Whole genome analysis of genetic susceptibility factors in psychotic disorders

Abstract

Schizophrenia is a complex neurodevelopmental illness affecting about one percent of the world’s population, throughout countries, cultural groups, and sexes. It is characterized by abnormal mental function and disturbed behavior, mostly appearing after puberty as a diverse mixture of positive and negative symptoms, and cognitive impairment. The severity of the symptoms and the chronic pattern of schizophrenia often cause a high degree of disability. Although extensive effort has been made in the quest of finding the origin of the disease, the new progress is hampered by the complexity and diversity of the symptoms combined with the fact that most symptoms of schizophrenia are usually noticed quite late in the disease process. Most of the genetic components of schizophrenia remain unknown (“the missing heritability”), as with the underlying biological mechanisms. The present study includes three papers and is based upon naturalistic data from the crosssectional part of the Thematically Organized Psychosis Research (TOP) Study, carried out in joint collaboration between the University of Oslo and University Hospitals of Oslo (now Oslo University Hospital). Through genome-wide association analysis in a homogenous Norwegian case-control sample, several potential susceptibility genes for schizophrenia were identified and replicated in a larger North-European case-control sample. The combined analysis identified phospholipase A-2 activating protein (PLAA), acyl-CoA synthetase medium-chain family member 1 (ACSM1) and ankyrin 3, node of Ranvier (ANK3) as putative candidate genes for schizophrenia. It has been hypothesized that genetic risk might overlap for different psychotic disorders. Neurotrophic tyrosine receptor 3 (NTRK3) has an important role in brain development and plasticity, and has been associated with hippocampal function in schizophrenia patients. By comparing allele frequencies of markers in NTRK3 between bipolar patients and controls, we found markers in intron 12 significantly associated with bipolar disorder. The markers were in close proximity to reported linkage regions reported in schizophrenia, early-onset major depressive disorder and eating disorder, further supporting the hypothesis of genes influencing risk beyond traditional diagnostic boundaries. Further, antipsychotics, antidepressants and mood-stabilizers are still cornerstones in the treatment of psychotic disorders, but the treatment is associated with serious clinical problems, like metabolic and cardiovascular side effects. Genetic variation could explain the difference in observed adverse effects in patients. Twelve indicator variables for metabolic side effects and cardiovascular risk factors were analyzed to identify genetic variants that mediate the effect of psychopharmacological agents on these variables. For body mass index and high density lipoprotein cholesterol, three loci were identified, two upstream of matrix metalloproteinase 16 and one on 12q21 respectively, that were found to significantly mediate drug-induced side effects.