Biology subjects

Walters, R.

Publications and source records attributed to Walters, R..

3 recordsLinked to original sources

bioRxiv2018

Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment

BackgroundBoth statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial, and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial.\n\nMethods228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors.\n\nResultsScaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid balance were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 showed weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C; P=2 x 10-7 for heterogeneity). Genetic inhibition of PCSK9 showed no robust effects on amino acids, ketones, and a marker of inflammation (GlycA); in contrast, statin treatment lowered GlycA levels.\n\nConclusionsGenetic inhibition of PCSK9 results in similar metabolic effects as statin therapy across a detailed lipid and metabolite profile. However, for the same lowering of LDL-C, PCSK9 inhibitors are predicted to be less efficacious than statins at lowering VLDL lipids, which could potentially translate into subtle differences in cardiovascular risk reduction.

epidemiology↗

bioRxiv2017

Common risk variants identified in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes, in contrast to what is typically seen in other complex disorders. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD, just as it has been in a broad range of important psychiatric and diverse medical phenotypes.

genetics↗

bioRxiv2016

Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations

Anorexia nervosa (AN) is a serious eating disorder characterized by restriction of energy intake relative to requirements, resulting in abnormally low body weight. It has a lifetime prevalence of approximately 1%, disproportionately affects females1,2, and has no well replicated evidence of effective pharmacological or psychological treatments despite high morbidity and mortality2. Twin studies support a genetic basis for the observed aggregation of AN in families3, with heritability estimates of 48%-74%4. Although initial genome-wide association studies (GWASs) were underpowered5,6, evidence suggested that signals for AN would be detected with increased power5. We present a GWAS of 3,495 AN cases and 10,982 controls with one genome-wide significant locus (index variant rs4622308, p=4.3x10-9) in a region (chr12:56,372,585-56,482,185) which includes six genes. The SNP-chip heritability [Formula] of AN from these data is 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability stems from common genetic variation. Using these GWAS results, we also find significant positive genetic correlations with schizophrenia, neuroticism, educational attainment, and HDL cholesterol, and significant negative genetic correlations with body mass, insulin, glucose, and lipid phenotypes. Our results support the reconceptualization of AN as a disorder with both psychiatric and metabolic components.

genomics↗