Biology subjects

Sugrue, L.

Publications and source records attributed to Sugrue, L..

2 recordsLinked to original sources

bioRxiv2018

Lipid associated polygenic enrichment in Alzheimer’s disease

Cardiovascular (CV) and lifestyle associated risk factors (RFs) are increasingly recognized as important for Alzheimers disease (AD) pathogenesis. Beyond the [isin]4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV associated genes also increase risk for AD (genetic pleiotropy). Using large genome-wide association studies (GWASs) (total n > 500,000 cases and controls) and validated tools to quantify genetic pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 57 SNPs on 19 different chromosomes that were jointly associated with AD and CV outcomes including APOA4, ABCA1, ABCG5, LIPG, and MTCH2/SPI1. We found that common genetic variants influencing AD are associated with multiple CV RFs, at times with a different directionality of effect. Expression of these AD/CV pleiotropic genes was enriched for lipid metabolism processes, over-represented within astrocytes and vascular structures, highly co-expressed, and differentially altered within AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid associated RFs. Rather than a single causal link between genetic loci, RF and the outcome, we found that common genetic variants influencing AD are associated with multiple CV RFs. Our collective findings suggest that a network of genes involved in lipid biology also influence Alzheimers risk.

genetics↗

bioRxiv2017

Learning Fast And Slow: Deviations From The Matching Law Can Reflect An Optimal Strategy Under Uncertainty

Behavior which deviates from our normative expectations often appears irrational. A classic example concerns the question of how choice should be distributed among multiple alternatives. The so-called matching law predicts that the fraction of choices made to any option should match the fraction of total rewards earned from the option. This choice strategy can maximize reward in a stationary reward schedule. Empirically, however, behavior often deviates from this ideal. While such deviations have often been interpreted as reflecting noisy, suboptimal, decision-making, here we instead suggest that they reflect a strategy which is adaptive in nonstationary and uncertain environments. We analyze the results of a dynamic foraging task. Animals exhibited significant deviations from matching, and animals turned out to be able to collect more rewards when deviation was larger. We show that this behavior can be understood if one considers that animals had incomplete information about the environments dynamics. In particular, using computational models, we show that in such nonstationary environments, learning on both fast and slow timescales is beneficial. Learning on fast timescales means that an animal can react to sudden changes in the environment, though this inevitably introduces large fluctuations (variance) in value estimates. Concurrently, learning on slow timescales reduces the amplitude of these fluctuations at the price of introducing a bias that causes systematic deviations. We confirm this prediction in data - monkeys indeed solved the bias-variance tradeoff by combining learning on both fast and slow timescales. Our work suggests that multi-timescale learning could be a biologically plausible mechanism for optimizing decisions under uncertainty.

neuroscience↗