Biology subjects

Perry, J. R.

Publications and source records attributed to Perry, J. R..

3 recordsLinked to original sources

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↗

bioRxiv2017

GDF15 Concentrations in Maternal Serum Associated with Vomiting in Pregnancy: the Cambridge Baby Growth Study

Nausea and vomiting in pregnancy (NVP) affects 70-90% of all pregnant women but its pathogenesis is unknown. Growth and Differentiation Factor 15 (GDF15), secreted from the trophoblast and decidual stromal cells, is present at high levels in the blood of pregnant women. The receptor for GDF15 has recently been identified and is specifically expressed in the hindbrain where it transmits aversive signals including nausea and conditioned taste aversion. We explored the relationship between GDF15 concentrations in maternal serum during pregnancy and self-reported NVP. In a study of 791 women from the Cambridge Baby Growth Study maternal GDF15 concentrations were higher in women who reported vomiting in the 2nd trimester (geometric mean: 11,670 pg/mL; 95% confidence interval: 11,056-12,318) and were even higher in the eleven women who reported taking anti-emetics during pregnancy (13,376 (10,821-16,535) compared to those who reported no nausea or vomiting during pregnancy (10,657 (10,121-11,222); P=0.02 and P=0.04, respectively, adjusted for gestational age at sampling and maternal BMI). In conclusion serum GDF15 concentrations early in the second trimester of pregnancy are significantly and positively associated with second trimester vomiting and with maternal anti-emetic use. In the context of the recently revealed biology of GDF15 this data suggests that antagonism of GDF15 may have some potential for therapeutic benefit in NVP.

developmental biology↗

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↗