Biology subjects

Davey Smith, G.

Publications and source records attributed to Davey Smith, G..

At least 19 recordsLinked to original sources

bioRxiv2018

Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank

Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we perform the largest genome-wide association study for osteoarthritis to date (77,052 cases and 378,169 controls), analysing 4 phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discover 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine map to a single variant. We identify putative effector genes by integrating eQTL colocalization, fine-mapping, human rare disease, animal model, and osteoarthritis tissue expression data. We find enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organisation biological pathways. Ten of the likely effector genes, including TGFB1, FGF18, CTSK and IL11 have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.

genetics↗

bioRxiv2018

MR-pheWAS with stratification and interaction: Searching for the causal effects of smoking heaviness identified an effect on facial aging

Mendelian randomization (MR) is an established approach for estimating the causal effect of an environmental exposure on a downstream outcome. The gene x environment (GxE) study design can be used within an MR framework to determine whether MR estimates may be biased if the genetic instrument affects the outcome through pathways other than via the exposure of interest (known as horizontal pleiotropy). MR phenome-wide association studies (MR-pheWAS) search for the effects of an exposure, and a recently published tool (PHESANT) means that it is now possible to do this comprehensively, across thousands of traits in UK Biobank. In this study, we introduce the GxE MR-pheWAS approach, and search for the causal effects of smoking heaviness - stratifying on smoking status (ever versus never) - as an exemplar. If a genetic variant is associated with smoking heaviness (but not smoking initiation), and this variant affects an outcome (at least partially) via tobacco intake, we would expect the effect of the variant on the outcome to differ in ever versus never smokers. If this effect is entirely mediated by tobacco intake, we would expect to see an effect in ever smokers but not never smokers. We used PHESANT to search for the causal effects of smoking heaviness, instrumented by genetic variant rs16969968, among never and ever smokers respectively, in UK Biobank. We ranked results by: 1) strength of effect of rs16969968 among ever smokers, and 2) strength of interaction between ever and never smokers. We replicated previously established causal effects of smoking heaviness, including a detrimental effect on lung function and pulse rate. Novel results included a detrimental effect of heavier smoking on facial aging. We have demonstrated how GxE MR-pheWAS can be used to identify causal effects of an exposure, while simultaneously assessing the extent that results may be biased by horizontal pleiotropy.\n\nAuthor summaryMendelian randomization uses genetic variants associated with an exposure to investigate causality. For instance, a genetic variant that relates to how heavily a person smokes has been used to test whether smoking causally affects health outcomes. Mendelian randomization is biased if the genetic variant also affects the outcome via other pathways. We exploit additional information - that the effect of heavy smoking only occurs in people who actually smoke - to overcome this problem. By testing associations in ever and never smokers separately we can assess whether the genetic variant affects an outcome via smoking or another pathway. If the effect is entirely via smoking heaviness, we would expect to see an effect in ever but not never smokers, and this would suggest that smoking causally influences the outcome. Previous Mendelian randomization studies of smoking heaviness focused on specific outcomes - here we searched for the causal effects of smoking heaviness across over 18,000 traits. We identified previously established effects (e.g. a detrimental effect on lung function) and novel results including a detrimental effect of heavier smoking on facial aging. Our approach can be used to search for the causal effects of other exposures, where the exposure only occurs in known subsets of the population.

epidemiology↗

bioRxiv2018

Evaluation of the causal effect of fibrinogen on incident coronary heart disease via Mendelian randomization

BackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.\n\nMethods and FindingsWe evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score incorporated data from 11 European-ancestry prospective cohorts to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI).\n\nIn single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.\n\nConclusionsA small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.\n\nAuthor SummaryInitial Mendelian Randomization (MR) analyses of the causal effect of fibrinogen on coronary heart disease (CHD) utilized single variants and did not take advantage of modern, multivariant approaches. This manuscript provides an important update to these initial analyses by incorporating larger sample sizes and employing multiple, modern multi-variant MR approaches to account for pleiotropy. We used incident cases to perform a MR study of the causal effect of fibrinogen on incident CHD and the nested outcome of myocardial infarction (MI) using an allele score approach. Then using data from a case-control genome-wide association study for CHD and MI we performed two sample MR analyses with multiple, pleiotropy robust approaches. Overall, the results indicated that associations between fibrinogen and CHD in observational studies are likely upwardly biased from any underlying causal effect. Single variant MR approaches show little evidence of a causal effect of fibrinogen on CHD or MI. Multi-variant MR analyses of fibrinogen on CHD indicate there may be a small positive effect, however this result needs to be interpreted carefully as the 95% confidence intervals were still consistent with a null effect. Multi-variant MR approaches did not suggest evidence of even a small causal effect of fibrinogen on MI.

genetics↗

bioRxiv2018

Cleft lip/palate and educational attainment: cause, consequence, or correlation? A Mendelian randomization study

ImportancePrevious studies have found that children born with a non-syndromic form of cleft lip and/or palate have lower-than-average educational attainment. These differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as school absence, social stigmatization and impaired speech and language development), or confounding by the prenatal environment. A clearer understanding of this mechanism will inform development of interventions to improve educational attainment in individuals born with a cleft, which could have wide-ranging knock-on effects on their quality of life.\n\nObjectiveTo assess evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment.\n\nDesignUsing summary data from genome-wide association studies (GWAS), we performed Linkage Disequilibrium (LD)-score regression and two-sample Mendelian randomization to evaluate the relationship between genetic liability to nsCL/P (GWAS n=3,987) and educational attainment (GWAS n=766,345), and intelligence (GWAS n=257,828).\n\nResultsThere was little evidence for shared genetic aetiology between nsCL/P and educational attainment (rg -0.03, 95% CI -0.14 to 0.08, P 0.58; {beta}MR 0.002, 95% CI -0.001 to 0.005, P 0.417) or intelligence (rg -0.01, 95% CI -0.12 to 0.10, P 0.85; {beta}MR 0.002, 95% CI -0.010 to 0.014, P 0.669).\n\nConclusions and relevanceCommon genetic variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This information will help tailor clinical-, school-, social- and family-level interventions to improve educational attainment in this group.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSDo children born with a non-syndromic cleft lip with or without palate (nsCL/P) have lower-than average academic achievement because of an underlying genetic predisposition to educational attainment and/or intelligence?\n\nFindingsThere was little evidence for shared common variant genetic correlation between nsCL/P, educational attainment and intelligence.\n\nMeaningCommon genetic variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This information will help tailor clinical-, school-, social- and family-level interventions to improve educational attainment in this group.

genetics↗

bioRxiv2018

Identifying novel subtypes of irritability using a developmental genetic approach

ObjectiveIrritability is a common reason for referral to services, strongly associated with impairment and negative outcomes, but is a nosological and treatment challenge. A major issue is how irritability should be conceptualized. This study used a developmental approach to test the hypothesis that there are several forms of irritability, including a neurodevelopmental/ADHD-like subtype with onset in childhood and a depression/mood subtype with onset in adolescence.\n\nMethodData were analyzed in the Avon Longitudinal Study of Parents and Children, a prospective UK population-based cohort. Irritability trajectory-classes were estimated for 7924 individuals with data at multiple time-points across childhood and adolescence (4 possible time-points from approximately ages 7 to 15 years). Psychiatric diagnoses were assessed at approximately ages 7 and 15 years. Psychiatric genetic risk was indexed by polygenic risk scores (PRS) for attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) derived using large genome-wide association study results.\n\nResultsFive irritability trajectory classes were identified: low (81.2%), decreasing (5.6%), increasing (5.5%), late-childhood limited (5.2%) and high-persistent (2.4%). The early-onset, high-persistent trajectory was associated with male preponderance, childhood ADHD (OR=108.64 (57.45-204.41), p<0.001) and ADHD PRS (OR=1.31 (1.09-1.58), p=0.005); the adolescent-onset, increasing trajectory was associated with female preponderance, adolescent MDD (OR=5.14 (2.47-10.73), p<0.001) and MDD PRS (OR=1.20, (1.05-1.38), p=0.009). Both trajectory classes were associated with MDD diagnosis and ADHD genetic risk.\n\nConclusionsThe developmental context of irritability may be important in its conceptualization: early-onset persistent irritability maybe more neurodevelopmental/ADHD-like and later-onset irritability more depression/mood-like. This has implications for treatment as well as nosology.

genetics↗

bioRxiv2018

Biomarker de-Mendelization: principles, potentials and limitations of a strategy to improve biomarker prediction by reducing the component of variance explained by genotype

In observational studies, the Mendelian randomization approach can be used to circumvent confounding, bias and reverse causation, and to assess a potential causal association between a biomarker and risk of disease. If, on the other hand, a substantial component of variance of a non-causal biomarker is explained by genotype, then genotype could potentially attenuate the observational association and the strength of the prediction. In order to reduce the component of variance explained by genotype, an approach that can be seen as the inverse of Mendelian randomization - biomarker de-Mendelization - appears plausible.Plasma YKL-40 is a good candidate for demonstrating principles of biomarker de-Mendelization because it is a non-causal biomarker with a substantial component of variance explained by genotype. This approach is an attempt to improve the observational association and the strength of a predictive biomarker; it is explicitly not aimed at detection of causal effects.\n\nWe studied 21 161 individuals form the Danish general population with measurements of YKL-40 concentration and rs4950928 genotype. Four different methods for biomarker de-Mendelization are explored for alcoholic liver cirrhosis and lung cancer.\n\nDe-Mendelization methods only improved predictive ability slighly. We observed an interaction between genotype and markers of developing disease with respect to YKL-40 concentration.\n\nEven when genotype explains 14% of the variance in a non-causal biomarker, we found no useful empirical improvement in risk prediction by biomarker de-Mendelization. This could reflect the predictive interaction between genotype and disease development being removed which counterbalanced any beneficial properties of the method in this situation.

epidemiology↗

bioRxiv2018

Alcohol consumption and mate choice in UK Biobank: comparing observational and Mendelian randomization estimates

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle the effects of alcohol consumption on mate-selection from social factors or cohabitation leading to spouses becoming more similar over time. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Therefore, in a sample of over 47,000 spouse-pairs in the UK Biobank we utilised a well-characterised alcohol related variant, rs1229984 in ADH1B, as a genetic proxy for alcohol use. We compared the phenotypic concordance between spouses for self-reported alcohol use with the association between an individuals self-reported alcohol use and their partners rs1229984 genotype using Mendelian randomization. This was followed up by an exploration of the spousal genotypic concordance for the variant and an analysis determining if relationship length may be related to spousal alcohol behaviour similarities. We found strong evidence that both an individuals self-reported alcohol consumption and rs1229984 genotype are associated with their partners self-reported alcohol use. The Mendelian randomization analysis found that each unit increase in an individuals weekly alcohol consumption increased their partners alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P=1.10x10-5). Furthermore, the rs1229984 genotype was concordant within spouse-pairs, suggesting that some spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest that this concordance is unlikely to be explained by population stratification. Overall, our findings suggest that alcohol behaviour directly influences mate selection.

genetics↗

bioRxiv2018

The contribution of psychiatric risk alleles to a general liability to psychopathology in early life

BackgroundPsychiatric disorders show phenotypic as well as genetic overlaps. Factor analyses of child and adult psychopathology have found that phenotypic overlaps largely can be explained by a latent general \"p\" factor that reflects general liability to psychopathology. We investigated whether shared genetic liability across disorders would be reflected in associations between multiple different psychiatric polygenic risk scores (PRS) and a general psychopathology factor in childhood.\n\nMethodsThe sample was a UK, prospective, population-based cohort (ALSPAC), including data on psychopathology at age 7 (N=8161) years. PRS were generated from large published genome-wide association studies.\n\nOutcomesThe general psychopathology factor was associated with both schizophrenia PRS and attention-deficit/hyperactivity disorder (ADHD) PRS, whereas there was no strong evidence of association with major depressive disorder and autism spectrum disorder PRS. Schizophrenia PRS was also associated with a specific \"emotional\" problems factor.\n\nInterpretationOur findings suggest that genetic liability to schizophrenia and ADHD may contribute to shared genetic risks across childhood psychiatric diagnoses at least partly via the general psychopathology factor. However, the pattern of observations could not be explained by a general \"p\" factor on its own.\n\nFundingThis work was supported by the Wellcome Trust (204895/Z/16/Z).Introduction

genetics↗

bioRxiv2018

Education, intelligence and Alzheimer’s disease: Evidence from a multivariable two-sample Mendelian randomization study

ObjectivesTo examine whether educational attainment and intelligence have causal effects on risk of Alzheimers disease (AD), independently of each other.\n\nDesignTwo-sample univariable and multivariable Mendelian Randomization (MR) to estimate the causal effects of education on intelligence and vice versa, and the total and independent causal effects of both education and intelligence on risk of AD.\n\nParticipants17,008 AD cases and 37,154 controls from the International Genomics of Alzheimers Project (IGAP) consortium\n\nMain outcome measureOdds ratio of AD per standardised deviation increase in years of schooling and intelligence\n\nResultsThere was strong evidence of a causal, bidirectional relationship between intelligence and educational attainment, with the magnitude of effect being similar in both directions. Similar overall effects were observed for both educational attainment and intelligence on AD risk in the univariable MR analysis; with each SD increase in years of schooling and intelligence, odds of AD were, on average, 37% (95% CI: 23% to 49%) and 35% (95% CI: 25% to 43%) lower, respectively. There was little evidence from the multivariable MR analysis that educational attainment affected AD risk once intelligence was taken into account, but intelligence affected AD risk independently of educational attainment to a similar magnitude observed in the univariate analysis.\n\nConclusionsThere is robust evidence for an independent, causal effect of intelligence in lowering AD risk, potentially supporting a role for cognitive training interventions to improve aspects of intelligence. However, given the observed causal effect of educational attainment on intelligence, there may also be support for policies aimed at increasing length of schooling to lower incidence of AD.

genetics↗

bioRxiv2018

The association between adiposity and inpatient hospital costs in the UK Biobank cohort

BackgroundHigh adiposity is associated with higher risks for a variety of adverse health outcomes, including higher rates of age-adjusted mortality and increased morbidity. This has important implications for the management of healthcare systems, since the endocrinal, cardiometabolic and other changes associated with increased adiposity may be associated with substantial healthcare costs.\n\nMethodsWe studied the association between various measures of adiposity and inpatient hospital costs through record linkage between UK Biobank and records of inpatient care in England and Wales. UK Biobank is a large prospective cohort study that aimed to recruit men and women aged between 40 and 69 from 2006 to 2010. We applied generalised linear models to cost per person year to estimate the marginal effect and averaged adjusted predicted cost of adiposity on inpatient costs.\n\nResultsValid cost and body mass index (BMI) data from 457,689 participants were available for inferential analysis. Some 54.4% of individuals included in the analysis sample had positive inpatient healthcare costs over the period of follow-up. Median hospital costs per person year of follow-up were {pound}89, compared to mean costs of {pound}481. Mean BMI overall was 27.4 kg/m2 (standard deviation 4.8). The marginal effect of a unit increase in BMI was {pound}13.61 (99% confidence interval: {pound}12.60 to {pound}14.63) per person year of follow up. The marginal effect of a standard deviation increase in BMI was {pound}69.20 (99% confidence interval: {pound}64.98 to {pound}73.42). The marginal effect of becoming obese was {pound}136.35 (99% confidence interval: {pound}124.62 to {pound}148.08). Average adjusted predicted inpatient hospital costs increased almost linearly when modelled using continuous measure of adiposity. Sensitivity analysis of different scenarios did not substantially change these conclusions, although there was some evidence of attenuation of the effects of adiposity when controlling for waist-hip ratios, and when individuals who self-reported any pre-existing conditions were excluded from analysis.\n\nConclusionsHigher adiposity is associated with higher inpatient hospital costs. Further scrutiny using causal inferential methods is warranted to establish if further public health investments are required to manage the large healthcare costs observationally associated with overweight and obesity.

epidemiology↗

bioRxiv2018

Systematic evaluation of the causal relationship between DNA methylation and C-reactive protein

Elevated C-reactive protein (CRP) levels are an indicator of chronic low-grade inflammation. Epigenetic modifications, including DNA methylation, have been linked to CRP, but systematic investigations into potential underlying causal relationships have not yet been performed.\n\nWe systematically performed two-sample Mendelian randomization and colocalization analysis between CRP and DNA methylation levels, using GWAS and EWAS summary statistics as well as individual level data available through the ARIES subset of the Avon Longitudinal Study of Parents and Children (ALSPAC; 1,616 participants).\n\nWe found no convincing examples for a causal association from CRP to DNA methylation. Testing for the reverse (a putative causal effect of DNA methylation on CRP), we found three CpG sites that had shared genetic effects with CRP levels after correcting for multiple testing (cg26470501 (offspring: beta=0.07 [0.03, 0.11]; mothers: beta=0.08 [0.04, 0.13]), cg27023597 (offspring: beta=0.18 [0.10, 0.25]; mothers: beta=0.20 [0.12, 0.28]) and cg12054453 (offspring: beta=0.09 [0.05, 0.13])) influenced CRP levels. For all three CpG sites, linked to the genes TMEM49, BCL3 and MIR21, increased methylation related to an increase in CRP levels. Two CpGs (cg27023597 and cg12054453) were influenced by SNPs in genomic regions that had not previously been implicated in CRP GWASs, implicating them as novel genetic associations.\n\nOverall, our findings suggest that CRP associations with DNA methylation are more likely to be driven by either confounding or causal influences of DNA methylation on CRP levels, rather than the reverse.

genetics↗

bioRxiv2018

Integrating Mendelian randomization and multiple-trait colocalization to uncover cell-specific inflammatory drivers of autoimmune and atopic disease

Immune mediated diseases (IMDs) arise from a lack of immune tolerance, causing chronic inflammation. Despite their growing prevalence, targeted therapies to treat IMDs are lacking. Cytokines and their receptors, which mediate inflammation, have been associated with IMD susceptibility. However, the complex signalling networks and multiple cell-types required to orchestrate inflammatory responses have made it difficult to pinpoint specific cytokines and immune cell-types which drive IMDs.\n\nIn this study, we developed an analytical framework which integrates Mendelian randomisation (MR) and multiple-trait colocalization (moloc) analyses to determine putative cell-specific drivers of IMDs. We used MR to determine the likelihood of causal associations between the levels of 10 circulating cytokines/cytokine receptors and 9 IMDs within human populations of European descent. Conservative (single SNP) and liberal (multiple SNP) MR analysis supported a causal role for IL-18 in inflammatory bowel disease (P = 1.17 x 10-4) and eczema/dermatitis (P = 2.81 x 10-3), as well as roles for IL-2r and IL-6R in several IMDs.\n\nWhere associations between cytokines/cytokine receptors and IMDs were discovered using MR, we undertook moloc analyses. This was to assess the likelihood that cytokine/cytokine receptor protein quantitative trait loci (pQTL) and IMD-associated loci share a causal genetic variant along with expression QTL (eQTL) using data from 3 immune cell-types: monocytes, neutrophils and T cells. We found a monocyte and neutrophil-driven role for IL-18 in IBD pathogenesis, amongst evidence supporting several other cell-specific inflammatory drivers of IMDs. Our study helps to elucidate causal pathways for the pathogeneses of IMDs which, together with other studies, highlights possible therapeutic targets for their treatment.

genetics↗

bioRxiv2018

Genomic analysis of diet composition finds novel loci and associations with health and lifestyle

We conducted genome-wide association study (GWAS) meta-analyses of relative caloric intake from fat, protein, carbohydrates and sugar in over 235,000 individuals. We identified 21 approximately independent lead SNPs. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease (rg {approx} 0.15 - 0.5). Relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood poverty (|rg| {approx} 0.1 - 0.3). Overall, our results show that the relative intake of each macronutrient has a distinct genetic architecture and pattern of genetic correlations suggestive of health implications beyond caloric content.

genetics↗

bioRxiv2018

Causal effects of lifetime smoking on risk for depression and schizophrenia: Evidence from a Mendelian randomisation study

BackgroundSmoking prevalence is higher amongst individuals with schizophrenia and depression compared to the general population. Mendelian randomisation (MR) can examine whether this association is causal using genetic variants identified in genome-wide association studies (GWAS).\n\nMethodsWe conducted a GWAS of lifetime smoking behaviour (capturing smoking duration, heaviness and cessation) in a sample of 462,690 individuals from the UK Biobank, and validated the findings via two-sample MR analyses of positive control outcomes (e.g., lung cancer). Having established the validity of our instrument, we used bi-directional two-sample Mendelian randomisation to explore its effects on schizophrenia and depression.\n\nOutcomesThere was strong evidence to suggest smoking is a causal risk factor for both schizophrenia (OR = 2.27, 95% CI = 1.67 - 3.08, P < 0.001) and depression (OR = 1.99, 95% CI = 1.71 - 2.32, P < 0.001). We also found some evidence that genetic risk for both schizophrenia and depression cause increased lifetime smoking ({beta} = 0.022, 95% CI = 0.005 - 0.038, P = 0.009; {beta}= 0.091, 95% CI = 0.027 - 0.155, P = 0.005).\n\nInterpretationThese findings suggest that the association between smoking, schizophrenia and depression is due, at least in part, to a causal effect of smoking, providing further evidence for the detrimental consequences of smoking for mental health.\n\nFundingThis work was supported by the Medical Research Council Integrative Epidemiology Unit, the NIHR Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSThe association between smoking and mental health (especially schizophrenia and depression) is often assumed to be the result of self-medication (for example, to alleviate symptoms). However, more recent evidence has suggested that smoking might also be a risk factor for schizophrenia and depression. This alternative direction of effect is supported by meta-analyses and previous prospective observational evidence using related individuals to control for genetic and environmental confounding. However, observational evidence cannot completely account for confounding or the possibility of reverse causation. One way to get around these problems is Mendelian randomisation (MR). Previous MR studies of smoking and mental health have not shown an effect of smoking on depression and are inconclusive for the effects of smoking on schizophrenia. However, these studies have only looked at individual aspects of smoking behaviour and some studies required stratifying participants into smokers and non-smokers, reducing power.\n\nAdded value of this studyWe have developed a novel genetic instrument for lifetime smoking exposure which can be used within a two-sample MR framework, using publicly-available GWAS summary statistics. We were therefore able to test the bi-directional association between smoking with schizophrenia and depression to see if the effects are causal. We found strong evidence to suggest that smoking is a causal risk factor for both schizophrenia and depression. There was some evidence to suggest that risk of schizophrenia and depression increases lifetime smoking (consistent with the self-medication hypothesis) but the effects were stronger for depression than schizophrenia.\n\nImplications of all the available evidenceThis study was the first to demonstrate evidence for an effect of lifetime smoking exposure on risk of schizophrenia and depression within a causal inference framework. This emphasises the detrimental public health consequences of smoking, not just for physical health, but also to mental illness.

epidemiology↗

bioRxiv2018

Schizophrenia risk and reproductive success: A Mendelian randomization study.

Schizophrenia is a debilitating and heritable mental disorder associated with lower reproductive success. However, the prevalence of schizophrenia is stable over populations and time, resulting in an evolutionary puzzle: how is schizophrenia maintained in the population given its apparent fitness costs? One possibility is that increased genetic liability for schizophrenia, in the absence of the disorder itself, may confer some reproductive advantage. We assessed the correlation and causal effect of genetic liability for schizophrenia with number of children and age at first birth using data from the Psychiatric Genomics Consortium and UK Biobank. Linkage disequilibrium score regression showed little evidence of genetic correlation between genetic liability for schizophrenia and number of children (rg=0.002, p=0.84) or age at first birth (rg=-0.007, p=0.45). Mendelian randomization indicated no robust evidence of a causal effect of genetic liability for schizophrenia on number of children (mean difference: 0.003 increase in number of children per doubling in the natural log odds ratio of schizophrenia risk, 95% CI: -0.003 to 0.009, p=0.39) or age at first birth (-0.004 years lower age at first birth, 95% CI: -0.043 to 0.034, p=0.82). These results suggest that increased genetic liability for schizophrenia does not confer a reproductive advantage.

evolutionary biology↗

bioRxiv2018

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

Cranial growth and development affects the closely related traits of head circumference (HC) and intracranial volume (ICV). Here we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV+HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood.

genetics↗

bioRxiv2018

CETP inhibition and ADCY9 genotype: evidence of a qualitative pharmacogenetic interaction in cardiovascular disease?

BackgroundCETP inhibitors raise circulating concentrations of HDL-cholesterol, and potent inhibitors also lower non-HDL-cholesterol and risk of vascular disease. Previous genome-wide pharmacogenetic analysis of a phase III randomized controlled trial (RCT) of the CETP inhibitor, dalcetrapib, found variants in ADCY9 to associate with response to treatment. More recently, findings from a pharmacogenetic analysis of the CETP inhibitor evacetrapib reported a lack of such an association.\n\nAimsTo clarify the totality of evidence on whether ADCY9 genotype modifies the treatment response to CETP inhibition on risk of major adverse cardiac events through systematic review and meta-analysis.\n\nMethodsWe searched PubMed on 22nd May 2018 to identify RCTs of CETP inhibition that reported vascular disease effect estimates stratified by ADCY9 genotype. Stratum-specific estimates were pooled using fixed effect meta-analysis. Tests of heterogeneity between, and trend across, genotypic strata were assessed using Chi2.\n\nResultsNine studies were identified from PubMed, of which two (dal-OUTCOMES and ACCELERATE) were RCTs reporting the treatment response to CETP inhibition by ADCY9 genotype, and fulfilled the inclusion criteria. In meta-analysis of dal-OUTCOMES and ACCELERATE, treatment with a CETP inhibitor was associated with a relative risk (RR) for major adverse cardiac events of RR 0.80 (95%CI, 0.65-0.99) in carriers of ADCY9 rs1967309 AA. For carriers of AG, the corresponding estimate was a RR of 1.01 (95%CI, 0.89-1.13), and for GG carriers, it was RR 1.21 (95%CI, 1.06-1.40). We identified evidence of heterogeneity (P=0.004) and a trend (P=0.0009) across genotypic groups.\n\nConclusionsIn contrast to the interpretation provided by authors of the analysis based in the ACCELERATE trial, the available evidence lends weak support to a potential interaction of CETP treatment by ADCY9 genotype on risk of major adverse cardiac events. Additional data, e.g. from the ongoing dal-GenE trial focused explicitly on this interaction, should provide further clarity regarding the robustness of this pharmacogenetic effect.

genetics↗

bioRxiv2018

PCSK9 genetic variants, life-long lowering of LDL-cholesterol and cognition: a large-scale Mendelian randomization study

AimsPCSK9 inhibitors lower LDL cholesterol and are efficacious at reducing risk of vascular disease, however questions remain about potential adverse effects on cognitive function. We examined the association of LDL cholesterol-lowering genetic variants in PCSK9 with continuous measures of cognitive ability\n\nMethods and ResultsSix independent SNPs in PCSK9 were used in up to 337,348 individuals from the UK Biobank who underwent measures of cognitive ability (fluid reasoning, reaction time, trial making test and digit symbol coding. Scaled to a 50mg/dL lower LDL cholesterol, the PCSK9 allele score was associated with a lower risk of CHD (odds ratio 0.73; 95% CI: 0.60 to 0.90, P = 0.003). The scaled PCSK9 allele score nominally associated with worse log reaction time (0.04 standard deviations; 95%CI: 0.00, 0.08; P=0.038). Although no strong associations of the PCSK9 allele score were identified with any cognitive trait, the imprecision around the estimates meant that we could not exclude a similar magnitude of effect of genetic inhibition of PCSK9 to that seen with established risk factors, including APOEe4 or smoking status for any of the individual cognition traits. Point estimates for the PCSK9 allele score and cognition traits were all on the harmful side of unity.\n\nConclusionsUsing currently available data in UK Biobank, we are not able to rule out meaningful associations of PCSK9 genetic variants with cognition traits. These data highlight the need for further large-scale genetic analyses and, in parallel, continued pharmacovigilance for patients currently treated with PCSK9 inhibitors.

epidemiology↗