SA2USING GENETIC INSTRUMENTS TO ASSESS CAUSAL PATHWAYS TO EDUCATIONAL ATTAINMENT IN ADHD AND AUTISM: EVIDENCE FROM A TWO SAMPLE MENDELIAN RANDOMISATION STUDY

AbstractGenome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to be systematically explored. We integrated multi-tissue expression quantitative trait loci (eQTLs) and glioma GWAS data using a combined Mendelian randomisation (MR) and colocalisation approach. We investigated how genetically predicted gene expression affects risk across tissue type (brain, estimated effective n = 1194 and whole blood, n = 31,684) and glioma subtype (all glioma (7400 cases, 8257 controls) glioblastoma (GBM, 3112 cases) and non-GBM gliomas (2411 cases)). We also leveraged tissue-specific eQTLs collected from 13 brain tissues (n = 114 to 209). The MR and colocalisation results suggested that genetically predicted increased gene expression of 12 genes were associated with glioma, GBM and/or non-GBM risk, three of which are novel glioma susceptibility genes (RETREG2/FAM134A, FAM178B and MVB12B/FAM125B). The effect of gene expression appears to be relatively consistent across glioma subtype diagnoses. Examining how risk differed across 13 brain tissues highlighted five candidate tissues (cerebellum, cortex, and the putamen, nucleus accumbens and caudate basal ganglia) and four previously implicated genes (JAK1, STMN3, PICK1 and EGFR). These analyses identified robust causal evidence for 12 genes and glioma risk, three of which are novel. The correlation of MR estimates in brain and blood are consistently low which suggested that tissue specificity needs to be carefully considered for glioma. Our results have implicated genes yet to be associated with glioma susceptibility and provided insight into putatively causal pathways for glioma risk.

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Cigarette smoking and personality: interrogating causality using Mendelian randomisation

Psychological Medicine ◽

10.1017/s0033291718003069 ◽

2018 ◽

Vol 49 (13) ◽

pp. 2197-2205 ◽

Cited By ~ 1

Author(s):

Hannah M. Sallis ◽

George Davey Smith ◽

Marcus R. Munafò

Keyword(s):

Personality Traits ◽

Association Studies ◽

Smoking Initiation ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

Individual Level ◽

Causal Pathways ◽

Genome Wide ◽

Level Data ◽

Causal Nature

AbstractBackgroundDespite the well-documented association between smoking and personality traits such as neuroticism and extraversion, little is known about the potential causal nature of these findings. If it were possible to unpick the association between personality and smoking, it may be possible to develop tailored smoking interventions that could lead to both improved uptake and efficacy.MethodsRecent genome-wide association studies (GWAS) have identified variants robustly associated with both smoking phenotypes and personality traits. Here we use publicly available GWAS summary statistics in addition to individual-level data from UK Biobank to investigate the link between smoking and personality. We first estimate genetic overlap between traits using LD score regression and then use bidirectional Mendelian randomisation methods to unpick the nature of this relationship.ResultsWe found clear evidence of a modest genetic correlation between smoking behaviours and both neuroticism and extraversion. We found some evidence that personality traits are causally linked to certain smoking phenotypes: among current smokers each additional neuroticism risk allele was associated with smoking an additional 0.07 cigarettes per day (95% CI 0.02–0.12, p = 0.009), and each additional extraversion effect allele was associated with an elevated odds of smoking initiation (OR 1.015, 95% CI 1.01–1.02, p = 9.6 × 10−7).ConclusionWe found some evidence for specific causal pathways from personality to smoking phenotypes, and weaker evidence of an association from smoking initiation to personality. These findings could be used to inform future smoking interventions or to tailor existing schemes.

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Genetically predicted levels of the human plasma proteome and risk of stroke: a Mendelian Randomization study

10.21203/rs.3.rs-984362/v1 ◽

2021 ◽

Author(s):

Lingyan Chen ◽

James Peters ◽

Bram Prins ◽

Elodie Persyn ◽

Matthew Traylor ◽

...

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Body Mass Index ◽

White Matter ◽

Body Mass ◽

White Matter Hyperintensity ◽

Mendelian Randomisation ◽

Beneficial Effects ◽

Causal Pathways

Abstract Proteins are the effector molecules of biology and are the target of most drugs. To identify proteins and related pathways that may play a causal role in stroke pathogenesis, we used Mendelian randomisation (MR). We tested potential causal effects of 308 plasma proteins (measured in 4,994 blood donors from the INTERVAL study) on stroke outcomes (derived from the MEGASTROKE GWAS) in a two-sample MR framework and assessed whether these associations could be mediated by cardiovascular risk factors. We extended the analysis to identify whether pharmacological targeting of these proteins might have potential adverse side-effects or beneficial effects for other conditions through Phenome-wide MR (Phe-MR) in UK Biobank. MR showed an association between stroke and genetically predicted plasma levels of TFPI, IL6RA, MMP12, CD40, TMPRSS5 and CD6 (P≤1.62⋅10−4). We identified six risk factors (atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes) that were associated with stroke (P≤0.0071) using MR. The association of TFPI, IL6RA and TMPRSS5 with stroke could be mediated by these risk factors, such as body mass index, white matter hyperintensity and atrial fibrillation. Thirty-six additional proteins were potentially causal for one or more of these risk factors. The Phe-MR suggested that targeting TFPI could have potential beneficial effects on other disorders of arteries and hyperlipidaemia in addition to stroke. Our results highlight novel causal pathways and potential therapeutic targets for stroke.

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Educational attainment impacts drinking behaviors and risk for alcohol dependence: results from a two-sample Mendelian randomization study with ~780,000 participants

Molecular Psychiatry ◽

10.1038/s41380-019-0535-9 ◽

2019 ◽

Cited By ~ 4

Author(s):

Daniel B. Rosoff ◽

Toni-Kim Clarke ◽

Mark J. Adams ◽

Andrew M. McIntosh ◽

George Davey Smith ◽

...

Keyword(s):

Alcohol Use ◽

Educational Attainment ◽

Alcohol Dependence ◽

Mendelian Randomization ◽

Association Studies ◽

Significant Snps ◽

Genome Wide Association Studies ◽

Reverse Causality ◽

Genome Wide ◽

Genetic Instruments

Abstract Observational studies suggest that lower educational attainment (EA) may be associated with risky alcohol use behaviors; however, these findings may be biased by confounding and reverse causality. We performed two-sample Mendelian randomization (MR) using summary statistics from recent genome-wide association studies (GWAS) with >780,000 participants to assess the causal effects of EA on alcohol use behaviors and alcohol dependence (AD). Fifty-three independent genome-wide significant SNPs previously associated with EA were tested for association with alcohol use behaviors. We show that while genetic instruments associated with increased EA are not associated with total amount of weekly drinks, they are associated with reduced frequency of binge drinking ≥6 drinks (ßIVW = −0.198, 95% CI, −0.297 to –0.099, PIVW = 9.14 × 10−5), reduced total drinks consumed per drinking day (ßIVW = −0.207, 95% CI, −0.293 to –0.120, PIVW = 2.87 × 10−6), as well as lower weekly distilled spirits intake (ßIVW = −0.148, 95% CI, −0.188 to –0.107, PIVW = 6.24 × 10−13). Conversely, genetic instruments for increased EA were associated with increased alcohol intake frequency (ßIVW = 0.331, 95% CI, 0.267–0.396, PIVW = 4.62 × 10−24), and increased weekly white wine (ßIVW = 0.199, 95% CI, 0.159–0.238, PIVW = 7.96 × 10−23) and red wine intake (ßIVW = 0.204, 95% CI, 0.161–0.248, PIVW = 6.67 × 10−20). Genetic instruments associated with increased EA reduced AD risk: an additional 3.61 years schooling reduced the risk by ~50% (ORIVW = 0.508, 95% CI, 0.315–0.819, PIVW = 5.52 × 10−3). Consistency of results across complementary MR methods accommodating different assumptions about genetic pleiotropy strengthened causal inference. Our findings suggest EA may have important effects on alcohol consumption patterns and may provide potential mechanisms explaining reported associations between EA and adverse health outcomes.

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Kidney Function and Blood Pressure: A Bi-directional Mendelian Randomisation Study

10.1101/856674 ◽

2019 ◽

Cited By ~ 1

Author(s):

Zhi Yu ◽

Josef Coresh ◽

Guanghao Qi ◽

Morgan Grams ◽

Eric Boerwinkle ◽

...

Keyword(s):

Blood Pressure ◽

Diastolic Blood Pressure ◽

Kidney Function ◽

Causal Effects ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

Summary Statistics ◽

Lower Blood Pressure ◽

Lower Blood ◽

Genetic Instruments

AbstractObjectiveTo evaluate the bi-directional causal relation between kidney function and blood pressure.DesignMendelian randomisation study.SettingWe performed two-sample Mendelian randomisation analyses. Genetic instruments of kidney function traits were selected from summary statistics of genome-wide association studies (GWAS) of glomerular filtration rate estimated from serum creatinine (eGFRcr) and blood urea nitrogen (BUN) and were required to be associated with both eGFRcr and BUN to ensure that the instruments were more likely to represent the underlying kidney function. Genetic instruments of blood pressure were selected from summary statistics of GWAS of systolic and diastolic blood pressure. We investigated Mendelian randomisation hypothesis using several alternative approaches, including methods that are most robust to the presence of horizontal pleiotropy.ParticipantsThe summary statistics of eGFRcr included 567,460 participants from 54 cohorts, and the summary statistics of BUN included 243,031 participants from 48 cohorts from the Chronic Kidney Disease Genetics (CKDGen) Consortium. The summary statistics of systolic and diastolic blood pressure included 757,601 participants from the UK Biobank and 78 cohorts from the International Consortium for Blood Pressure (ICBP).ResultsSignificant evidence supported the causal effects of higher kidney function on lower blood pressure with multiple methods. Based on the mode-based Mendelian randomisation analysis approach, known for its robustness to the presence of pleiotropic effect, the effect estimate for 1 SD higher in eGFRcr was −0.17 SD unit (95 % CI: −0.09 to −0.24) in systolic blood pressure (SBP) and −0.15 SD unit (95% CI: −0.07 to −0.22) in diastolic blood pressure (DBP). In contrast, the causal effects of blood pressure on kidney function were not statistically significant.ConclusionsMendelian randomisation analyses support causal effects of higher kidney function on lower blood pressure. These results suggest preventing kidney function decline can reduce the public health burden of hypertension.

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Links between obesity, weight stigma and learning in adolescence: a qualitative study

BMC Public Health ◽

10.1186/s12889-022-12538-w ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Rebecca Langford ◽

Alisha Davies ◽

Laura Howe ◽

Christie Cabral

Keyword(s):

Educational Attainment ◽

Social Acceptance ◽

Economic Status ◽

Later Life ◽

Young Person ◽

Social Determinant ◽

Weight Stigma ◽

Disruptive Behaviour ◽

Healthy Weight ◽

Causal Pathways

Abstract Background Educational attainment is a key social determinant of health. Health and education are linked by multiple pathways, many of which are not well understood. One such pathway is the association between being above a healthy weight and lower academic achievement. While various explanations have been put forward to explain this relationship, evidence for causal pathways is sparse and unclear. This study addresses that evidence gap. Methods We interviewed 19 adults (late 20s; 14 female, 5 male) and one young person (14 years, male) from the UK in 2019/2020. Participants were recruited from the ALSPAC 1990s birth cohort, sampled to ensure diversity in socio-economic status and educational attainment, and a community-based weight management group for young people. Interviews focused on experiences of being above a healthy weight during secondary school and how this may have affected their learning and achievement. Interviews were face-to-face, digitally recorded, and transcribed verbatim. We analysed the data thematically. Results We identified key pathways through which higher body weight may negatively impact educational performance and showed how these are linked within a novel theoretical model. Because larger body size is highly stigmatised, participants engaged in different strategies to minimise their exposure to negative attention. Participants sought to increase their social acceptance or become less socially visible (or a combination of both). A minority navigated this successfully; they often had many friends (or the ‘right’ friends), experienced little or no bullying at school and weight appeared to have little effect on their achievement at school. For most however, the behaviours resulting from these strategies (e.g. disruptive behaviour, truanting, not working hard) or the physical, social or mental impacts of their school experiences (e.g. hungry, tired, self-conscious, depressed) made it difficult to concentrate and/or participate in class, which in turn affected how teachers viewed them. Conclusions Action to combat weight stigma, both within schools and in wider society, is urgently required to help address these educational disparities that in turn can impact health in later life.

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Modifiable traits, healthy behaviours, and leucocyte telomere length

10.1101/2021.12.13.21267707 ◽

2021 ◽

Author(s):

Vasiliki Bountziouka ◽

Crispin Musicha ◽

Elias Allara ◽

Stephen Kaptoge ◽

Qingning Wang ◽

...

Keyword(s):

Life Expectancy ◽

Educational Attainment ◽

Telomere Length ◽

Lower Risk ◽

Smoking Behaviour ◽

Mendelian Randomisation ◽

Age Related ◽

Clinical Consequences ◽

Artery Disease ◽

Sufficient Magnitude

Background: Telomere length is associated with risk of several age-related diseases and cancers. The extent to which telomere length may be modifiable through lifestyle and behaviour and whether this has any clinical consequences is unknown. Methods: In up to 422,797 participants in UK Biobank, we investigated associations of leucocyte telomere length (LTL) with 117 potentially modifiable traits, as well as two indices of healthy behaviours incorporating smoking, physical activity, diet, maintenance of a healthy body weight and alcohol intake. Associations were interpreted as age-related change in LTL by dividing the trait beta coefficients with the age-coefficient. We used Mendelian Randomisation (MR) to test causality of the observed associations of educational attainment and smoking behaviour with LTL. We investigated whether the associations of LTL with 22 diseases were modified by the number of healthy behaviours and the extent to which the associations of more healthy behaviours with greater life expectancy and lower risk of coronary artery disease (CAD) may be mediated through LTL. Results: 71 traits showed significant associations with LTL but most were modest, equivalent to <1 year of age-related change in LTL. In multivariable analyses of 17 traits with stronger associations (equivalent to ≥2 years of age-related change in LTL), five traits (oily fish intake, educational attainment, general health status, walking pace and current smoking) remained significant. MR analysis suggested that educational attainment and smoking behaviour causally affect LTL. Both indices of healthy behaviour were positively and linearly associated with LTL, with those with the healthiest behaviour having longer LTL equivalent to approx. 3.5 years of age-related change in LTL when compared with those with the least heathy behaviours (P<0.001). However, healthy behaviours only explained <0.2% of the total variation in LTL and did not significantly modify the association of LTL with risk of any of the diseases studied. Neither the association of more healthy behaviours on greater life expectancy or lower risk of CAD were substantially mediated through LTL. Conclusions: Several potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal. However, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy.

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Mendelian randomisation analysis of the effect of educational attainment and cognitive ability on smoking behaviour

Nature Communications ◽

10.1038/s41467-019-10679-y ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 15

Author(s):

Eleanor Sanderson ◽

George Davey Smith ◽

Jack Bowden ◽

Marcus R. Munafò

Keyword(s):

Educational Attainment ◽

Cognitive Ability ◽

Smoking Behaviour ◽

Mendelian Randomisation

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Does smoking cause lower educational attainment and general cognitive ability? Triangulation of causal evidence using multiple study designs

Psychological Medicine ◽

10.1017/s0033291720003402 ◽

2020 ◽

pp. 1-9

Author(s):

Suzanne H. Gage ◽

Hannah M. Sallis ◽

Glenda Lassi ◽

Robyn E. Wootton ◽

Claire Mokrysz ◽

...

Keyword(s):

Educational Attainment ◽

Cognitive Ability ◽

Fluid Intelligence ◽

Causal Effect ◽

Smoking Initiation ◽

Sensitivity Analyses ◽

Mendelian Randomisation ◽

General Cognitive Ability ◽

Inverse Variance ◽

Lower Educational Attainment

Abstract Background Observational studies have found associations between smoking and both poorer cognitive ability and lower educational attainment; however, evaluating causality is challenging. We used two complementary methods to explore this. Methods We conducted observational analyses of up to 12 004 participants in a cohort study (Study One) and Mendelian randomisation (MR) analyses using summary and cohort data (Study Two). Outcome measures were cognitive ability at age 15 and educational attainment at age 16 (Study One), and educational attainment and fluid intelligence (Study Two). Results Study One: heaviness of smoking at age 15 was associated with lower cognitive ability at age 15 and lower educational attainment at age 16. Adjustment for potential confounders partially attenuated findings (e.g. fully adjusted cognitive ability β −0.736, 95% CI −1.238 to −0.233, p = 0.004; fully adjusted educational attainment β −1.254, 95% CI −1.597 to −0.911, p < 0.001). Study Two: MR indicated that both smoking initiation and lifetime smoking predict lower educational attainment (e.g. smoking initiation to educational attainment inverse-variance weighted MR β −0.197, 95% CI −0.223 to −0.171, p = 1.78 × 10−49). Educational attainment results were robust to sensitivity analyses, while analyses of general cognitive ability were less so. Conclusion We find some evidence of a causal effect of smoking on lower educational attainment, but not cognitive ability. Triangulation of evidence across observational and MR methods is a strength, but the genetic variants associated with smoking initiation may be pleiotropic, suggesting caution in interpreting these results. The nature of this pleiotropy warrants further study.

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Effects of increased body mass index on employment status: a Mendelian randomisation study

International Journal of Obesity ◽

10.1038/s41366-021-00846-x ◽

2021 ◽

Author(s):

Desmond D. Campbell ◽

Michael Green ◽

Neil Davies ◽

Evangelia Demou ◽

Joey Ward ◽

...

Keyword(s):

Body Mass Index ◽

Educational Attainment ◽

Household Income ◽

Employment Status ◽

Early Retirement ◽

Causal Effect ◽

Causal Effects ◽

Mendelian Randomisation ◽

Social Discrimination ◽

Obesity Epidemic

Abstract Background The obesity epidemic may have substantial implications for the global workforce, including causal effects on employment, but clear evidence is lacking. Obesity may prevent people from being in paid work through poor health or through social discrimination. We studied genetic variants robustly associated with body mass index (BMI) to investigate its causal effects on employment. Dataset/methods White UK ethnicity participants of working age (men 40–64 years, women 40–59 years), with suitable genetic data were selected in the UK Biobank study (N = 230,791). Employment status was categorised in two ways: first, contrasting being in paid employment with any other status; and second, contrasting being in paid employment with sickness/disability, unemployment, early retirement and caring for home/family. Socioeconomic indicators also investigated were hours worked, household income, educational attainment and Townsend deprivation index (TDI). We conducted observational and two-sample Mendelian randomisation (MR) analyses to investigate the effect of increased BMI on employment-related outcomes. Results Regressions showed BMI associated with all the employment-related outcomes investigated. MR analyses provided evidence for higher BMI causing increased risk of sickness/disability (OR 1.08, 95% CI 1.04, 1.11, per 1 Kg/m2 BMI increase) and decreased caring for home/family (OR 0.96, 95% CI 0.93, 0.99), higher TDI (Beta 0.038, 95% CI 0.018, 0.059), and lower household income (OR 0.98, 95% CI 0.96, 0.99). In contrast, MR provided evidence for no causal effect of BMI on unemployment, early retirement, non-employment, hours worked or educational attainment. There was little evidence for causal effects differing by sex or age. Robustness tests yielded consistent results. Discussion BMI appears to exert a causal effect on employment status, largely by affecting an individual’s health rather than through increased unemployment arising from social discrimination. The obesity epidemic may be contributing to increased worklessness and therefore could impose a substantial societal burden.

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