Unidirectional and bidirectional causation between smoking and blood DNA methylation: evidence from twin-based Mendelian randomisation.

Cigarette smoking is associated with numerous differentially-methylated genomic loci in multiple human tissues. These associations are often assumed to reflect the causal effects of smoking on DNA methylation (DNAm), which may underpin some of the adverse health sequelae of smoking. However, prior causal analyses with Mendelian Randomisation (MR) have found limited support for such effects.

No Evidence of Interaction Between FADS2 Genotype and Breastfeeding on Cognitive or Other Traits in the UK Biobank.

Breastfeeding is hypothesised to benefit child health and cognitive functioning by providing long-chain polyunsaturated fatty acids, which are essential for brain development. In 2007, Caspi et al. found evidence in two cohorts for an interaction between genetic variation in the FADS2 gene (a gene involved in fatty acid metabolism) and breastfeeding on IQ.

Positive and negative affect, related mental health traits, and cognitive performance: shared genetic architecture and potential causality.

Altered affect and cognitive dysfunction are transdiagnostic, burdensome, and pervasive features of many psychiatric conditions which remain poorly understood and have few efficacious treatments. Research on the genetic architecture of these phenotypes and causal relationships between them may provide insight into their aetiology and comorbidity. Using data from the Lifelines Cohort Study, we conducted genome-wide association studies (GWAS) on positive and negative affect and four cognitive domains (working memory, reaction time, visual learning and memory, executive function).

The importance of family-based sampling for biobanks.

Biobanks aim to improve our understanding of health and disease by collecting and analysing diverse biological and phenotypic information in large samples. So far, biobanks have largely pursued a population-based sampling strategy, where the individual is the unit of sampling, and familial relatedness occurs sporadically and by chance. This strategy has been remarkably efficient and successful, leading to thousands of scientific discoveries across multiple research domains, and plans for the next wave of biobanks are underway.

Role of Inflammation in Depressive and Anxiety Disorders, Affect, and Cognition: Genetic and Non-Genetic Findings in the Lifelines Cohort Study.

Inflammation is associated with a range of neuropsychiatric symptoms; however, the nature of the causal relationship is unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognition. We tested in ≈ 55,098 (59% female) individuals from the Dutch Lifelines cohort the concurrent/prospective associations of C-reactive protein (CRP) with: depressive and anxiety disorders; positive/negative affect; and attention, psychomotor speed, episodic memory, and executive functioning.

Use of genetic correlations to examine selection bias.

Observational studies are rarely representative of their target population because there are known and unknown factors that affect an individual's choice to participate (the selection mechanism). Selection can cause bias in a given analysis if the outcome is related to selection (conditional on the other variables in the model). Detecting and adjusting for selection bias in practice typically requires access to data on nonselected individuals.

Protein Identification for Stroke Progression via Mendelian Randomization in Million Veteran Program and UK Biobank.

Background: Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke.

Methods: We performed genome-wide association studies for subsequent major adverse cardiovascular events (MACE; n=51 929; n=39 980) and subsequent arterial ischemic stroke (AIS; n=45 120; n=46 789) after the first incident stroke within the Million Veteran Program and UK Biobank.

Unidirectional and Bidirectional Causation between Smoking and Blood DNA Methylation: Evidence from Twin-based Mendelian Randomisation.

Cigarette smoking is associated with numerous differentially-methylated genomic loci in multiple human tissues. These associations are often assumed to reflect the causal effects of smoking on DNA methylation (DNAm), which may underpin some of the adverse health sequelae of smoking. However, prior causal analyses with Mendelian Randomisation (MR) have found limited support for such effects.

Role of Inflammation in Depressive and Anxiety Disorders, Affect, and Cognition: Genetic and Non-Genetic Findings in the Lifelines Cohort Study.

Background: Low-grade systemic inflammation is implicated in the pathogenesis of various neuropsychiatric conditions affecting mood and cognition. While much of the evidence concerns depression, large-scale population studies of anxiety, affect, and cognitive function are scarce. Importantly, causality remains unclear.

Ancestry, ethnicity, and race: explaining inequalities in cardiometabolic disease.

Population differences in cardiometabolic disease remain unexplained. Misleading assumptions over genetic explanations are partly due to terminology used to distinguish populations, specifically ancestry, race, and ethnicity. These terms differentially implicate environmental and biological causal pathways, which should inform their use.

Genetics impact risk of Alzheimer's disease through mechanisms modulating structural brain morphology in late life.

Background: Alzheimer's disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or increasing brain atrophy, respectively.

Methods: We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8-81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank).

Design and quality control of large-scale two-sample Mendelian randomization studies.

Background: Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses.

PheWAS-based clustering of Mendelian Randomisation instruments reveals distinct mechanism-specific causal effects between obesity and educational attainment.

Mendelian Randomisation (MR) estimates causal effects between risk factors and complex outcomes using genetic instruments. Pleiotropy, heritable confounders, and heterogeneous causal effects violate MR assumptions and can lead to biases. To alleviate these, we propose an approach employing a Phenome-Wide association Clustering of the MR instruments (PWC-MR) and apply this method to revisit the surprisingly large apparent causal effect of body mass index (BMI) on educational attainment (EDU): [Formula: see text] = -0.

Protein identification for stroke progression via Mendelian Randomization in Million Veteran Program and UK Biobank.

Background: Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke.

Methods: We performed genome-wide association studies (GWAS) for subsequent major adverse cardiovascular events (MACE) (N=51,929, N=39,980) and subsequent arterial ischemic stroke (AIS) N=45,120, N=46,789) after first incident stroke within the Million Veteran Program and UK Biobank.

Genetic influences on alcohol flushing in East Asian populations.

Background: Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited.

Methods: We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake.

Review and further developments in statistical corrections for Winner's Curse in genetic association studies.

Genome-wide association studies (GWAS) are commonly used to identify genomic variants that are associated with complex traits, and estimate the magnitude of this association for each variant. However, it has been widely observed that the association estimates of variants tend to be lower in a replication study than in the study that discovered those associations. A phenomenon known as Winner's Curse is responsible for this upward bias present in association estimates of significant variants in the discovery study.

A comparison of the genes and genesets identified by GWAS and EWAS of fifteen complex traits.

Identifying genomic regions pertinent to complex traits is a common goal of genome-wide and epigenome-wide association studies (GWAS and EWAS). GWAS identify causal genetic variants, directly or via linkage disequilibrium, and EWAS identify variation in DNA methylation associated with a trait. While GWAS in principle will only detect variants due to causal genes, EWAS can also identify genes via confounding, or reverse causation.

Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases.

Proteome-wide Mendelian randomization (MR) shows value in prioritizing drug targets in Europeans but with limited evidence in other ancestries. Here, we present a multi-ancestry proteome-wide MR analysis based on cross-population data from the Global Biobank Meta-analysis Initiative (GBMI). We estimated the putative causal effects of 1,545 proteins on eight diseases in African (32,658) and European (1,219,993) ancestries and identified 45 and 7 protein-disease pairs with MR and genetic colocalization evidence in the two ancestries, respectively.

Evaluating and implementing block jackknife resampling Mendelian randomization to mitigate bias induced by overlapping samples.

Participant overlap can induce overfitting bias into Mendelian randomization (MR) and polygenic risk score (PRS) studies. Here, we evaluated a block jackknife resampling framework for genome-wide association studies (GWAS) and PRS construction to mitigate overfitting bias in MR analyses and implemented this study design in a causal inference setting using data from the UK Biobank. We simulated PRS and MR under three scenarios: (1) using weighted SNP estimates from an external GWAS, (2) using weighted SNP estimates from an overlapping GWAS sample and (3) using a block jackknife resampling framework.

Collection of genetic data at scale for a nationally representative population: the UK Millennium Cohort Study.

A DNA bank has been created from the Millennium Cohort Study (MCS) saliva samples. A total of 23,336 samples are available, from 9,259 cohort members (4,630 males and 4,629 females), 8,898 mothers and 5,179 fathers. There are 4,533 mother, child, father 'triads'.

Evaluating indirect genetic effects of siblings using singletons.

Estimating effects of parental and sibling genotypes (indirect genetic effects) can provide insight into how the family environment influences phenotypic variation. There is growing molecular genetic evidence for effects of parental phenotypes on their offspring (e.g.

The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: a Mendelian randomization study.

Despite early interest, the evidence linking fatty acids to cardiovascular diseases (CVDs) remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the etiology of several CVD endpoints in up to 1 153 768 European (maximum 123 668 cases) and 212 453 East Asian (maximum 29 319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms mapping to genes with well-known roles in PUFA (i.