Assessing the genetic overlap between BMI and cognitive function.

Obesity and low cognitive function are associated with multiple adverse health outcomes across the life course. They have a small phenotypic correlation (r=-0.11; high body mass index (BMI)-low cognitive function), but whether they have a shared genetic aetiology is unknown. We investigated the phenotypic and genetic correlations between the traits using data from 6815 unrelated, genotyped members of Generation Scotland, an ethnically homogeneous cohort from five sites across Scotland. Genetic correlations were estimated using the following: same-sample bivariate genome-wide complex trait analysis (GCTA)-GREML; independent samples bivariate GCTA-GREML using Generation Scotland for cognitive data and four other samples (n=20 806) for BMI; and bivariate LDSC analysis using the largest genome-wide association study (GWAS) summary data on cognitive function (n=48 462) and BMI (n=339 224) to date. The GWAS summary data were also used to create polygenic scores for the two traits, with within- and cross-trait prediction taking place in the independent Generation Scotland cohort. A large genetic correlation of -0.51 (s.e. 0.15) was observed using the same-sample GCTA-GREML approach compared with -0.10 (s.e. 0.08) from the independent-samples GCTA-GREML approach and -0.22 (s.e. 0.03) from the bivariate LDSC analysis. A genetic profile score using cognition-specific genetic variants accounts for 0.08% (P=0.020) of the variance in BMI and a genetic profile score using BMI-specific variants accounts for 0.42% (P=1.9 × 10(-7)) of the variance in cognitive function. Seven common genetic variants are significantly associated with both traits at P<5 × 10(-5), which is significantly more than expected by chance (P=0.007). All these results suggest there are shared genetic contributions to BMI and cognitive function.

Cortical thickness and surface area correlates with cognitive dysfunction among first-episode psychosis patients.

BACKGROUND: In studies using magnetic resonance imaging (MRI), some have reported specific brain structure-function relationships among first-episode psychosis (FEP) patients, but findings are inconsistent. We aimed to localize the brain regions where cortical thickness (CTh) and surface area (cortical area; CA) relate to neurocognition, by performing an MRI on participants and measuring their neurocognitive performance using the Cambridge Neuropsychological Test Automated Battery (CANTAB), in order to investigate any significant differences between FEP patients and control subjects (CS). METHOD: Exploration of potential correlations between specific cognitive functions and brain structure was performed using CANTAB computer-based neurocognitive testing and a vertex-by-vertex whole-brain MRI analysis of 63 FEP patients and 30 CS. RESULTS: Significant correlations were found between cortical parameters in the frontal, temporal, cingular and occipital brain regions and performance in set-shifting, working memory manipulation, strategy usage and sustained attention tests. These correlations were significantly dissimilar between FEP patients and CS. CONCLUSIONS: Significant correlations between CTh and CA with neurocognitive performance were localized in brain areas known to be involved in cognition. The results also suggested a disrupted structure-function relationship in FEP patients compared with CS.

Factorial validity, measurement equivalence and cognitive performance of the Cambridge Neuropsychological Test Automated Battery (CANTAB) between patients with first-episode psychosis and healthy volunteers.

BACKGROUND: The purpose of this study was to use selected Cambridge Neuropsychological Test Automated Battery (CANTAB) tests to examine the dimensional structure of cognitive dysfunction in first episode of psychosis (FEP) patients compared with cognition in healthy subjects. METHOD: A total of 109 FEP patients and 96 healthy volunteers were administered eight CANTAB tests of cognitive function. Principal components analysis (PCA) was used to estimate dimensionality within the test results. The dimensions identified by the PCA were assumed to reflect underlying cognitive traits. The plausibility of latent factor models was estimated using confirmatory factor analysis (CFA). Multi-group CFA (MGCFA) was used to test for measurement invariance of factors between groups. The nature and severity of cognitive deficits amongst patients as opposed to controls were evaluated using a general linear model. RESULTS: Amongst subjects PCA identified two underlying cognitive traits: (i) a broad cognitive domain; (ii) attention/memory and executive function domains. Corresponding CFA models were built that fitted data well for both FEP patients and healthy volunteers. As in MGCFA latent variables appeared differently defined in patient and control groups, differences had to be ascribed using subtest scores rather than their aggregates. At subtest score level the patients performed significantly worse than healthy subjects in all comparisons (p < 0.001). CONCLUSIONS: Results of this study demonstrate that the structure of underlying cognitive abilities as measured by a selection of CANTAB tests is not the same for healthy individuals and FEP patients, with patients displaying widespread cognitive impairment.

Predicting cognitive ability in ageing cohorts using Type 2 diabetes genetic risk.

AIMS: To investigate whether there is overlap in the genetic determinants of Type 2 diabetes and cognitive ageing by testing whether a genetic risk score for Type 2 diabetes can predict variation in cognitive function in older people without dementia. METHODS: Type 2 diabetes genetic risk scores were estimated using various single nucleotide polymorphism significance inclusion criteria from an initial genome-wide association study, the largest in Type 2 diabetes to date. Scores were available for 2775-3057 individuals, depending on the cognitive trait. RESULTS: Type 2 diabetes genetic risk was associated with self-reported diabetes mellitus. Across varying single nucleotide polymorphism-inclusion levels, a significant association between Type 2 diabetes genetic risk and change in general cognitive function was found (median r = 0.04); however, this was such that higher Type 2 diabetes genetic risk related to higher cognitive scores. CONCLUSIONS: To investigate more fully the source of the often observed comorbidity between Type 2 diabetes and cognitive impairment, one direction for future research will be to use cognitive ability polygenic risk scores to predict Type 2 diabetes in line with the reverse causation hypothesis that people with lower pre-morbid cognitive ability are more likely to develop Type 2 diabetes.

Mutational analysis of a histone deacetylase in Drosophila melanogaster: missense mutations suppress gene silencing associated with position effect variegation.

For many years it has been noted that there is a correlation between acetylation of histones and an increase in transcriptional activity. One prediction, based on this correlation, is that hypomorphic or null mutations in histone deacetylase genes should lead to increased levels of histone acetylation and result in increased levels of transcription. It was therefore surprising when it was reported, in both yeast and fruit flies, that mutations that reduced or eliminated a histone deacetylase resulted in transcriptional silencing of genes subject to telomeric and heterochromatic position effect variegation (PEV). Here we report the first mutational analysis of a histone deacetylase in a multicellular eukaryote by examining six new mutations in HDAC1 of Drosophila melanogaster. We observed a suite of phenotypes accompanying the mutations consistent with the notion that HDAC1 acts as a global transcriptional regulator. However, in contrast to recent findings, here we report that specific missense mutations in the structural gene of HDAC1 suppress the silencing of genes subject to PEV. We propose that the missense mutations reported here are acting as antimorphic mutations that "poison" the deacetylase complex and propose a model that accounts for the various phenotypes associated with lesions in the deacetylase locus.

A cytogenetic analysis of chromosomal region 31 of Drosophila melanogaster.

Cytogenetic region 31 of the second chromosome of Drosophila melanogaster was screened for recessive lethal mutations. One hundred and thirty nine new recessive lethal alleles were isolated that fail to complement Df(2L)J2 (31A-32A). These new alleles, combined with preexisting mutations in the region, define 52 complementation groups, 35 of which have not previously been described. Among the new mutations were alleles of the cdc2 and mfs(2)31 genes. Six new deficiencies were also isolated and characterized identifying 16 deficiency subintervals within region 31. The new deficiencies were used to further localize three loci believed to encode non-histone chromosomal proteins. Suvar(2)1/Su(var)214, a dominant suppressor of position-effect variegation (PEV), maps to 31A-B, while the recessive suppressors of PEV mfs(2)31 and wdl were localized to regions 31E and 31F-32A, respectively. In addition, the cytological position of several mutations that interact with heterochromatin were more precisely defined.

Unique gene organization: alternative splicing in Drosophila produces two structurally unrelated proteins.

The Ub80 gene in eukaryotes produces a ubiquitin fusion protein in which ubiquitin is fused in frame to a tail protein (Redman and Rechsteiner, 1988; Finley et al., 1989; Barrio et al., 1994). The tail protein is incorporated into the ribosome, and ubiquitin is thought to act as a chaperone. The DUb80 gene of Drosophila melanogaster was cloned by Barrio et al. (1994) and contains a 5'-untranslated exon, followed by a large intron and then the first coding exon. We report that the large intron of DUb80 contains an open reading frame, which produces a 259-aa protein (IP259) that is conserved in eukaryotes from yeast to mammals. Transcription of the DUb80 and IP259 mRNAs begins at the same start sites. However, alternate splicing of the primary transcript produces two structurally unrelated proteins. This is the second reported instance of two structurally unrelated proteins being produced via alternate splicing, suggesting that this form of genomic organization may be more common than previously thought.

Butyrate suppression of position-effect variegation in Drosophila melanogaster.

The strain of Drosophila melanogaster carrying the inversion of In(1)wm4, which juxtaposes the normal w+ gene to the centromeric heterochromatin, variegages for pigmentation in the eye. This strain was treated with various concentrations of n-butyrate and n-proprionate during the embryonic and larval stages. Concentrations as low as 70 mM markedly suppress the variegated eye phenotype. This suggests that non-acetylated histones play a major role in the phenomenon of position-effect variegation.