Genetic stratification of depression in UK Biobank

Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whether genetic data could be used to identify subgroups within people with depression using the UK Biobank. Examination of cross-locus correlations were used to test for evidence of subgroups using genetic data from seven other complex traits and disorders that were genetically correlated with depression and had sufficient power (>0.6) for detection. We found no evidence for subgroups within depression for schizophrenia, bipolar disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, anorexia nervosa, inflammatory bowel disease or obesity. This suggests that for these traits, genetic correlations with depression were driven by pleiotropic genetic variants carried by everyone rather than by a specific subgroup

Sleep and cognitive ageing in the 8th decade of life

We examined associations between self-reported sleep measures and cognitive level and change (age 70-76 years) in a longitudinal, same-year-of-birth cohort study (baseline N = 1,091; longitudinal N = 664). We also leveraged GWAS summary data to ascertain whether polygenic scores (PGS) of chronotype and sleep duration related to self-reported sleep, and to cognitive level and change. Shorter sleep latency was associated with significantly higher levels of visuospatial ability, processing speed, and verbal memory (β ≥ |0.184|, SE ≤ 0.075, p ≤ 0.003). Longer daytime sleep duration was significantly associated slower processing speed (β = -0.085, SE = 0.027, p = 0.001), and with steeper 6-year decline in visuospatial reasoning (β = -0.009, SE = 0.003, p = 0.008), and processing speed (β = -0.009, SE = 0.002, p < 0.001). Only longitudinal associations between longer daytime sleeping and steeper cognitive declines survived correction for important health covariates and false discovery rate (FDR). PGS of chronotype and sleep duration were nominally associated with specific self-reported sleep characteristics for most SNP thresholds (standardised β range = |0.123 to 0.082|, p range = 0.003 to 0.046), but neither PGS predicted cognitive level or change following FDR. Daytime sleep duration is a potentially important correlate of cognitive decline in visuospatial reasoning and processing speed in older age, whereas cross-sectional associations are partially confounded by important health factors. A genetic propensity toward morningness and sleep duration were weakly, but consistently, related to self-reported sleep characteristics, and did not relate to cognitive level or change

GWAS on family history of Alzheimer’s disease

Alzheimer’s disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. We show that self-report of parental history of Alzheimer’s dementia for case ascertainment in a genome-wide association study of 314,278 participants from UK Biobank (27,696 maternal cases, 14,338 paternal cases) is a valid proxy for an AD genetic study. After meta-analysing with published consortium data (n = 74,046 with 25,580 cases across the discovery and replication analyses), three new AD-associated loci (P &lt; 5 × 10−8) are identified. These contain genes relevant for AD and neurodegeneration: ADAM10, BCKDK/KAT8 and ACE. Novel gene-based loci include drug targets such as VKORC1 (warfarin dose). We report evidence that the association of SNPs in the TOMM40 gene with AD is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. However, it is likely that multiple variants are affecting the trait and gene methylation/expression. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, as they contain genes that are drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications

Single nucleotide polymorphisms associated with reading ability show connection to socio-economic outcomes

Impairments in reading and in language have negative consequences on life outcomes, but it is not known to what extent genetic effects influence this association. We constructed polygenic scores for difficulties with language and learning to read from genome-wide data in ~6,600 children, adolescents and young adults, and tested their association with health, socioeconomic outcomes and brain structure measures collected in adults (maximal N = 111,749). Polygenic risk of reading difficulties was associated with reduced income, educational attainment, self-rated health and verbal-numerical reasoning (p

Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank

Background: Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants. Methods: In the present analysis, three cohort studies (ntotal = 48,002) were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS), the English Longitudinal Study of Ageing (ELSA), and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions. Results: None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator (DAOA) gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer’s disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10-7), was the butyrylcholinesterase (BCHE) gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer’s disease and its role in cognitive ability merits further investigation. Conclusions: Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect

Polygenic risk for coronary artery disease is associated with cognitive ability in older adults

Background: Coronary artery disease (CAD) is associated with cognitive decrements and risk of later dementia, but it is not known if shared genetic factors underlie this association. We tested whether polygenic risk for CAD was associated with cognitive ability in community-dwelling cohorts of middle-aged and older adults. Methods: Individuals from Generation Scotland: Scottish Family Health Study (GS:SFHS, N = 9865) and from the Lothian Birth Cohorts of 1921 (LBC1921, N  = 517) and 1936 (LBC1936, N  = 1005) provided cognitive data and genome-wide genotype data. Polygenic risk profile scores for CAD were calculated for all of the cohorts using the largest available genome-wide association studies (GWAS) data set, the CARDIoGRAM consortium (22 233 cases and 64 762 controls). Polygenic risk profile scores for CAD were then tested for their association with cognitive abilities in the presence and absence of manifest cardiovascular disease. Results: A meta-analysis of all three cohorts showed a negative association between CAD polygenic risk and fluid cognitive ability (β = −0.022, P  = 0.016), verbal intelligence (β = −0.024, P  = 0.011) and memory (β = −0.021, P  = 0.028). Conclusions: Increased polygenic risk for CAD is associated with lower cognitive ability in older adults. Common genetic variants may underlie some of the association between age-related cognitive decrements and the risk for CAD

Molecular genetic contributions to self-rated health

Poorer 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.We 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 single nucleotide polymorphisms (SNPs) for SRH. Linkage disequilibrium (LD) score regression and polygenic risk scoring, two complementary methods, were used to investigate pleiotropy between SRH in the UK Biobank and up to 21 health-related and personality and cognitive traits from published GWAS consortia.The 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 = 1.77 x 10 -10 ) close to KLF7 . A second strong peak was identified on chromosome 6 in the major histocompatibility region (rs76380179, P = 6.15 x 10 -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, body mass index (BMI), longevity, attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, lung function, blood pressure, coronary artery disease, large vessel disease stroke and type 2 diabetes.Individual 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

Genetic risk for neurodegenerative disorders, and its overlap with cognitive ability and physical function

Neurodegenerative disorders are associated with impaired cognitive function and worse physical health outcomes. This study aims to test whether polygenic risk for Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), or frontotemporal dementia (FTD) is associated with cognitive function and physical health in the UK Biobank, a cohort of healthy individuals. Group-based analyses were then performed to compare the top and bottom 10% for the three neurodegenerative polygenic risk scores; these groups were compared on the cognitive and physical health variables. Higher polygenic risk for AD, ALS, and FTD was associated with lower cognitive performance. Higher polygenic risk for FTD was also associated with increased forced expiratory volume in 1s and peak expiratory flow. A significant group difference was observed on the symbol digit substitution task between individuals with high polygenic risk for FTD and high polygenic risk for ALS. The results suggest some overlap between polygenic risk for neurodegenerative disorders, cognitive function and physical health

Molecular Genetic Contributions to Social Deprivation and Household Income in UK Biobank

SummaryIndividuals 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 SNPs have been found collectively to explain around 18% of the phenotypic variance of an area-based social deprivation measure of SES [5]. Molecular genetic studies have also shown that common physical and psychiatric diseases are partly heritable [6]. It is possible 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 112,151 participants of UK Biobank. We find that common SNPs explain 21% of the variation in social deprivation and 11% of household income. Two independent loci attained genome-wide significance for household income, with the most significant SNP in each of these loci being 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 SES and illnesses, anthropometric variables, psychiatric disorders, and cognitive ability. These findings suggest that some SNPs associated with SES are involved in the brain and central nervous system. The genetic associations with SES obviously do not reflect direct causal effects and are probably mediated via other partly heritable variables, including cognitive ability, personality, and health

Addendum:Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways

No abstract available