Vierailuluento: Maik Pietzner "A genetic map of human metabolism across the allele frequency spectrum"

A genetic map of human metabolism across the allele frequency spectrum

Maik Pietzner
Precision Healthcare University Research Institute, Queen Mary University of London, UK & Berlin Institute of Health (BIH), Germany

Abstract: Genetic studies of human metabolism identified unknown disease processes and novel metabolic regulators, but have been limited in scale and allelic breadth. Here, we provide a data-driven map of the genetic regulation of circulating small molecules and lipoprotein characteristics (249 metabolic traits) measured using protein nuclear magnetic resonance spectroscopy (¹H-NMR) across the allele frequency spectrum in ~450.000 individuals. In trans-ancestry analyses, we identify 29,824 locus–metabolite associations mapping to 753 regions, including 310 regions with previously unreported signals, with effects largely consistent between men and women and major ancestral groups represented in UK Biobank. We develop a framework for classifying the observed extreme genetic pleiotropy, enabling identification of upstream ‘master’ regulators of lipid metabolism ('proportional pleiotropy’), such as ANGPTL3. We establish rare-to-common allelic series by integrating machine-learning guided effector gene assignments with rare exonic variant analyses for more than 100 genes that facilitates the discovery of unknown biological pathways contributing to disease risk. Our results demonstrate how rare-to-common genetic variation combined with deep molecular profiling can identify unknown and inform on poorly understood regulators of human metabolism to guide prevention and treatment of diseases.

Bio: As a chair for Health Data Modelling, Maik has a keen interest in the computational integration of different health data modalities to translate (big) data into better health for patients, with a particular focus on underrepresented diseases and patient groups. He holds a chair for Health Data Modelling at the Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Germany, and at the Precision Healthcare University Research Institute at Queen Mary University of London, UK. His work focuses on the discovery of new genetic variants that predispose to so far neglected diseases that he and his team integrate with large-scale molecular data sets to identify novel drug targets or opportunities to repurpose already existing drugs. Maik has led multiple efforts on the intersection between the genome and phenome to identify disease predisposing mechanisms through the integration of various circulating ‘omics’ in large-scale population-based studies.