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The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P

Brain-derived neurotrophic factor (BDNF) is a pleiotropic protein involved in neuronal proliferation, differentiation, synaptic plasticity and survival. Independent studies investigating association between the functional BDNF Val66Met polymorphism and cognitive abilities have reported some conflicting findings, which may reflect inadequate sample size, variation in testing methods, population stratification or the confounding effects of other genes. To test the latter hypothesis, we screened and genotyped polymorphisms in the RE1-silencing transcription factor (REST) gene whose function includes the downregulation of BDNF expression. We identified an exon 4 hexadecapeptide variable number tandem repeat (VNTR) with either four or five copies that was located within a proline-rich domain and investigated a further five single nucleotide polymorphisms (SNPs). Using a cohort of 746 community-dwelling older volunteers, we analysed REST genotype data both independently and in combination with the BDNF Val66Met polymorphism. A haplotype within the REST gene containing the four copy VNTR and a non-synonymous SNP showed a weak but significant association with a higher score of general intelligence ( P = 0.05). Analysis of this haplotype and the BDNF Val66Met polymorphism in combination showed a significant interaction (global P-value = 0.0003) with an additive increase in cognitive performance for those possessing the BDNF Val66 allele and the REST haplotype containing the four copy repeat ( P = 0.004). The REST haplotypes in combination with the BDNF Met66 polymorphism did not reduce cognitive performance more than the independent influence of the Met66 allele. Our results suggest that investigation of a common REST polymorphism may be necessary to help reduce contrasting reports based around BDNF Val66Met and cognition. [ABSTRACT FROM AUTHOR]

A functional brain-derived neurotrophic factor (BDNF) gene polymorphism (Val66Met) that alters activity-dependent secretion has previously been reported to influence cognitive functioning. A large proportion of these reports suggest that the Met allele, which results in reduced secretion of BDNF, impairs long-term memory as a direct consequence of its influence on hippocampal function but has little influence on working memory. In contrast, other studies have found that the Met allele can also play a protective role in certain neurological conditions and is associated with improved non-verbal reasoning skills in the elderly suggesting effects that appear disease, domain and age specific. We have investigated six haplotype-tagging single nucleotide polymorphisms (SNPs) using a cohort of 722 elderly individuals who have completed cognitive tests that measured the domains of fluid intelligence, processing speed and memory. We found that the presence of the Met allele reduced cognitive performance on all cognitive tests. This reached nominal significance for tests of processing speed ( P = 0.001), delayed recall ( P = 0.037) and general intelligence (g) ( P = 0.008). No association was observed between cognitive tests and any other SNPs once the Val66Met was adjusted for. Our results support initial findings that the Met allele is associated with reduced cognitive functioning. We found no evidence that the Met allele plays a protective role in older non-demented individuals. Magnetic resonance imaging data collected from a subgroup of 61 volunteers showed that the left and right hippocampus were 5.0% and 3.9% smaller, respectively, in those possessing the Met allele, although only a non-significant trend was observed. [ABSTRACT FROM AUTHOR]

Cathepsin D (CTSD), human leukocyte antigen DRB1 (HLA-DRB1) and apolipoprotein E (APOE) have all been associated with cognitive ability in both demented and non-demented individuals. CTSD is a pleiotrophic protein whose functions include the processing of proteins prior to presentation by HLA. Several studies have also reported that a functional exon 2 polymorphism in the CTSD gene interacts with APOEɛ4 resulting in an increased risk of developing Alzheimer's disease (AD). We have previously reported that the CTSD exon 2 polymorphism regulates fluid intelligence. In this study, we extend this finding to other cognitive domains and investigate interactions with APOE and HLA-DRB1. Using a cohort of 766 non-demented volunteers, we found that the CTSD exon 2 T allele was associated with a decrease in several cognitive domains that comprise processing speed [random letters (RLs) test, P = 0.012; alphabet-coding task (ACT), P = 0.001], spatial recall (SR) ( P = 0.016) and an additional test of fluid intelligence ( P = 0.010). We also observed that the HLA-DR1 was associated with enhanced cumulative recall ability ( P = 0.006), and conversely HLA-DR5 was associated with diminished delayed verbal recall and SR abilities ( P = 0.014 and P = 0.003, respectively). When analysed independently, APOEɛ4 did not influence any cognitive domains. In contrast, CTSD T/APOEɛ4-positive volunteers scored lower on tests of fluid intelligence ( P = 0.015), processing speed (ACT, P = 0.001; RL, P = 0.013) and immediate recall ( P = 0.029). Scores were lower for all these tests than when CTSD and APOE were analysed independently. This supports previous findings in AD that have also reported an epistatic interaction. In addition, we found that CTSD T/HLA-DR2-positive volunteers had reduced processing speed (ACT, P = 0.040; RL, P = 0.014) and had significantly lower cumulative and SR abilities ( P = 0.003 and P = 0.001, respectively). Biological interaction between these two proteins has previously been shown where HLA-DR2 binds more readily to the myelin basic protein (MBP) compared with other DR antigens, preventing MBP cleavage by CTSD. [ABSTRACT FROM AUTHOR]