Association between polymorphisms 3' of ApoE and susceptibility to schizophrenia and its subtypes

This study investigated the effects of rs439401 and three other polymorphisms (rs5112, +7203 C/T, rs7247227) located within or close to regulatory elements in the 3' region downstream of the ApoE gene on susceptibility to Schizophrenia and on cognitive performance in affected and normal individuals. Association analysis was conducted in a case-control sample of 427 schizophrenia cases and 208 controls derived from the Western Australian Family Study of Schizophrenia (WAFSS). The clinically affected individuals were divided into two distinct subtypes: cognitive deficit (CD; n=185)/ cognitive spared (CS; n=154). Additional analysis was also performed in a sample of 563 men (aged≥65; representative of the general elderly population) obtained from the Health in Men Study (HIMS). rs439401 was the only SNR found to be associated with increased risk of schizophrenia (P=0.0176) and cognitive deficit (P=0.0049). Within Schizophrenia subjects, significant association was found between the minor allele of rs439401 and decline in general cognitive ability (P=0.0131) and verbal memory (P=0.0489). In the HIMS cohort, the minor allele of rs439401 was associated with verbal memory decline (P=0.0202), with its effects independent of the ApoE ε alleles. rs439401 is located close to a peroxisome proliferator-activated receptor-y (PPAR-y) response element (PPRE) in the ApoE/ApoCI intergenic region. Expression analysis, using lymphoblastoid cell lines (LCLs) as a model, revealed no difference in APOE levels between Schizophrenia and controls, and between rs439401 genotypes. Overall, the results point to the contribution of rs439401 and possibly APOE to increased susceptibility of schizophrenia and decline in cognitive function. rs439401 may affect PPRE function, which consequently alters APOE expression. APOE distribution may influence schizophrenia risk through its effects on neurite outgrowth. neuronal plasticity, CNS glucose and cholesterol homeostasis, or tau phosphorylation