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Genetics of schizophrenia: what do we know: researchers are discovering clues to predict susceptibility, improve treatment.

Genetic factors play a major role in the etiology and development of schizophrenia. Genetic linkage studies and twin studies have estimated the heritability of schizophrenia to be 70% to 90%. (1) Research on the genetic underpinnings of schizophrenia has accelerated since the Human Genome Project was completed in 2001, which opened the door to expanding our understanding of molecular mechanisms of human diseases. Experts have hailed the dawn of personalized medicine, (2) hoping that we will be able to use knowledge of the human genome to tailor individual treatment.

In this article we review some significant recent findings in genetics of schizophrenia. Gene names are italicized and proteins coded by genes are not. The names, functions, and locations of all genes included in this article appear in the Table (page 26). For a glossary of genetic terms, -see this article at CurrentPsychiatry.com.

Focusing on single nucleotide polymorphisms

Genetic research of diseases previously relied on linkage studies, which focus on linking a chromosome region to transmission of a particular trait across multiple familial generations. This approach has identified several genomic regions that may be associated with schizophrenia, but most of these regions contain multiple genes and are not specific to schizophrenia.

Today, many genetic studies examine variations of a single nucleotide in the DNA sequence, ie, a change of 1 letter in a particular location on the DNA chain. Single nucleotide polymorphisms (SNPs)--relatively common DNA variations found in >5% of the population--have been a major focus of psychiatric genetics in the past decade. Technology now allows researchers to simultaneously genotype millions of SNPs across the genome, producing tremendous power to investigate the entire genome in relation to a phenotype (a disease or a trait) in genome-wide association studies (GWAS). (3) GWAS do not require an a priori hypothesis regarding which regions or genes may be important, and have yielded many novel genetic variants implicated in schizophrenia.

Susceptibility genes

Genetic researchers initially hoped to find that one or a few genes are responsible for schizophrenia. However, recent research revealed that many genes may be involved in susceptibility to schizophrenia, and that a particular gene may contribute to the risk of not only schizophrenia but also other psychiatric disorders such as bipolar disorder (BD).


Table

Select genes and their functions

Gene      Name Location                 Location  Function(s)

CACNA1C   Calcium channel,               12p13.3  Calcium channels
          voltage-dependent, L type,              mediate the influx of
          alpha 1C sub-unit                       calcium ions into the
                                                  cell upon membrane
                                                  polarization

COMT      Catechol-O-methyttransferase       22q  Key enzyme in
                                           11.21  degradation of
                                                  dopamine and
                                                  norepinephrine

CSMD1     CUB and Sushi multiple          8p23.2  One of the proteins
          domains 1                               that modulate the
                                                  classical complement
                                                  pathway, part of the
                                                  immune system

CYP2D6    Cytochrome P450 2D6            22q13.1  Key enzyme in drug
                                                  metabolism

C10orf26  Chromosome 10 open reading    10q24.32  Unknown
          frame 26

DISC1     Disrupted In schizophrenia 1      1q42  Neurite outgrowth,
                                                  cortical development
                                                  synaptic function

DRD1      Dopamine receptor D1            5q35.1  D1 receptors regulate
                                                  neuronal growth and
                                                  development, mediate
                                                  behavioral responses,
                                                  and modulate D2
                                                  receptor-mediated
                                                  events

DRD2      Dopamine receptor D2             11q23  D2 receptors regulate
                                                  motor activities and
                                                  information
                                                  processing in the
                                                  brain

DTNBP1    Dystrobrevin binding protein      6p22  Neurodevelopment and
          1                                       synaptic
                                                  transmission

HLA-DQB1  Major histocompatibility        6p21.3  Plays a central role
          complex, class II. DQ betal             in the immune system
                                                  by presenting
                                                  peptides derived from
                                                  extracellular
                                                  proteins

HTR2C     Serotonin receptor 2C             Xq24  Modulate mood, food
                                                  intake behavior, and
                                                  feeling of satiety

MC4R      Melanocortin 4 receptor          18q22  Modulate food intake
                                                  behavior and feeling
                                                  of satiety

MHC       Major histocompatibility       6p21-22  Immune function;
region    complex                                 neurodevelopment,
                                                  synaptic plasticity

MIR 137   MicroRNA 137                   1 p23.3  Post-transcriptional
                                                  regulation of
                                                  messenger RNAs;
                                                  neuron maturation,
                                                  adult neurogenesis

MTHFR     Methylenetetrahydrofolate       1p36,3  Key enzyme in folate
          reductase                               metabolism

TCF4      Transcription factor 4         18q21.2  Neuronal
                                                  transcriptional
                                                  factor, neurogenesis

TPH1      Tryptophan hydroxylase 1       11p15.3  Key enzyme in
                                                  biosynthesis of
                                                  serotonin

ZNF804A   Zinc finger protein 804A        2q32.1  Transcription factor,
                                                  neuronal connectivity
                                                  in the dorsolateral
                                                  prefrontal cortex


Discovery of the ma gene is an example of how our understanding of the complex genetic architecture in psychiatric disorders has evolved. In 2000, a linkage study in a Scottish family cohort found a translocation on chromosome 1, t(1:11), highly correlated with schizophrenia. (4) Later studies found that this translocation directly disrupts a gene, which researchers named "disrupted in schizophrenia 1." The protein encoded by DISCI appears to provide a scaffold to other proteins involved in multiple cellular functions, particularly regulation of brain development and maturation. It is involved in neuronal proliferation, differentiation, and migration via various signaling pathways by interacting with many other proteins. (5) Disruption of DISCI results in dysfunction in multiple neurodevelopmental processes, significantly increasing susceptibility not only for schizophrenia but also for BD and depression.

Many common variants of DISCI. slightly alter expression levels of the gene, which may exert subtle but pervasive effects on neural circuitry development. DISCI knockout mouse models showed close interactions between DISCI and N-methyl-o-aspartate receptors and dopamine D2 receptors, linking to the glutamate hypothesis of schizophrenia and the common site of action of antipsychotics. Despite advances in understanding the biology of DISCI, large case-control studies have not found a consistent association between DISCI and schizophrenia. (6), (7) It is possible that DISCI. pathology represents one subtype of schizophrenia that is not prevalent among the general population; therefore, large-scale epidemiologic studies could not find evidence to support DISC1's role in schizophrenia.

DTNBP1 is another schizophrenia susceptibility gene discovered in linkage studies. Originally found in a large Irish cohort, several SNPs of DTNBP1 were significantly associated with schizophrenia. (8) A meta-analysis of candidate genes identified DTNBP1 as one of 4 genes with the strongest evidence for association with schizophrenia (the other 3 are DRDI, MTHFR, and TPH1). (9) DTNBP1 is widely expressed in the brain and is present in presynaptic, postsynaptic, and microtubule locations implicated in a number of brain functions, including synaptic transmission and neurite outgrowth in a developing organism. Furthermore, DTNBP1 is associated with cognitive functions in schizophrenia patients (10) as well as in control subjects. (11) Cognitive impairment is considered an endophenotype for schizophrenia. Similar to DISCI and other candidate genes, DTNBP1 has not emerged as a significant hit in later, large-scale GWAS studies.

Since the first schizophrenia GWAS in 2007, (12) >15 GWAS have been published, with increasingly larger samples sizes. GWAS are based on the "common disease/ common variant hypothesis" that common disorders such as diabetes, macular degeneration, and schizophrenia are caused by multiple common variants in the genome. Because GWAS can analyze hundreds of thousands of SNPs simultaneously, a stringent criterion (usually P < 5x[10.sup.-8]) is used to gauge statistical significance to correct for multiple testing. Because most effect sizes associated with genetic markers in psychiatry are fairly small (odds ratios [ORs] are approximately 1.1 to 1.2), large samples are required to detect significant effects. Several international consortia have accumulated large samples. The Psychiatric GWAS Consortium has >17,000 patients with schizophrenia, >11,000 with BD, >16,000 with major depression, and >50,000 healthy controls. This wave of GWAS has implicated several novel genomic regions in schizophrenia pathophysiology, including ZNF804A, the major histocompatibility complex (MHC) region, and MIR137.

ZNF804A was the first gene that reached genome-wide significance in a large GWAS, (13) and this finding has been replicated. The function of this novel gene largely is unknown. ZNF804A is widely expressed in the brain, especially in the developing hippocampus and the cortex as well as in the adult cerebellum. Recent studies found that ZNF804A is a putative transcription factor, upregulating expression of catechol-0-methyltransferase while downregulating dopamine D2 receptors in animal studies. (14) The minor allele of SNP rs1344706 was associated with impaired brain functional connectivity in a human study. (15) More work is needed to understand how this gene increases schizophrenia susceptibility continued

The MHC region on chromosome 6p22.1,1 also was significant in schizophrenia GWAS, (16), (17) and this may be the most replicated schizophrenia GWAS finding. This region is a recombination hotspot and harbors many genetic variants. Many immune-related genes previously were associated with autoimmune and infectious disorders, which may suggest that the immunologic system plays a role in schizophrenia pathogenesis. These genes also may involve neurodevelopment, synaptic plasticity, and other neuronal processes. (18) However, the complex gene composition in the region makes it difficult to pinpoint the exact signal to schizophrenia pathophysiology.

The most recent finding from the largest GWAS is MIR137, (19) coding for microRNA 137, which was associated with schizophrenia at P = 1.6x[10.sup.-11] in 17,836 patients and 33,859 controls. MicroRNAs are small, non-coding RNA fragments that are involved in post-transcriptional regulation of messenger RNAs. MIR137 plays important roles in neuron maturation and adult neurogenesis by acting at the level of dendritic morphogenesis and spine development. (20) More interestingly, the other 4 loci achieving genome-wide significance in the same GWAS (TCF4, CACNATC, CSMD1, and C/Oorf26) contain predicted target sites of M1R737. This suggests MIR137-mediated dysregulation may be an etiologic mechanism in schizophrenia.

Limitations of these findings. The effect sizes of these genetic variants are small, explaining only 1% to 2% of genetic risks of schizophrenia. However, this is not unique to schizophrenia or psychiatry. "Missing heritability" is puzzling in other branches of medicine. (21) Future research will focus on gene-environment interactions as well as gene-gene interactions in relation to schizophrenia's neurodevelopmental processes.

In addition, many top hits in GWAS are SNPs that are not functional or located in intergenic regions with unknown functions. They may be proxies of causal variants that truly play causal roles in pathogenesis of diseases but were not genotyped in those studies. Recently, researchers have grown increasingly interested in copy number variations (CNVs) in the etiology of complex diseases. Compared with SNPs, CNVs usually are much larger changes in the DNA sequence, including deletions and duplications of a large chunk of DNA segments. Disease-causing CNVs are rare but have large effect sizes. Recent studies have examined the role of CNVs in schizophrenia. (22), (23)

Although genes such as DISCI and CACNAIC are linked to schizophrenia, they are neither necessary nor sufficient for developing the disorder, and also are linked equally, if not more strongly, to other neuropsychiatric disorders, including BD and autism. Therefore, they are not "schizophrenia genes." Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia.

Nevertheless, these schizophrenia GWAS findings provide insight into this complex disorder. Much work is needed to move from these association signals to understanding the function and regulation of these genes to turn basic biologic knowledge into targets for new drugs or other interventions.

Antipsychotic pharmacogenetics

Genetic research of schizophrenia also contributes to our knowledge of how to best use existing drugs. Medications for treating schizophrenia often need to be changed because patients experience lack of efficacy or intolerable side effects, which may lead them to discontinue treatment. Clinical predictors of which medication would work for an individual patient are lacking. Pharmacogenetics may be able to fulfill the promise of personalized medicine in psychiatry by using genetic information to guide drug selection to maximize therapeutic efficacy and minimize drug-induced side effects.

Researchers first attempted to find genetic predictors of antipsychotic efficacy in the early 1990s. One replicated finding is that DRD2, the gene coding for dopamine receptor D2, is associated with antipsychotic efficacy This may not be surprising because D2 receptor antagonism is a common and necessary drug action mechanism for all antipsychotics. One SNP, -141C Ins/Del (rs1799732), represents a deletion (vs insertion) of cytosine at position -141, located in the 5' promoter region of DRD2. Pre-clinical studies showed that this SNP might modulate DR D2 gene expression and influence D2 receptor density in the brain. Del allele carriers had poor response to clozapine among a treatment-refractory sample (24) and took longer to respond to olanzapine and risperidone among first-episode schizophrenia patients. (25) A 2010 meta-analysis of approximately 700 patients (26) showed that the -141C Ins/Del polymorphism is significantly associated with antipsychotic response. Patients who carry 1 or 2 Del alleles tend to have a less favorable antipsychotic response than patients with the Ins/Ins genotype. Patients with the Ins/Ins genotype are 54% more likely to respond to antipsychotics than those with copy of the Del allele.

Researchers have studied other genes in relation to antipsychotic efficacy, but have yielded few consistent findings. (27) Some have looked at combining multiple SNPs across several genes to predict antipsychotic efficacy, but these findings have not been replicated. For example, a combination of variants in the HTR2A, HTR2C, and 5-HTTLPR genes and genes coding for H2 receptors was found to correctly predict clozapine response in 76% of patients. (28) However, this finding was not replicated in an independent samp1e. (29) A recent GWAS (30) found that a combination of 6 genetic mark-ers--NPAS3, XKR4, TNR, GRIA4, GFRA2, and NUDT9P1--predicted treatment response to iloperidone. Although promising, this finding needs to be validated in independent samples.

Predicting adverse drug events

In other branches of medicine, researchers have used pharmacogenetics to successfully identify predictors of drug-induced adverse events. A GWAS found that a specific human leukocyte antigen (HLA) allele markedly increases the risk of liver toxicity from flucloxacillin (OR=80.6). (31) This HLA marker also is related to hypersensitivity reaction to abacavir, a common medication for treating AIDS, and lamotrigine-induced Stevens-Johnson syndrome.

Clozapine-induced granulocytosis also may be related to genetic variation in the HLA region. Despite superior efficacy, clozapine remains underutilized in part because it carries the risk of potentially fatal agranulocytosis. Identifying a genetic marker for agranulocytosis would lift the burden of weekly blood monitoring. A recent pharmacogenetic study detected a replicated association of an allele at the HLA-DQB1 locus with risk of agranulocytosis in 2 small groups of clozapine-treated schizophrenia patients. (32) Effect sizes were extremely high (OR=16.86); nearly 90% of allele carriers developed agranulocytosis. Unfortunately, the overall sensitivity of the marker was 21%, indicating that most individuals who develop agranulocytosis are not carriers of the allele and presumably have other genetic risk factors. A more comprehensive risk profile would be necessary to obviate the need for weekly blood monitoring.

Weight gain and metabolic syndrome are common side effects of antipsychotics, and no clear clinical predictors have been identified. Researchers have examined potential genetic markers in association with antipsychotic-induced weight gain. One consistent finding has been that a single SNP in the promoter region of the HTR2C gene (serotonin receptor 2C), C-759T (rs3813929), affects antipsychotic-induced weight gain. The 5-HT2C receptor is involved in regulating food intake in rodents and is related to late-onset diabetes and obesity in humans. HTR2C knockout mice display chronic hyperphagia that leads to obesity and hyper-insulinemia. Since the original finding in 2002, (33) at least 17 studies have reported on the association between the C-759T SNP in HTR2C and antipsychotic-induced weight gain. A meta-analysis found that the T allele was significantly protective against antipsychotic-induced weight gain. (34) The C allele was associated with >2-fold increase of risk for clinically significant weight gain (gaining >7% of baseline body weight).

In a GWAS of antipsychotic-induced weight gain in pediatric patients who were prescribed antipsychotics for the first time, researchers discovered a single top signal at a marginally genome-wide significant level (P = 1.6x 10-7). (35) This was replicated in 3 other independent samples. The peak signal is located on chromosome 18q21, overlapping a peak identified as a predictor of obesity. This locus is approximately 150 kb downstream from MC4R, the melanocortin 4 receptor gene, which has long been suspected as a candidate for weight-related phenotypes, including antipsychotic-induced weight gain. (36) Mutations in this gene are linked with extreme obesity in humans, and MC4R knockout mice develop obesity. MC4R-expressing neurons in the ventromedial hypothalamus are regulated by circulating levels of leptin via pathways in the arcuate nucleus. In turn, MC4R regulates 5-HT2C receptors, which are implicated in weight gain. In the discovery sample, risk allele homozygotes gained twice as much weight as other patients after 12 weeks of treatment, and the genetic effect was not drug-specific.

The consistency of HTR2C-MC4R findings poses a possibility that a drug may be developed at these targets to treat or prevent antipsychotic-induced weight gain.

Drug metabolism. Pharmacogenetic studies of antipsychotic drug response also have focused on genes that code for enzymes in drug metabolism, particidarly cytochrome (CYP) 450 enzymes, which are responsible for the metabolism of many drugs. CYP2D6 is the main metabolic pathway for several antipsychotics, including risperidone, aripiprazole, haloperidol, and perphenazine. The CYP2D6 gene contains >100 variants, many of which yield nonfunctional or reduced-function enzymes. There are 4 phenotypes of CYP2D6 produced by combinations of various alleles with different degrees of enzymatic activities: poor (PM), intermediate (INI), extensive (EM), and ultrarapid metabolizers (UM). Compared with EMs with normal CYP2D6 enzyme activity, PMs and 'Ms have minimal or reduced activity, respectively. UMs have duplicate or multiple copies of the gene that result in increased enzyme activity. Approximately 7% to 10% of whites and 1% to 2% of Asians are PMs, who tend to accumulate higher serum drug levels and, theoretically, require lower doses to achieve therapeutic effects. UMs, in contrast, consist of 1% of the population and may require higher doses because of faster drug elimination. (37) Therefore, CYP2D6 metabolic status could play an important role in determining patients' antipsychotic response. So far, no empirical data support the association between CYP2D6 and antipsychotic efficacy, although studies have found significant relationships between PMs and higher rates of drug-induced side effects such as tardive dyskinesia (TD), extrapyramidal symptoms, and weight gain. A meta-analysis (38) of 8 studies showed that PMs had a 43% higher risk of developing TD compared with EMs. An FDA-approved pharmacogenetic test, AmpliChip[R] CYP450 Test, is available to assess CYP2D6 and CYP2C19 genotypes, (39) but its use is limited, perhaps because of clinician concerns about how to interpret test results, paucity of prospective data suggesting that using the test can improve clinical outcomes, and lack of reimbursement.

Implications for clinical practice

Although schizophrenia genetic research has made tremendous progress in the past decade, most findings are at basic science level and clinical applications are limited. It is premature to attempt to use genetic markers to help diagnose schizophrenia or other psychiatric disorders. (40) Researchers hope that new gene discovery will translate to better understanding of the pathophysiologi-cal mechanisms underlying schizophrenia, which in turn lead to finding novel molecular targets for new drug development. Furthermore, pharmacogenetics helps clinicians use existing drugs more efficiently by maximizing efficacy and minimizing side effects. Several institutions have experimented with genotyping CYP450 in routine clinical practice, (41) but prospective pharmacogenetic clinical trials are needed to validate the utility and cost-effectiveness of genetic testing-guided treatment a1gorithms. (42)

Clinical Point

Genome-wide association studies have implicated ZNF804A, the MHC region, and MIR137 in schizophrenia pathophysiology

Discuss this article at www.facebook.com/CurrentPsychiatry

Clinical Point

ZNF804A is a putative transcription factor, upregulating expression of COMT while downregulating dopamine D2 receptors

See this article at CurrentPsychiatry.com for a glossary 01 genetic terms

Clinical Point

The -141C Ins/ Del polymorphism of the DRD2 gene is significantly associated with antipsychotic response

Clinical Point

Clozapine-induced agranulocytosis may be related to genetic variation

in the human leukocyte antigen region

Clinical Point

A single nucleotide polymorphism in the promoter region of the HTR2C gene affects antipsychotic-induced weight gain

Related Resource

* National Institute of Mental Health Center for Collaborative Genomic Studies on Mental Disorders. Schizophrenia. www.nimhgenetics.org/available_dataischizophrenia.

Drug Brand Names

Abacavir * Ziagen Lamotrigine * Lamictal

Aripiprazole * Abilify Olanzapine * Zyprexa

Clozapine * Clozaril Perphenazine * Trilafon

Haloperidol * Haldol Risperidone * Risperdal

Ilopendone * Fanapt

Disclosures

Dr. Zhang reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Malhotra is a consultant to Genomind, Inc.

This work was partly supported by a Young Investigator Award from the Brain and Behavior Research Foundation (Dr. Zhang), and by the National Institute of Mental Health (P50M1-1080173 to Dr. Malhotra and 1K23MH097108 to Dr. Zhang).

Clinical Point

CYP2D6 metabolic status could play an important role in determining patients' antipsychotic response

Clinical Point

Prospective pharmacogenetic trials are needed to validate the utility of genetic testing-guided treatment algorithms

Bottom Line

Variatiosn in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development o fschizophrenia. Genome-wide association studies are allowing researchers to gain insight into which patients may have increased susceptibility to the disorder, identify potential molecular targets for new drugs, and expand their knowledge of how to best use medications.

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Jian-Ping Zhang, MD, PhD

Attending Psychiatrist

The Zucker Hillside Hospital

Glen Oaks, NY

Assistant Investigator, Center for Psychiatric Neuroscience

Feinstein Institute of Medical Research

North Shore-Long Island Jewish (LIJ) Health System

Manhasset, NY

Anil K. Malhotra, MD

Director, Division of Psychiatry Research

The Zucker Hillside Hospital

Glen Oaks, NY

Investigator, Center for Psychiatric Neuroscience

Feinstein Institute for Medical Research

Manhasset, NY

Professor of Psychiatry and Molecular Medicine

Hofstra North Shore-LIJ School of Medicine

Hempstead, NY
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Date:Mar 1, 2013
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