Genetics of schizophrenia: What do we know?

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 sample.²⁹ A recent GWAS³⁰ found that a combination of 6 genetic markers—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 hyperinsulinemia. 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=1.6×10^-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, particularly 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 (IM), extensive (EM), and ultrarapid metabolizers (UM). Compared with EMs with normal CYP2D6 enzyme activity, PMs and IMs 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-analysis³⁸ of 8 studies showed that PMs had a 43% higher risk of developing TD compared with EMs. An FDA-approved pharmacogenetic test, AmpliChip^® 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.