Biology subjects

Day, F. R.

Publications and source records attributed to Day, F. R..

5 recordsLinked to original sources

bioRxiv2018

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individuals own genotype on BW and subsequent disease risk from indirect effects of their mothers correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offsprings later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.

genetics↗

bioRxiv2018

Genome-wide scan and fine-mapping of rare nonsynonymous associations implicates intracellular lipolysis genes in fat distribution and cardio-metabolic risk

Difficulties in identifying causal variants and genes underlying genetic associations have limited the translational potential of genetic studies of body fat distribution, an important, partly-heritable risk factor for cardio-metabolic disease. Rare variant associations facilitate fine-mapping of causal alleles, but their contribution to fat distribution is understudied. We performed a genome-wide scan of rare nonsynonymous variants for body mass index-adjusted waist-to-hip-ratio (BMI-adjusted WHR; a widely-used measure of fat distribution) in 450,562 European ancestry individuals, followed by systematic Bayesian fine-mapping at six genome-wide (p<5x10-08; main-analysis) and two subthreshold signals (significant at a Bonferroni-corrected p<1.3x10-06). We found strong statistical evidence of causal association for nonsynonymous alleles in CALCRL (p.L87P, pconditional=5.9x10-12; posterior-probability of association [PPA]=52%), PLIN1 (p.L90P, pconditional=5.5x10-13; PPA>99%), PDE3B (p.R783X, pconditional=6.2x10-15; PPA>99%), ACVR1C (p.I195T; pconditional=5.4x10-12; PPA>99%), and FGF1 (p.G21E, pconditional=1.6x10-07; PPA=98%). Alleles at the four likely-causal main-analysis genes affected fat distribution primarily via larger hip-rather than smaller waist-circumference and six of nine conditionally-independent WHR-lowering index-variants were associated with protection from cardiovascular or metabolic disease. All four genes are expressed in adipose tissue and have been linked with the regulation of intracellular lipolysis, which controls fat retention in mature cells. Targeted follow-up analyses of key intracellular-lipolysis genes revealed associations for a variant in the initiator of intracellular lipolysis PNPLA2 (p.N252K) with higher BMI-adjusted-WHR and higher cardio-metabolic risk. This study provides human genetic evidence of a link between intracellular lipolysis, fat-distribution and its cardio-metabolic complications in the general population.

genetics↗

bioRxiv2018

Genome-wide association analysis of lifetime cannabis use (N=184,765) identifies new risk loci, genetic overlap with mental health, and a causal influence of schizophrenia on cannabis use

Cannabis use is a heritable trait [1] that has been associated with adverse mental health outcomes. To identify risk variants and improve our knowledge of the genetic etiology of cannabis use, we performed the largest genome-wide association study (GWAS) meta-analysis for lifetime cannabis use (N=184,765) to date. We identified 4 independent loci containing genome-wide significant SNP associations. Gene-based tests revealed 29 genome-wide significant genes located in these 4 loci and 8 additional regions. All SNPs combined explained 10% of the variance in lifetime cannabis use. The most significantly associated gene, CADM2, has previously been associated with substance use and risk-taking phenotypes [2-4]. We used S-PrediXcan to explore gene expression levels and found 11 unique eGenes. LD-score regression uncovered genetic correlations with smoking, alcohol use and mental health outcomes, including schizophrenia and bipolar disorder. Mendelian randomisation analysis provided evidence for a causal positive influence of schizophrenia risk on lifetime cannabis use.

genetics↗

bioRxiv2017

Dissecting causal pathways using Mendelian randomization with summarized genetic data: application to age at menarche and risk of breast cancer

Mendelian randomization is the use of genetic variants as instrumental variables to estimate causal effects of risk factors on outcomes. The total causal effect of a risk factor is the change in the outcome resulting from intervening on the risk factor. This total causal effect may potentially encompass multiple mediating mechanisms. For a proposed mediator, the direct effect of the risk factor is the change in the outcome resulting from a change in the risk factor keeping the mediator constant. A difference between the total effect and the direct effect indicates that the causal pathway from the risk factor to the outcome acts at least in part via the mediator (an indirect effect). Here, we show that Mendelian randomization estimates of total and direct effects can be obtained using summarized data on genetic associations with the risk factor, mediator, and outcome, potentially from different data sources. We perform simulations to test the validity of this approach when there is unmeasured confounding and/or bidirectional effects between the risk factor and mediator. We illustrate this method using the relationship between age at menarche and risk of breast cancer, with body mass index (BMI) as a potential mediator. We show an inverse direct causal effect of age at menarche on risk of breast cancer (independent of BMI) and a positive indirect effect via BMI. In conclusion, multivariable Mendelian randomization using summarized genetic data provides a rapid and accessible analytic strategy that can be undertaken using publicly-available data to better understand causal mechanisms.

epidemiology↗

bioRxiv2017

GWAS of epigenetic ageing rates in blood reveals a critical role for TERT

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P<2.7x10-11). Causal modelling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

genetics↗