Asian ancestry prior to carbamazepine initiation.

PGx implementation
Currently, only HLA genotyping for carbamazepine and oxcarbazepine to reduce SCARs has a clearly defined clinical role for PGx testing in the management of schizophrenia.There is insufficient evidence to guide the use of CYP2D6 genotyping in clinical practice.One potential strategy is to consider is genotyping only for those patients with atypical responses to antipsychotics.This includes patients with extreme sensitivity to low dose antipsychotics or those without any response at high dose.CYP2D6 genotyping may aid clinical decision making by confirming clinician suspicion of either particularly slow or rapid antipsychotic metabolism and proceed with dose adjustments more rapidly and reduce the number of medication switches, although this has not been definitively demonstrated.There is no clinical indication for PGx testing in the management of clozapine currently.

Polygenic risk
One of the longstanding goals in psychiatric research is to better predict who will develop severe mental disorders like schizophrenia.Cohorts of young patients with early, subthreshold, psychotic symptoms who are deemed "clinically high-risk (CHR)" for psychosis have been tracked to identify risk factors for converting to fully-manifested schizophrenia (Carrión et al., 2016).This effort has led to the development of risk calculators that predict (imperfectly) an individual's risk of conversion (Carrión et al., 2016) based on clinical factors.There has been a hope that genetics can improve these risk predictions.Polygenic score (PGS) (i.e., the cumulative effect of many SNPs associated with a disease or trait) for schizophrenia were incorporated into the risk calculator, conversion prediction modestly improved, with greater benefit for individuals of European ancestry than non-European ancestry (Perkins et al., 2020), a well-documented problem due to an overemphasis of genetics research in populations of European ancestry (Martin et al., 2019).This case highlights the potential for genetics research to exacerbate disparities in psychiatry if not conducted thoughtfully and equally (Martin et al., 2019).
Schizophrenia PGS also have the potential to inform genetic counseling, as demonstrated for breast cancer (McGuinness et al., 2021) and diabetes (Huvinen et al., 2022).However, unlike monogenic disorders where disease variants are highly penetrant, disease risk due to PGS must be understood in the context of probabilities, which may be more difficult for some patients to fully grasp and appropriately weigh in medical decision making (Peck et al., 2022).Furthermore, schizophrenia PGS have the clearest application for pediatric CHR populations who must defer to their guardians as proxy decision makers, although the genetic test is for a mostly adult-onset condition.Whether guardians should make such decisions remains controversial (Botkin, 2016), as the American Academy of Pediatrics (Caga-anan et al., 2012) and others have recommended that testing should be deferred until adulthood or until an adolescent interested in testing has developed mature decisionmaking capacities if there is no immediate medical benefit.There has also been speculation that elevated schizophrenia PGS might create a vulnerability to the effects of environmental factors associated with schizophrenia, such as cannabis exposure (Elkrief et al., 2023).However, recent studies have not supported this theory, and have instead indicated that cannabis use remains a risk factor for schizophrenia, over and above genetic vulnerability for schizophrenia (Elkrief et al., 2023).This suggests that schizophrenia PGS would not be a helpful biomarker of vulnerability to the psychosis-inducing properties of cannabis.
Ethical use of schizophrenia PGS must also be carefully considered in the new field of polygenic embryo screening, where embryos are selected for based on their genetic profile, such as low schizophrenia PGS (Lencz et al., 2022).There are several potential unintended consequences of this approach, such as selecting for adverse traits, altering population demographics, exacerbating inequalities in society, and devaluing certain traits (Turley et al., 2021).Clinicians should proceed with great caution to avoid ushering in a new era of genetics-based stigma and discrimination, especially around psychiatric disorders.In the specific case of sperm or egg donation, it is common practice for donors to complete a family history and sperm and eggs to undergo basic genetic screening to assess for genetic conditions including cystic fibrosis, spinal muscular atrophy, haemoglobinopathies, Tay-Sachs disease and Fragile X syndrome (Amor et al., 2018).However, both donors and recipients are wary of expanding genetic screening beyond current levels (Amor et al., 2018) and there is scant evidence to suggest that genetic screening improves the likelihood of live birth for recipients of donor oocytes (Doyle et al., 2020).
To summarize, there is currently no clinical indication for schizophrenia PGS, but there is promise that they may be used, in combination with other factors, to improve individual risk prediction of schizophrenia onset (Murray et al., 2021).Careful consideration should be given to the ethical implications of using schizophrenia PGS, given the potential to exacerbate healthcare inequalities, the challenges of properly communicating their probabilistic nature to patients, the potential for unintended harm and genetic discrimination, and their future potential to predict the onset of an adult disorder in a pediatric population.Given the uncertainty around clinical benefit, tests for schizophrenia PRS are not readily available through insurance, so if clinicians felt there was a strong clinical indication for such testing, cash payment would likely be necessary through a direct-to-consumer company.

Genetics-guided treatment
There are no current clinical practice guidelines recommending the use of genetics to guide psychiatric management for any disorder.There are, however, several rare neurogenetics conditions associated with schizophrenia where adjustments to pharmacologic treatment can be considered based on the genetic diagnosis.For individuals with 22q11.2deletion syndrome, psychotropic management can be adjusted based on known drug sensitives, but not based on a genetics-informed understanding of pathophysiology.For example, it has been observed that individuals with 22q11.2deletion syndrome are particularly susceptible to the seizure-lowering effects of antipsychotics and great care should be taken when starting antipsychotics that significantly lower the threshold, such as clozapine (Butcher et al., 2015;Fung et al., 2015).In fact, co-initiation with antiepileptic drugs should be considered in these cases.Likewise, risperidone has been observed to be particularly effective in treating psychosis in patients with Prader-Willi syndrome due to uniparental disomy (Bonnot et al., 2016).In contrast, there are certain neurogenetic conditions associated with schizophrenia where the genetic mechanism of disease may directly inform treatment.Two individuals with schizophrenia associated with glycine decarboxylase triplication disorder in n-of-1 placebo-controlled trials were responsive to the psychotropic augmentation with N-methyl-D-aspartate receptor (NMDA-R) co-agonists, glycine and D-cycloserine (Bodkin et al., 2019).
Both psychotic and mood symptoms improved significantly in response to the co-agonists, which were selected based on presumed NMDA-R hypofunction.Similarly, there are reports of individuals with 15q13.3deletion syndrome associated with schizophrenia, intellectual disability, epilepsy, aggression and autism spectrum disorders (ASD) where CHRNA7, the gene encoding the α7-nicotinic acetylcholine receptor subunit, is deleted (Casas-Alba et al., 2021;Cubells et al., 2011).The acetylcholinesterase inhibitor, galantamine, was observed to reduce aggression in one adult with psychosis and intellectual disability (Cubells et al., 2011) and improve fluid reasoning, working memory, and processing speed in one youth with ASD (Casas-Alba et al., 2021).
The reality remains that for most patients with schizophrenia a genetic diagnosis will not impact psychotropic management.But there has been progress in leveraging our current knowledgebase on the genetics of schizophrenia to advance therapeutic development.For example, genome-wide association data was combined with gene expression data to identify subgroups of individuals with schizophrenia that could respond to repurposed drugs (Reay et al., 2022).The repurposed drugs normalized aberrant gene expression associated with the specific genomic subtype of schizophrenia (Reay et al., 2022).New preclinical in vitro methods hold promise as neuropsychiatric disease models for drug screening.For example, a patient-derived three-dimensional cerebral cortical organoid model of 22q11.2deletion syndrome was developed that recapitulates many aspects of human pathophysiology (Khan et al., 2020).However, current organoid models of neuropsychiatric disease contain limited cell types, tend to recapitulate very early stages of brain development, and can be hard to reliably reproduce (Levy and Pas ¸ca, 2023).More complex assembloid models may offer additional promise as in vitro disease models, perhaps even allowing for high-throughput drug screening (Levy and Pas ¸ca, 2023).Gene modifying therapies are being actively pursued for neuropsychiatric disorders, although most efforts are currently in neurodevelopmental genetic disorders, such as Angelman's syndrome (Markati et al., 2021) and Rett syndrome (Shao et al., 2021).Another potential therapeutic strategy is isoform-specific targeting of dysregulated gene expression in schizophrenia using antisense oligonucleotides or related technologies (Gandal et al., 2018).

Conclusion
This review highlights the complex role of genetics in schizophrenia management and the challenges in developing genetically-informed, effective treatments.Despite progress in identifying genetic risk factors, their translation into improved clinical outcomes remains limited.The growing prevalence of patients with known genetic conditions necessitates that mental health clinicians enhance their genetic expertise and collaborate with professionals like psychiatric genetic counselors (Besterman et al., 2019).Further research on the potential of PGS is crucial, with emphasis on establishing a strong ethical framework to ensure equitable benefits and informed understanding of genetic implications.Further advances in PGx may enable personalized dosing and medication selection, contributing to better prevention, treatment, and quality of life for those with schizophrenia.Genetics-informed disease modeling and treatments hold great promise in revolutionizing the therapeutic landscape, paving the way for more targeted and personalized approaches to alleviate the burdens of schizophrenia, but many challenges remain.As our understanding of genetic factors associated with schizophrenia deepens, it is vital to remain attentive to the social implications of clinical translation, striving for the benefit of all patients.

Declaration of competing interest
None.

Table 1
Summary of Genetics-guided Approaches to Clinical Management of Schizophrenia.