Association of a schizophrenia risk variant with memory function

Introduction Schizophrenia is a highly inherited severe psychiatric disorder characterized by disturbed intellectual abilities. In comparison to healthy controls, deficits in memory performance have been observed in schizophrenia patients, with verbal learning in particular, but also verbal and visual working memory being impaired. As memory deficits have also been found in non-affected first-degree relatives of schizophrenia patients, memory performance seems to be a suitable endophenotype for further investigations. Therefore, we conducted an association analysis of the 128 schizophrenia risk variants found in a genome-wide association study by Ripke et al. (2014) with memory performance.

Methods A cohort of 368 schizophrenia patients and a cohort of 633 healthy subjects were investigated in this study. The Structured Clinical Interview for DSM-IV (SCID 1 and SCID 2) was used to confirm the diagnosis of schizophrenia in patients and to rule out psychiatric disorders in healthy subjects. Healthy individuals with a positive family history of psychiatric disorders and subjects aged 60 years and older with evidence of cognitive impairment in the Mini Mental Status Examination (MMSE) were excluded. Memory function was assessed using the Wechsler Memory Scale revised (WMS-R; Wechsler, 1987). Genotype data was obtained using chip technology and imputation. For association analysis 128 variants associated with schizophrenia were selected. For each cohort and the total sample, an additive linear regression model was calculated with the 5 WMS-R indices using age, sex and education as covariates.

Results For rs13240464, which is an intronic variant within the IMMP2L gene, significant associations after correction for multiple testing were obtained for “Delayed Recall” in healthy subjects and for “Visual Memory” in the combined sample and in healthy controls. Nominally significant associations with 4 of the 5 WMS-R indices were detected for 2 variants in the total sample (rs12148337, rs7405404) and for 2 other variants in the patient cohort (rs7523273, rs6434928).

Conclusion The results of this study indicate an influence of schizophrenia-associated variations on memory performance in both schizophrenia patients and healthy controls. The most significant associations were found for a variant within the IMMP2L gene that encodes subunit 2 of the inner membrane peptidase (IMP2), which is part of a mitochondrial peptidase. An impact of IMMP2L on memory function is conceivable, as its knockout leads to mitochondrial dysfunction and genetic variants are implicated in autism spectrum disorders, Gilles de la Tourette syndrome and neurodevelopmental disorders. Further research is needed to validate the associations found and to determine their functional relevance.

 

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