Methodological approaches, challenges, and opportunities in the application of Mendelian randomisation to lifecourse epidemiology: A systematic literature review.

Diseases diagnosed in adulthood may have antecedents throughout (including prenatal) life. Gaining a better understanding of how exposures at different stages in the lifecourse influence health outcomes is key to elucidating the potential benefits of disease prevention strategies. Mendelian randomisation (MR) is increasingly used to estimate causal effects of exposures across the lifecourse on later life outcomes.

Establishing the relationships between adiposity and reproductive factors: a multivariable Mendelian randomization analysis.

Background: Few studies have investigated associations between adiposity and reproductive factors using causal methods, both of which have a number of consequences on women's health. Here we assess whether adiposity at different points in the lifecourse affects reproductive factors differently and independently, and the plausibility of the impact of reproductive factors on adiposity.

Methods: We used genetic data from UK Biobank (273,238 women) and other consortia (EGG, GIANT, ReproGen and SSGAC) for eight reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age first had sexual intercourse and lifetime number of sexual partners, and two adiposity traits: childhood and adulthood body size.

The EWAS Catalog: a database of epigenome-wide association studies.

Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and published. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p<1x10 ) from published EWAS, each assaying over 100,000 CpGs in at least 100 individuals.

The relationships between women's reproductive factors: a Mendelian randomisation analysis.

Background: Women's reproductive factors include their age at menarche and menopause, the age at which they start and stop having children and the number of children they have. Studies that have linked these factors with disease risk have largely investigated individual reproductive factors and have not considered the genetic correlation and total interplay that may occur between them. This study aimed to investigate the nature of the relationships between eight female reproductive factors.

Integrative multiomics analysis highlights immune-cell regulatory mechanisms and shared genetic architecture for 14 immune-associated diseases and cancer outcomes.

Developing functional insight into the causal molecular drivers of immunological disease is a critical challenge in genomic medicine. Here, we systematically apply Mendelian randomization (MR), genetic colocalization, immune-cell-type enrichment, and phenome-wide association methods to investigate the effects of genetically predicted gene expression on ten immune-associated diseases and four cancer outcomes. Using whole blood-derived estimates for regulatory variants from the eQTLGen consortium (n = 31,684), we constructed genetic risk scores for 10,104 genes.

Investigating the DNA methylation profile of e-cigarette use.

Background: Little evidence exists on the health effects of e-cigarette use. DNA methylation may serve as a biomarker for exposure and could be predictive of future health risk. We aimed to investigate the DNA methylation profile of e-cigarette use.

Novel nonsense variants in SLURP1 and DSG1 cause palmoplantar keratoderma in Pakistani families.

Background: Inherited palmoplantar keratodermas (PPKs) are clinically and genetically heterogeneous and phenotypically diverse group of genodermatoses characterized by hyperkeratosis of the palms and soles. More than 20 genes have been reported to be associated with PPKs including desmoglein 1 (DSG1) a key molecular component for epidermal adhesion and differentiation. Mal de Meleda (MDM) is a rare inherited autosomal recessive genodermatosis characterized by transgrediens PPK, associated with mutations in the secreted LY6/PLAUR domain containing 1 (SLURP1) gene.

Investigating the impact of cigarette smoking behaviours on DNA methylation patterns in adolescence.

Smoking usually begins in adolescence, and early onset of smoking has been linked to increased risk of later life disease. There is a need to better understand the biological impact of cigarette smoking behaviours in adolescence. DNA methylation profiles related to smoking behaviours and cessation in adulthood have been previously identified, but alterations arising from smoking initiation have not been thoroughly investigated.