Improving GWAS discovery and genomic prediction accuracy in biobank data.

Genetically informed, deep-phenotyped biobanks are an important research resource and it is imperative that the most powerful, versatile, and efficient analysis approaches are used. Here, we apply our recently developed Bayesian grouped mixture of regressions model (GMRM) in the UK and Estonian Biobanks and obtain the highest genomic prediction accuracy reported to date across 21 heritable traits. When compared to other approaches, GMRM accuracy was greater than annotation prediction models run in the LDAK or LDPred-funct software by 15% (SE 7%) and 14% (SE 2%), respectively, and was 18% (SE 3%) greater than a baseline BayesR model without single-nucleotide polymorphism (SNP) markers grouped into minor allele frequency-linkage disequilibrium (MAF-LD) annotation categories.

Blood-based epigenome-wide analyses of cognitive abilities.

Background: Blood-based markers of cognitive functioning might provide an accessible way to track neurodegeneration years prior to clinical manifestation of cognitive impairment and dementia.

Results: Using blood-based epigenome-wide analyses of general cognitive function, we show that individual differences in DNA methylation (DNAm) explain 35.0% of the variance in general cognitive function (g).

Probabilistic inference of the genetic architecture underlying functional enrichment of complex traits.

We develop a Bayesian model (BayesRR-RC) that provides robust SNP-heritability estimation, an alternative to marker discovery, and accurate genomic prediction, taking 22 seconds per iteration to estimate 8.4 million SNP-effects and 78 SNP-heritability parameters in the UK Biobank. We find that only ≤10% of the genetic variation captured for height, body mass index, cardiovascular disease, and type 2 diabetes is attributable to proximal regulatory regions within 10kb upstream of genes, while 12-25% is attributed to coding regions, 32-44% to introns, and 22-28% to distal 10-500kb upstream regions.

Genomic architecture and prediction of censored time-to-event phenotypes with a Bayesian genome-wide analysis.

While recent advancements in computation and modelling have improved the analysis of complex traits, our understanding of the genetic basis of the time at symptom onset remains limited. Here, we develop a Bayesian approach (BayesW) that provides probabilistic inference of the genetic architecture of age-at-onset phenotypes in a sampling scheme that facilitates biobank-scale time-to-event analyses. We show in extensive simulation work the benefits BayesW provides in terms of number of discoveries, model performance and genomic prediction.

Author Correction: Bayesian reassessment of the epigenetic architecture of complex traits.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults.

Background: The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets.

Methods: In this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel).

Bayesian reassessment of the epigenetic architecture of complex traits.

Linking epigenetic marks to clinical outcomes improves insight into molecular processes, disease prediction, and therapeutic target identification. Here, a statistical approach is presented to infer the epigenetic architecture of complex disease, determine the variation captured by epigenetic effects, and estimate phenotype-epigenetic probe associations jointly. Implicitly adjusting for probe correlations, data structure (cell-count or relatedness), and single-nucleotide polymorphism (SNP) marker effects, improves association estimates and in 9,448 individuals, 75.

Closed-loop cycles of experiment design, execution, and learning accelerate systems biology model development in yeast.

One of the most challenging tasks in modern science is the development of systems biology models: Existing models are often very complex but generally have low predictive performance. The construction of high-fidelity models will require hundreds/thousands of cycles of model improvement, yet few current systems biology research studies complete even a single cycle. We combined multiple software tools with integrated laboratory robotics to execute three cycles of model improvement of the prototypical eukaryotic cellular transformation, the yeast () diauxic shift.

Integrating transcriptional activity in genome-scale models of metabolism.

Background: Genome-scale metabolic models provide an opportunity for rational approaches to studies of the different reactions taking place inside the cell. The integration of these models with gene regulatory networks is a hot topic in systems biology. The methods developed to date focus mostly on resolving the metabolic elements and use fairly straightforward approaches to assess the impact of genome expression on the metabolic phenotype.

A Bayesian approach for structure learning in oscillating regulatory networks.

Motivation: Oscillations lie at the core of many biological processes, from the cell cycle, to circadian oscillations and developmental processes. Time-keeping mechanisms are essential to enable organisms to adapt to varying conditions in environmental cycles, from day/night to seasonal. Transcriptional regulatory networks are one of the mechanisms behind these biological oscillations.