Biology subjects

Ian J Deary

Publications and source records attributed to Ian J Deary.

11 recordsLinked to original sources

bioRxiv2016

Association of polygenic risk for major psychiatric illness with subcortical volumes and white matter integrity in UK Biobank

Major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BP) are common, disabling and heritable psychiatric diseases with a complex overlapping polygenic architecture. Individuals with these disorders, as well as their unaffected relatives, show widespread structural differences in corticostriatal and limbic networks. Structural variation in many of these brain regions is also heritable and polygenic but whether their genetic architecture overlaps with major psychiatric disorders is unknown. We sought to address this issue by examining the impact of polygenic risk of MDD, SCZ, and BP on subcortical brain volumes and white matter (WM) microstructure in a large single sample of neuroimaging data; the UK Biobank Imaging study. The first release of UK Biobank imaging data compromised participants with overlapping genetic data and subcortical volumes (N = 978) and WM measures (N = 816). Our, findings however, indicated no statistically significant associations between either subcortical volumes or WM microstructure, and polygenic risk for MDD, SCZ or BP. In the current study, we found little or no evidence for genetic overlap between major psychiatric disorders and structural brain measures. These findings suggest that subcortical brain volumes and WM microstructure may not be closely linked to the genetic mechanisms of major psychiatric disorders.

Neuroscience↗

bioRxiv2016

A genome-wide haplotype association analysis of major depressive disorder identifies two genome-wide significant haplotypes

Genome-wide association studies using genotype data have had limited success in the identification of variants associated with major depressive disorder (MDD). Haplotype data provide an alternative method for detecting associations between variants in weak linkage disequilibrium with genotyped variants and a given trait of interest. A genome-wide haplotype association study for MDD was undertaken utilising a family-based population cohort, Generation Scotland: Scottish Family Health Study (n = 18 773), as a discovery cohort with UK Biobank used as a population-based cohort replication cohort (n = 25 035). Fine mapping of haplotype boundaries was used to account for overlapping haplotypes potentially tagging the same causal variant. Within the discovery cohort, two haplotypes exceeded genome-wide significance (P < 5 x 10-8) for an association with MDD. One of these haplotypes was nominally significant in the replication cohort (P < 0.05) and was located in 6q21, a region which has been previously associated with bipolar disorder, a psychiatric disorder that is phenotypically and genetically correlated with MDD. Several haplotypes with P < 10-7 in the discovery cohort were located within gene coding regions associated with diseases that are comorbid with MDD. Using such haplotypes to highlight regions for sequencing may lead to the identification of the underlying causal variants.

Genetics↗

bioRxiv2016

Do Regional Brain Volumes and Major Depressive Disorder Share Genetic Architecture: a study in Generation Scotland (n=19,762), UK Biobank (n=24,048) and the English Longitudinal Study of Ageing (n=5,766)

Major depressive disorder (MDD) is a heritable and highly debilitating condition. It is commonly associated with subcortical volumetric abnormalities, the most replicated of these being reduced hippocampal volume. Using the most recent published data from ENIGMA consortiums genome-wide association study (GWAS) of regional brain volume, we sought to test whether there is shared genetic architecture between 8 subcortical brain volumes and MDD. Using LD score regression utilising summary statistics from ENIGMA and the Psychiatric Genomics Consortium, we demonstrated that hippocampal volume was positively genetically correlated with MDD (rG=0.46, P=0.02), although this did not survive multiple comparison testing. None of other six brain regions studied were genetically correlated and amygdala volume heritability was too low for analysis. We also generated polygenic risk scores (PRS) to assess potential pleiotropy between regional brain volumes and MDD in three cohorts (Generation Scotland; Scottish Family Health Study (n=19,762), UK Biobank (n=24,048) and the English Longitudinal Study of Ageing (n=5,766). We used logistic regression to examine volumetric PRS and MDD and performed a meta-analysis across the three cohorts. No regional volumetric PRS demonstrated significant association with MDD or recurrent MDD. In this study we provide some evidence that hippocampal volume and MDD may share genetic architecture, albeit this did not survive multiple testing correction and was in the opposite direction to most reported phenotypic correlations. We therefore found no evidence to support a shared genetic architecture for MDD and regional subcortical volumes.

Genetics↗

bioRxiv2016

Age differences in brain white matter microstructure in UK Biobank (N = 3,513)

Quantifying the microstructural properties of the human brains connections is necessary for understanding normal ageing and disease states. We examined brain white matter MRI data in 3,513 generally healthy people aged 45-75 years from the UK Biobank sample. Using conventional water diffusion measures and newer, as-yet rarely-studied indices from neurite orientation dispersion and density imaging (NODDI), we document large age differences in white matter microstructure. Mean diffusivity was the most age-sensitive diffusion measure, with negative age associations strongest in the thalamic radiation and association fibres. Inter-individual differences in white matter microstructure across brain tracts become increasingly correlated in older age. This connectivity de-differentiation may reflect an age-related aggregation of systemic detrimental effects on the brain. We report several other novel results, including comparative age associations with volumetric indices and associations with hemisphere and sex. Results from this unusually large, single-scanner sample provide one of the most definitive characterisations to date of age differences in major white matter tracts in the human brain.\n\nAbbreviations

Neuroscience↗

bioRxiv2016

Genetic contributions to self-reported tiredness

Self-reported tiredness and low energy, often called fatigue, is associated with poorer physical and mental health. Twin studies have indicated that this has a heritability between 6% and 50%. In the UK Biobank sample (N = 108 976) we carried out a genome-wide association study of responses to the question, \"Over the last two weeks, how often have you felt tired or had little energy?\" Univariate GCTA-GREML found that the proportion of variance explained by all common SNPs for this tiredness question was 8.4% (SE = 0.6%). GWAS identified one genome-wide significant hit (Affymetrix id 1:64178756_C_T; p = 1.36 x 10-11). LD score regression and polygenic profile analysis were used to test for pleiotropy between tiredness and up to 28 physical and mental health traits from GWAS consortia. Significant genetic correlations were identified between tiredness and BMI, HDL cholesterol, forced expiratory volume, grip strength, HbA1c, longevity, obesity, self-rated health, smoking status, triglycerides, type 2 diabetes, waist-hip ratio, ADHD, bipolar disorder, major depressive disorder, neuroticism, schizophrenia, and verbal-numerical reasoning (absolute rg effect sizes between 0.11 and 0.78). Significant associations were identified between tiredness phenotypic scores and polygenic profile scores for BMI, HDL cholesterol, LDL cholesterol, coronary artery disease, HbA1c, height, obesity, smoking status, triglycerides, type 2 diabetes, and waist-hip ratio, childhood cognitive ability, neuroticism, bipolar disorder, major depressive disorder, and schizophrenia (standardised {beta}s between -0.016 and 0.03). These results suggest that tiredness is a partly-heritable, heterogeneous and complex phenomenon that is phenotypically and genetically associated with affective, cognitive, personality, and physiological processes.\n\n\"Hech, sirs! But Im wabbit, Im back frae the toon;\n\nI haena dune pechin--jist let me sit doon.\n\nFrom Glesca\n\nBy William Dixon Cocker (1882-1970)

Genetics↗

bioRxiv2016

Molecular genetic contributions to social deprivation and household income in UK Biobank (n = 112,151)

Individuals with lower socio-economic status (SES) are at increased risk of physical and mental illnesses and tend to die at an earlier age [1-3]. Explanations for the association between SES and health typically focus on factors that are environmental in origin [4]. However, common single nucleotide polymorphisms (SNPs) have been found collectively to explain around 18% (SE = 5%) of the phenotypic variance of an area-based social deprivation measure of SES [5]. Molecular genetic studies have also shown that physical and psychiatric diseases are at least partly heritable [6]. It is possible, therefore, that phenotypic associations between SES and health arise partly due to a shared genetic etiology. We conducted a genome-wide association study (GWAS) on social deprivation and on household income using the 112,151 participants of UK Biobank. We find that common SNPs explain 21% (SE = 0.5%) of the variation in social deprivation and 11% (SE = 0.7%) in household income. Two independent SNPs attained genome-wide significance for household income, rs187848990 on chromosome 2, and rs8100891 on chromosome 19. Genes in the regions of these SNPs have been associated with intellectual disabilities, schizophrenia, and synaptic plasticity. Extensive genetic correlations were found between both measures of socioeconomic status and illnesses, anthropometric variables, psychiatric disorders, and cognitive ability. These findings show that some SNPs associated with SES are involved in the brain and central nervous system. The genetic associations with SES are probably mediated via other partly-heritable variables, including cognitive ability, education, personality, and health.

Genetics↗

bioRxiv2016

Intelligence and neuroticism in relation to depression and psychological distress: evidence of interaction using data from Generation Scotland: Scottish Family Health Study and UK Biobank

BackgroundNeuroticism is a risk factor for selected mental and physical illnesses and is inversely associated with intelligence. Intelligence appears to interact with neuroticism and mitigate its detrimental effects on physical health and mortality. However, the inter-relationships of neuroticism and intelligence for major depressive disorder (MDD) and psychological distress has not been well examined.\n\nMethodsAssociations and interactions between neuroticism and general intelligence (g) on MDD and psychological distress were examined in two population-based cohorts: Generation Scotland: Scottish Family Health Study (GS:SFHS, N=19,200) and UK Biobank (N=90,529). The Eysenck Personality Scale Short Form-Revised measured neuroticism and g was extracted from multiple cognitive ability tests in each cohort. Family structure was adjusted for in GS:SFHS.\n\nResultsNeuroticism was associated with MDD and psychological distress in both samples. A significant interaction between neuroticism and g in predicting MDD status was found in UK Biobank (OR = 0.96, p < .01), suggesting that higher g ameliorated the adverse effects of neuroticism on the likelihood of having MDD. This interaction was not found in GS:SFHS. In both samples, higher neuroticism and lower intelligence were associated with increased psychological distress. A significant interaction was also found in both cohorts (GS:SFHS: {beta} = -0.05, p < .01; UK Biobank: {beta} = -0.02, p < .01), such that intelligence protected against the deleterious effect of neuroticism on psychological distress.\n\nConclusionsFrom two large cohort studies, our findings suggest intelligence acts a protective factor in mitigating the effects of neuroticism on risk for depressive illness and psychological distress.

Genomics↗

bioRxiv2015

Genome-wide analysis of over 106,000 individuals identifies 9 neuroticism-associated loci

Neuroticism is a personality trait of fundamental importance for psychological wellbeing and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes and heterogeneity in the measurement of neuroticism. Here we report a genome-wide association study of neuroticism in 91,370 participants of the UK Biobank cohort and a combined meta-analysis which includes a further 7,197 participants from the Generation Scotland Scottish Family Health Study (GS:SFHS) and 8,687 participants from a Queensland Institute of Medical Research (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Forms Neuroticism scale. We found a SNP-based heritability estimate for neuroticism of approximately 15% (SE = 0.7%). Meta-analysis identified 9 novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (p = 1.28x10-15) spanning 4 Mb and containing at least 36 genes. Other associated loci included genes of interest on chromosome 1 (GRIK3, glutamate receptor ionotropic kainate 3), chromosome 4 (KLHL2, Kelch-like protein 2), chromosome 17 (CRHR1, corticotropin-releasing hormone receptor 1 and MAPT, microtubule-associated protein Tau), and on chromosome 18 (CELF4, CUGBP elav-like family member 4). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a large genetic correlation between neuroticism and MDD (0.64) and a smaller genetic correlation with schizophrenia (0.22) but not with bipolar disorder. Polygenic scores derived from the primary UK Biobank sample captured about 1% of the variance in trait liability to neuroticism. Overall, our findings confirm a polygenic basis for neuroticism and substantial shared genetic architecture between neuroticism and MDD. The identification of 9 new neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

Genetics↗

bioRxiv2015

Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N = 112 151) and 24 GWAS consortia.

The causes of the known associations between poorer cognitive function and many adverse neuropsychiatric outcomes, poorer physical health, and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular-metabolic, neuropsychiatric, physiological-anthropometric, and cognitive traits in the participants of UK Biobank, a very large population-based sample (N = 112 151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics applied to the method of linkage disequilibrium regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, autism, major depressive disorder, BMI, intracranial volume, infant head circumference, and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples.

Genetics↗

bioRxiv2015

Pleiotropy between neuroticism and physical and mental health: findings from 108 038 men and women in UK Biobank

There is considerable evidence that people with higher levels of the personality trait neuroticism have an increased risk of several types of mental disorder. Higher neuroticism has also been associated, less consistently, with increased risk of various physical health outcomes. We hypothesised that these associations may, in part, be due to shared genetic influences. We tested for pleiotropy between neuroticism and 12 mental and physical diseases or health traits using linkage disequilibrium regression and polygenic profile scoring. Genetic correlations were derived between neuroticism scores in 108 038 people in UK Biobank and health-related measures from 12 large genome-wide association studies (GWAS). Summary information for the 12 GWAS was used to create polygenic risk scores for the health-related measures in the UK Biobank participants. Associations between the health-related polygenic scores and neuroticism were examined using regression, adjusting for age, sex, genotyping batch, genotyping array, assessment centre, and population stratification. Genetic correlations were identified between neuroticism and anorexia nervosa (rg = 0.17), major depressive disorder (rg = 0.66) and schizophrenia (rg = 0.21). Polygenic risk for several health-related measures were associated with neuroticism, in a positive direction in the case of bipolar disorder ({beta} = 0.017), major depressive disorder ({beta} = 0.036), schizophrenia ({beta} = 0.036), and coronary artery disease ({beta} = 0.011), and in a negative direction in the case of BMI ({beta} = -0.0095). These findings indicate that a high level of pleiotropy exists between neuroticism and some measures of mental and physical health, particularly major depressive disorder and schizophrenia.

Genetics↗

bioRxiv2015

Molecular genetic contributions to self-rated health

BackgroundPoorer self-rated health (SRH) predicts worse health outcomes, even when adjusted for objective measures of disease at time of rating. Twin studies indicate SRH has a heritability of up to 60% and that its genetic architecture may overlap with that of personality and cognition.\n\nMethodsWe carried out a genome-wide association study (GWAS) of SRH on 111 749 members of the UK Biobank sample. Univariate genome-wide complex trait analysis (GCTA)-GREML analyses were used to estimate the proportion of variance explained by all common autosomal SNPs for SRH. Linkage Disequilibrium (LD) score regression and polygenic risk scoring, two complementary methods, were used to investigate pleiotropy between SRH in UK Biobank and up to 21 health-related and personality and cognitive traits from published GWAS consortia.\n\nResultsThe GWAS identified 13 independent signals associated with SRH, including several in regions previously associated with diseases or disease-related traits. The strongest signal was on chromosome 2 (rs2360675, p = 1.77x10-10) close to KLF7, which has previously been associated with obesity and type 2 diabetes. A second strong peak was identified on chromosome 6 in the major histocompatibility region (rs76380179, p = 6.15x10-10). The proportion of variance in SRH that was explained by all common genetic variants was 13%. Polygenic scores for the following traits and disorders were associated with SRH: cognitive ability, education, neuroticism, BMI, longevity, ADHD, major depressive disorder, schizophrenia, lung function, blood pressure, coronary artery disease, large vessel disease stroke, and type 2 diabetes.\n\nConclusionsIndividual differences in how people respond to a single item on SRH are partly explained by their genetic propensity to many common psychiatric and physical disorders and psychological traits.\n\nKey MessagesO_LIGenetic variants associated with common diseases and psychological traits are associated with self-rated health.\nC_LIO_LIThe SNP-based heritability of self-rated health is 0.13 (SE 0.006).\nC_LIO_LIThere is pleiotropy between self-rated health and psychiatric and physical diseases and psychological traits.\nC_LI

Genetics↗