Psychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studying cognitive measures as endophenotypes for psychiatric disorders, with the hope that their genetic basis will be clearer. To investigate this, we performed a genome-wide association study involving 11 cognitive phenotypes from the Cambridge Neuropsychological Test Automated Battery. We showed these measures to be heritable by comparing the correlation in 100 monozygotic and 100 dizygotic twin pairs. The full battery was tested in approximately 750 subjects, and for spatial and verbal recognition memory, we investigated a further 500 individuals to search for smaller genetic effects. We were unable to find any genome-wide significant associations with either SNPs or common copy number variants. Nor could we formally replicate any polymorphism that has been previously associated with cognition, although we found a weak signal of lower than expected P-values for variants in a set of 10 candidate genes. We additionally investigated SNPs in genomic loci that have been shown to harbor rare variants that associate with neuropsychiatric disorders, to see if they showed any suggestion of association when considered as a separate set. Only NRXN1 showed evidence of significant association with cognition. These results suggest that common genetic variation does not strongly influence cognition in healthy subjects and that cognitive measures do not represent a more tractable genetic trait than clinical endpoints such as schizophrenia. We discuss a possible role for rare variation in cognitive genomics.

It was recently suggested that the Kibra polymorphism rs17070145 has a strong effect on multiple episodic memory tasks in humans. We attempted to replicate this using two cohorts of European genetic origin (n = 319 and n = 365). We found no association with either the original SNP or a set of tagging SNPs in the Kibra gene with multiple verbal memory tasks, including one that was an exact replication (Auditory Verbal Learning Task, AVLT). These results suggest that Kibra does not have a strong and general effect on human memory.

Introduction A highly polymorphic T-homopolymer was recently discovered to be associated with late onset Alzheimer’s disease (LOAD) risk and age of onset. Objective To explore the effects of the polymorphic polyT tract (rs10524523, referred as ‘523’) on cognitive performance in cognitively healthy elderly. Methods 181 participants were recruited from local independent-living retirement communities. Informed consent was obtained and participants completed demographic questionnaires, a conventional paper and pencil neuropsychological battery, and the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB). Saliva samples were collected for determination of the TOMM40 ‘523’ (S, L, VL) and the APOE (ε2, 3, 4) genotypes. From the initial sample of 181 individuals, 127 participants were eligible for the association analysis. Participants were divided into three groups based on ‘523’ genotypes (S/S, S/L-S/VL, and L/L-L/VL-VL/VL) Generalized linear models were used to evaluate the association between the ‘523’ genotypes and neuropsychological test performance. Analyses were adjusted for age, sex, education, depression, and APOE ε4 status. A planned sub analysis was undertaken to evaluate the association between ‘523’ genotypes and test performance in a sample restricted to APOE ε3 homozygotes. Results The S homozygotes performed better, although not significantly, than the S/L-S/VL and the VL/L-L/VL-VL/VL genotype groups on measures associated with memory (CANTAB Paired-Associate Learning, and VRM Free Recall) and executive function (CANTAB measures of Intra-Extradimensional set shifting). Follow-up analysis of APOEε 3 homozygotes only, showed that the S/S group performed significantly better than the S/VL group on measures of episodic memory (CANTAB Paired-Associate Learning and VRM Free Recall), attention (CANTAB RVP Latency) and executive function (Digit-Symbol substitution). The S/S group performed marginally better than the VL/VL group on Intra-Extradimensional set shifting. None of the associations remained significant after applying a Bonferroni correction for multiple testing. Conclusions Results suggest important APOE-independent associations between the TOMM40 ‘523’ polymorphism and specific cognitive domains of memory and executive control that are preferentially affected in early stage AD.