Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach

Abstract

Background: Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia.

Methods: We defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36 989 cases and 113 075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance.

Findings: We combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029).

Interpretation: Our results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism.

Funding: US National Institutes of Health.

Figure 1

Description of sample and phenotypes for rare variant analyses

Figure 2. Construction of the analysis pipeline

ATC=Anatomical Therapeutic Chemical. SEA=Similarity Ensemble Approach. GWAS=genome-wide association study.

Figure 3. Proportion of individuals carrying singleton disruptive mutations within the 347 gene targets of antipsychotics stratified by case/control and treatment response

OR=odds ratio.

Figure 4. Enrichment results of singleton disruptive mutations for both schizophrenia and treatment resistance in antipsychotic targets and sets of previously identified genes enriched for rare variants in schizophrenia

SCZ de novo (disruptive) relates to genes carrying disruptive mutations in schizophrenia probands. SCZ de novo (nonsyn) relates to genes carrying non-synonymous mutations in schizophrenia probands. SCZ de novo (CNV) relates to genes carrying de novo copy number variants in schizophrenia probands. Calcium channels relates to genes related to voltage-gated calcium ion channel functioning. ARC relates to signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density. NMDAR relates to N-methyl-D-aspartate receptor (NMDAR) postsynaptic signalling complex. PSD-95 relates to postsynaptic density set encoded by DLG3, FMRP targets (Darnell) relates to targets of the fragile X mental retardation protein from Darnell et al. Sets of pharmacogenetic genes described in the methods. p values presented are before multiple hypothesis correction.