Biology subjects

Millard, L. A. C.

Publications and source records attributed to Millard, L. A. C..

3 recordsLinked to original sources

bioRxiv2019

Proxy gene-by-environment Mendelian randomization study confirms a causal effect of maternal smoking on offspring birthweight, but little evidence of long-term influences on offspring health

ObjectiveTo validate a novel proxy gene-by-environment (GxE) Mendelian randomization (MR) approach by replicating the previously established effect of maternal smoking heaviness in pregnancy on offspring birthweight, and then use GxE MR to investigate the effect of smoking heaviness in pregnancy on offspring health outcomes in later life and grandchilds birthweight.\n\nDesignA proxy GxE MR using participants genotype (i.e. rs16969968 in CHRNA5) as a proxy for their mothers genotype.\n\nSettingUK Biobank.\n\nParticipants289,684 white British men and women aged 40-69 in UK Biobank.\n\nMain outcome measuresParticipants birthweight and later life outcomes (height, body mass index, lung function, asthma, blood pressure, age at menarche, years of education, fluid intelligence score, depression/anxiety, happiness), and birthweight of female participants first child.\n\nResultsIn our proof of principle analysis, each additional smoking-increasing allele was associated with a 0.018 (95% confidence interval (CI): -0.026, -0.009) kg lower birthweight in the \"maternal smoking during pregnancy\" stratum, but no meaningful effect (-0.002kg; 95% CI: -0.008, 0.003) in the \"maternal non-smoking during pregnancy\" stratum (interaction P-value=0.004). We found little evidence of an effect of maternal smoking heaviness on participants later life outcomes. We found the differences in associations of rs16969968 with grandchilds birthweight between grandmothers who did versus did not smoke were heterogeneous (interaction P-value=0.042) among female participants who did (-0.020kg per allele; 95% CI: -0.044, 0.003) versus did not (0.007kg per allele; 95% CI: -0.005, 0.020) smoke in pregnancy.\n\nConclusionsOur study demonstrated how offspring genotype can be used to proxy for mothers genotype in GxE MR. We confirmed the previously established causal effect of maternal smoking on offspring birthweight but found little evidence of an effect on long-term health outcomes in the offspring. For grandchilds birthweight, the effect of grandmothers smoking heaviness in pregnancy may be modulated by maternal smoking status in pregnancy.\n\nWHAT IS ALREADY KNOWN TO THIS TOPICHeavier maternal smoking in pregnancy causes lower offspring birthweight Maternal smoking in pregnancy is also associated with offspring outcomes in later life and grandchilds birthweight, but it is not known whether these associations are causal Understanding the transgenerational causal effects of maternal smoking heaviness in pregnancy is important to inform public health policies\n\nWHAT THIS STUDY ADDSThe proxy gene-by-environment Mendelian randomization approach can be used to explore maternal effects on offspring phenotypes when maternal genetic information is unavailable The approach confirmed the causal effect of smoking on offspring birthweight.\n\nMaternal smoking status in pregnancy modulates the effect of grandmothers smoking heaviness in pregnancy on grandchilds birthweight, highlighting the importance of smoking cessation before pregnancy in each generation

epidemiology↗

bioRxiv2018

Testing the causal effects between subjective wellbeing and physical health using Mendelian randomisation

ObjectivesTo investigate whether the association between subjective wellbeing (subjective happiness and life satisfaction) and physical health is causal.\n\nDesignWe conducted two-sample bidirectional Mendelian randomisation between subjective wellbeing and six measures of physical health: coronary artery disease, myocardial infarction, total cholesterol, HDL cholesterol, LDL cholesterol and body mass index (BMI).\n\nParticipantsWe used summary data from four large genome-wide association study consortia: CARDIoGRAMplusC4D for coronary artery disease and myocardial infarction; the Global Lipids Genetics Consortium for cholesterol measures; the Genetic Investigation of Anthropometric Traits consortium for BMI; and the Social Science Genetics Association Consortium for subjective wellbeing. A replication analysis was conducted using 337,112 individuals from the UK Biobank (54% female, mean age =56.87, SD=8.00 years at recruitment).\n\nMain outcome measuresCoronary artery disease, myocardial infarction, total cholesterol, HDL cholesterol, LDL cholesterol, BMI and subjective wellbeing.\n\nResultsThere was evidence of a causal effect of BMI on subjective wellbeing such that each 1 kg/m2 increase in BMI caused a 0.045 (95%CI 0.006 to 0.084, p=0.023) SD reduction in subjective wellbeing. Replication analyses provided strong evidence of an effect of BMI on satisfaction with health ({beta}=0.034 (95% CI: -0.042 to -0.026) unit decrease in health satisfaction per SD increase in BMI, p<2-16). There was no clear evidence of a causal effect between subjective wellbeing and the other physical health measures in either direction.\n\nConclusionsOur results suggest that a higher BMI lowers subjective wellbeing. Our replication analysis confirmed this finding, suggesting the effect in middle-age is driven by satisfaction with health. BMI is a modifiable determinant and therefore, our study provides further motivation to tackle the obesity epidemic because of the knock-on effects of higher BMI on subjective wellbeing.

epidemiology↗

bioRxiv2017

Searching for the causal effects of BMI in over 300 000 individuals, using Mendelian randomization

Mendelian randomization (MR) has been used to estimate the causal effect of body mass index (BMI) on particular traits thought to be affected by BMI. However, BMI may also be a modifiable, causal risk factor for outcomes where there is no prior reason to suggest that a causal effect exists. We perform a MR phenome-wide association study (MR-pheWAS) to search for the causal effects of BMI in UK Biobank (n=334 968), using the PHESANT open-source phenome scan tool. Of the 20 461 tests performed, our MR-pheWAS identified 519 associations below a stringent P value threshold corresponding to a 5% estimated false discovery rate, including many previously identified causal effects. We also identified several novel effects, including protective effects of higher BMI on a set of psychosocial traits, identified initially in our preliminary MR-pheWAS and replicated in an independent subset of UK Biobank. Such associations need replicating in an independent sample.

epidemiology↗