MULTIPLE DRUG USE IN SCHIZOPHRENIA - THE ROLE OF EARLY ENVIRONMENTAL RISK ACCUMULATION AND GENETIC PREDISPOSITION

Abstract Background Drug (ab)use and substance use disorders are frequently observed in patients with psychiatric illness, but the underlying causes remain widely unknown. A number of environmental risk factors have been proposed to affect the use of one or multiple drugs in the general population and adolescents. Whereas most previous studies focused on the influence of single risk factors on the use of one or a few selected drugs, the effect of accumulated environmental risk in early life on multiple drug use remains to be studied. Similarly, evidence on genetic susceptibility to the (ab)use of a single drug, e.g. nicotine, alcohol, cocaine, is abundant, while the role of genetic predisposition for multiple drug use - in particular during early life - is yet to be explored. Thus, the current work aims to study the role of environmental as well as genetic risk factors for multiple drug abuse (‘polytoxicomania’) in a large sample of schizophrenic/schizoaffective patients. Methods Information from ~2000 schizophrenia/schizoaffective patients on (preadult) multiple drug use (> 2 drugs) and environmental risk factors was extracted from the Göttingen Research Association for Schizophrenia (GRAS) data collection – currently the largest data base of deeply phenotyped patients with schizophrenia/schizoaffective disorder or other neuropsychiatric diseases. In addition, genetic data from these patients and 2111 healthy blood donors were used in a novel genetic approach that employs multiple genome-wide association studies (GWAS) to identify genetic associations with preadult multiple drug use. Genotyping was performed on a semi-custom Axiom MyDesign Genotyping Array (Affymetrix, Santa Clara, CA, USA), based on a CEU (Caucasian residents of European ancestry from UT, USA) marker backbone. Results The accumulation of environmental risk factors, i.e. sexual abuse, physical abuse, migration, urbanicity, together with alcohol and cannabis consumption as secondary risk factors, in early life (< 18 years) were strongly associated with lifetime multiple drug use (p = 3.48 x 10^-44, extreme group comparison odds ratio (OR) = 31.8). When the sample was split into preadult and adult multiple drug users, there was a remarkable association of the number of preadult environmental risk factors with preadult multiple drug use (p = 1.12 x 10^-25, OR = 243.6). Furthermore, preadult environmental risk accumulation strongly predicted onset of multiple drug use in adulthood (> 18 years; p = 6.27 x 10^-18, OR = 19.4). The application of the novel genetic approach yielded 35 single-nucleotide variants (SNPs) that potentially confer susceptibility to preadult multiple drug use. Out of these, 14 were located in gene-coding regions. Interestingly, 9 of these genes are implicated in neuronal development/function or metabolite transport/transformation. Additional gene-based analyses identified another 4 genes relevant for metabolite transport/transformation as well as 4 genes that play a role in hypoxia signaling. Discussion The present results show that an accumulation of environmental risk factors during early life (< 18 years) is a strong predictor of multiple drug use during adolescence and later life. These findings suggest that exposure to accumulated environmental risk during early life is not only associated with violent aggression – as previously reported by our lab – but is also an important predictor of multiple drug use. Moreover, we present first evidence of a genetic susceptibility to preadult multiple drug use, which will benefit from future replication in suitable samples of patients with mental illness or the general population.