Risk factor profiles for depression following childbirth or a chronic disease diagnosis:case-control study

BACKGROUND: Progress towards understanding the aetiology of major depression is compromised by its clinical heterogeneity. The variety of contexts underlying the development of a major depressive episode may contribute to such heterogeneity. AIMS: To compare risk factor profiles for three subgroups of major depression according to episode context. METHOD: Using self-report questionnaires and administrative records from the UK Biobank, we characterised three contextual subgroups of major depression: postpartum depression (3581 cases), depression following diagnosis of a chronic disease (409 cases) and a more typical (named heterogeneous) major depression phenotype excluding the two other contexts (34 699 cases). Controls with the same exposure were also defined. We tested each subgroup for association with the polygenic risk scores (PRS) for major depression and with other risk factors previously associated with major depression (bipolar disorder PRS, neuroticism, reported trauma in childhood and adulthood, socioeconomic status, family history of depression, education). RESULTS: Major depression PRS was associated with all subgroups, but postpartum depression cases had higher PRS than heterogeneous major depression cases (OR = 1.06, 95% CI 1.02–1.10). Relative to heterogeneous depression, postpartum depression was more weakly associated with adulthood trauma and neuroticism. Depression following diagnosis of a chronic disease had weaker association with neuroticism and reported trauma in adulthood and childhood relative to heterogeneous depression. CONCLUSIONS: The observed differences in risk factor profiles according to the context of a major depressive episode help provide insight into the heterogeneity of depression. Future studies dissecting such heterogeneity could help reveal more refined aetiological insights

Genetic contributions to health literacy

Higher health literacy is associated with higher cognitive function and better health. Despite its wide use in medical research, no study has investigated the genetic contributions to health literacy. Using 5783 English Longitudinal Study of Ageing (ELSA) participants (mean age = 65.49, SD = 9.55) who had genotyping data and had completed a health literacy test at wave 2 (2004-2005), we carried out a genome-wide association study (GWAS) of health literacy. We estimated the proportion of variance in health literacy explained by all common single nucleotide polymorphisms (SNPs). Polygenic profile scores were calculated using summary statistics from GWAS of 21 cognitive and health measures. Logistic regression was used to test whether polygenic scores for cognitive and health-related traits were associated with having adequate, compared to limited, health literacy. No SNPs achieved genome-wide significance for association with health literacy. The proportion of variance in health literacy accounted for by common SNPs was 8.5% (SE = 7.2%). Greater odds of having adequate health literacy were associated with a 1 standard deviation higher polygenic score for general cognitive ability [OR = 1.34, 95% CI (1.26, 1.42)], verbal-numerical reasoning [OR = 1.30, 95% CI (1.23, 1.39)], and years of schooling [OR = 1.29, 95% CI (1.21, 1.36)]. Reduced odds of having adequate health literacy were associated with higher polygenic profiles for poorer self-rated health [OR = 0.92, 95% CI (0.87, 0.98)] and schizophrenia [OR = 0.91, 95% CI (0.85, 0.96)). The well-documented associations between health literacy, cognitive function and health may partly be due to shared genetic etiology. Larger studies are required to obtain accurate estimates of SNP-based heritability and to discover specific health literacy-associated genetic variants.</p

Sex-specific moderation by lifestyle and psychosocial factors on the genetic contributions to adiposity in 112,151 individuals from UK Biobank

Abstract Evidence suggests that lifestyle factors, e.g. physical activity, moderate the manifestation of genetic susceptibility to obesity. The present study uses UK Biobank data to investigate interaction between polygenic scores (PGS) for two obesity indicators, and lifestyle and psychosocial factors in the prediction of the two indicators, with attention to sex-specific effects. Analyses were of 112 151 participants (58 914 females; 40 to 73 years) whose genetic data passed quality control. Moderation effects were analysed in linear regression models predicting body mass index (BMI) and waist-to-hip ratio (WHR), including interaction terms for PGS and each exposure. Greater physical activity, more education, higher income, moderate vs low alcohol consumption, and low material deprivation were each associated with a relatively lower risk for manifestation of genetic susceptibility to obesity (p < 0.001); the moderating effects of physical activity and alcohol consumption were greater in women than men (three-way interaction: p = 0.009 and p = 0.008, respectively). More income and less neuroticism were related to reduced manifestation of genetic susceptibility to high WHR (p = 0.007; p = 0.003); the effect of income was greater in women (three-way interaction: p = 0.001). Lifestyle and psychosocial factors appear to offset genetic risk for adiposity in mid to late adulthood, with some sex-specific associations

Genetic contributions to trail making test performance in UK Biobank

The Trail Making Test (TMT) is a widely used test of executive function and has been thought to be strongly associated with general cognitive function. We examined the genetic architecture of the TMT and its shared genetic aetiology with other tests of cognitive function in 23 821 participants from UK Biobank. The single-nucleotide polymorphism-based heritability estimates for trail-making measures were 7.9% (part A), 22.4% (part B) and 17.6% (part B−part A). Significant genetic correlations were identified between trail-making measures and verbal-numerical reasoning (rg&gt;0.6), general cognitive function (rg&gt;0.6), processing speed (rg&gt;0.7) and memory (rg&gt;0.3). Polygenic profile analysis indicated considerable shared genetic aetiology between trail making, general cognitive function, processing speed and memory (standardized β between 0.03 and 0.08). These results suggest that trail making is both phenotypically and genetically strongly associated with general cognitive function and processing speed.</p

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

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

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 architecture of human neuroanatomical diversity

International audienceWe analyzed the genomic architecture of neuroanatomical diversity using magnetic resonance imaging and single nucleotide polymorphism (SNP) data from >26 000 individuals from the UK Biobank project and 5 other projects that had previously participated in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our results confirm the polygenic architecture of neuroanatomical diversity, with SNPs capturing from 40% to 54% of regional brain volume variance. Chromosomal length correlated with the amount of phenotypic variance captured, r ~ 0.64 on average, suggesting that at a global scale causal variants are homogeneously distributed across the genome. At a local scale, SNPs within genes (~51%) captured ~1.5 times more genetic variance than the rest, and SNPs with low minor allele frequency (MAF) captured less variance than the rest: the 40% of SNPs with MAF <5% captured <one fourth of the genetic variance. We also observed extensive pleiotropy across regions, with an average genetic correlation of rG ~ 0.45. Genetic correlations were similar to phenotypic and environmental correlations; however, genetic correlations were often larger than phenotypic correlations for the left/right volumes of the same region. The heritability of differences in left/right volumes was generally not statistically significant, suggesting an important influence of environmental causes in the variability of brain asymmetry. Our code is available at https://github.com/neuroanatomy/genomic-architecture

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