Nat Commun, co-auth: C. Auwerx (group Reymond)

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Leveraging large-scale biobank EHRs to enhance pharmacogenetics of cardiometabolic disease medications

Marie C Sadler  1   2   3 , Alexander Apostolov  3 , Caterina Cevallos  4 , Chiara Auwerx  1   2   3   4 , Diogo M Ribeiro  3 , Russ B Altman  5 , Zoltán Kutalik  6   7   8

Affiliations

Abstract

Electronic health records (EHRs) coupled with large-scale biobanks offer great promises to unravel the genetic underpinnings of treatment efficacy. However, medication-induced biomarker trajectories stemming from such records remain poorly studied. Here, we extract clinical and medication prescription data from EHRs and conduct GWAS and rare variant burden tests in the UK Biobank (discovery) and the All of Us program (replication) on ten cardiometabolic drug response outcomes including lipid response to statins, HbA1c response to metformin and blood pressure response to antihypertensives (N = 932-28,880). Our discovery analyses in participants of European ancestry recover previously reported pharmacogenetic signals at genome-wide significance level (APOE, LPA and SLCO1B1) and a novel rare variant association in GIMAP5 with HbA1c response to metformin. Importantly, these associations are treatment-specific and not associated with biomarker progression in medication-naive individuals. We also found polygenic risk scores to predict drug response, though they explained less than 2% of the variance. In summary, we present an EHR-based framework to study the genetics of drug response and systematically investigated the common and rare pharmacogenetic contribution to cardiometabolic drug response phenotypes in 41,732 UK Biobank and 14,277 All of Us participants.

bioRxiv, auth: group Benton

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An integrated anatomical, functional and evolutionary view of the Drosophila olfactory system

Richard Benton  1 , Jérôme Mermet  1 , Andre Jang  2 , Keita Endo  3 , Steeve Cruchet  1 , Karen Menuz  2   4

Affiliations

Abstract

The Drosophila melanogaster olfactory system is one of the most intensively studied parts of the nervous system in any animal. Composed of ~60 independent olfactory neuron classes, with several associated hygrosensory and thermosensory pathways, it has been subject to diverse types of experimental analyses. However, synthesizing the available data is limited by the incompleteness and inconsistent nomenclature found in the literature. In this work, we first “complete” the peripheral sensory map through the identification of a previously uncharacterized antennal sensory neuron population expressing Or46aB, and the definition of an exceptional “hybrid” olfactory neuron class comprising functional Or and Ir receptors. Second, we survey developmental, anatomical, connectomic, functional and evolutionary studies to generate an integrated dataset of these sensory neuron pathways – and associated visualizations – creating an unprecedented comprehensive resource. Third, we illustrate the utility of the dataset to reveal relationships between different organizational properties of this sensory system, and the new questions these stimulate. These examples emphasize the power of this resource to promote further understanding of the construction, function and evolution of these neural circuits.

bioRxiv, auth: group Benton

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Multilayer regulation underlies the functional precision and evolvability of the olfactory system

Jérôme Mermet  1 , Steeve Cruchet  1 , Asfa Sabrin Borbora  1 , Daehan Lee  1 , Phing Chian Chai  1 , Andre Jang  2 , Karen Menuz  2   3 , Richard Benton  1

Affiliations

Abstract

Sensory neurons must be reproducibly specified to permit accurate neural representation of external signals but also able to change during evolution. We studied this paradox in the Drosophila olfactory system by establishing a single-cell transcriptomic atlas of all developing antennal sensory lineages, including latent neural populations that normally undergo programmed cell death (PCD). This atlas reveals that transcriptional control is robust, but imperfect, in defining selective sensory receptor expression. A second layer of precision is afforded by the intersection of expression of functionally-interacting receptor subunits. A third layer is defined by stereotyped PCD patterning, which masks promiscuous receptor expression in neurons fated to die and removes “empty” neurons lacking receptors. Like receptor choice, PCD is under lineage-specific transcriptional control; promiscuity in this regulation leads to previously-unappreciated heterogeneity in neuronal numbers. Thus functional precision in the mature olfactory system belies developmental noise that might facilitate the evolution of sensory pathways.

Welcome Pauline Rogg!

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Hello ! My name is Pauline Rogg, I am very happy to join Alexandre Reymond’s lab as a PhD student. 

I come from Geneva and I moved to Lausanne to study at EPFL where I obtained my Bachelor in Life Sciences and Technologies and later my Master in Life Sciences Engineering. During my studies, I developed a great interest in genetics and bioinformatics in general, which was confirmed during my master project, where I developed a method to test for association between rare and deleterious variants and a given phenotype.

Before joining the CIG, I worked in the Biotech department of a pharmaceutical company where I monitored the production of recombinant hormones.  In my free time, I enjoy going out for a run or a hike in the mountains. I also enjoy reading tons of books and playing the guitar. 

I am very excited about joining the CIG and I’m looking forward to meeting you ! 😊