NJ Timpson

<h3></h3> Elevated morning plasma cortisol is associated with multiple cardiovascular risk factors in metabolic syndrome. Epidemiological studies have reported positive associations between plasma cortisol and coronary heart disease (CHD) however traditional observational studies do not allow causality to be determined and are unable rule out the possibility of confounding. A two-sample Mendelian randomisation approach was used to estimate the causal effect of plasma cortisol on risk of CHD. A genetic instrument for plasma cortisol comprised three SNPs which were associated with plasma cortisol in the recent Cortisol Network (CORNET) genome wide association meta-analysis (GWAMA) (n = 12,597). We investigated the association between this genetic instrument and risk of CHD in 22,223 cases/64,762 controls from the CARDIOGRAM consortium. Each standard deviation rise in genetically predicted plasma cortisol was associated with an odds ratio of 1.27 (95% CI: 1.01–1.60) for CHD. These results are compatible with a causal effect for the observational association between plasma cortisol and CHD. The inconsistent results from observational studies may be explained by: the inverse association between cortisol and obesity, which confounded the positive association of cortisol with other cardiovascular risk factors; and the use of single ‘snapshot’ plasma cortisol measurement rather than cumulative measure of cortisol exposure provided by genetic prediction. A bidirectional Mendelian randomisation analysis between plasma cortisol and BMI may yield greater clarity. To improve the strength of our genetic instrument an expanded CORNET GWAMA is currently underway. Measurements of cortisol may add value to predictions of CHD risk.

<h3>Background</h3> An emerging technique is a Phenome Wide Association Study (PheWAS), which reverses the phenotype to genotype methods used within a GWAS, instead taking a pre-determined set of genetic variants, and testing which of a wide range of phenotypes these genetic variants may be associated with. We can further investigate the genetic architecture of multiple traits and disease outcomes through linking a chosen genetic variant to multiple phenotypes, in varying populations. In this study we constructed polygenic risk scores (PRS) from single nucleotide polymorphisms (SNPs) shown to be robustly related to alcohol use, to test: These genetic signals within two sub populations of adolescents, and for pregnant women. If there are any associations (other than with alcohol use) of these PRS with many mental health phenotypes. Intrauterine effects of Maternal PRS for alcohol use for associations with offspring phenotypes. <h3>Methods</h3> Participants were mothers and offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were genotyped and PRS were constructed based on genome-wide significant SNPs for alcohol consumption. Targeted phenotypes were selected from substance use (<i>n</i>=22<i>)</i> and mental health/behavioural variables (n=91) within ALSPAC. Linear and logistic regression analyses were used to investigate if PRS for alcohol use were associated with alcohol use (mothers in pregnancy; children) and health phenotypes (mothers during pregnancy; children both pre-alcohol use around ages 7–10, and post-alcohol use around ages 13–23). <h3>Results</h3> The PRS were associated with multiple alcohol consumption phenotypes (strongest signal for alcohol amount at 18 weeks gestation: <i>p</i>=1.01×10^-5) in pregnant mothers. There was an effect of maternal PRS for alcohol use on mother’s perinatal depression (<i>p</i>=0.02), offspring intellect (<i>p</i>=0.016), and ADHD (<i>p</i><i>=</i>0.04). <h3>Discussion</h3> The effects of alcohol PRS previously found in the general population are also shown during pregnancy. We found an intrauterine effect of alcohol PRS on offspring intellect and ADHD. The effects shown are not due to offspring’s own alcohol use, as these effects were not found within the child’s analyses.